1. Management Of Hyperlipidemia ATP IV Guidelines
Hadeel Sahar
DMC/WSU
Detroit ,MI

2. Introduction to ATP IV :
ATP IV builds on the foundation of prior guidelines, but also represents a significant change in management of hyperlipidemia.
Gone is the concept of 'treat to target', in which treatment was based on getting a patient’s LDL-cholesterol level below a targeted threshold. 'Treat to target' was abandoned because of the lack of evidence of a specific target and lack of comparison data on different targets.

3. Introduction:
Instead, the intensity of lipid lowering based on risk becomes the focus. Also new in ATP IV:
Broadening the guideline focus from coronary heart disease (CHD) to atherosclerotic cardiovascular disease (ASCVD) (i.e., including coronary artery disease, cerebrovascular disease, and peripheral artery disease)
Broadening risk assessment for primary prevention
Definition of new treatment benefit groups

4. New vs old focus

5. Critical questions
ATP IV guidelines were developed by the American Heart Association and the American College of Cardiology, who focused on the presence or absence of high-quality scientific evidence to formulate recommendations. In addition, rather than a comprehensive approach to lipid management, ATP IV focused on answering specific "critical questions“.

6. Critical question
On critical questions 1 and 2, insufficient evidence was found to support treatment targets in primary and secondary CHD prevention. As a result, treatment targets were abandoned. The focus of ATP IV shifted to baseline risk as determined by the presence of known ASCVD risk (e.g., prior ASCVD; diabetes) or 10-year risk of an ASCVD event.
On critical question 3, insufficient evidence was found to broadly recommend classes of lipid lowering agents other than statins. The panel noted that most studies of drugs other than statins focused on effectiveness of LDL-C reduction (a surrogate marker), rather than effectiveness of clinical outcome reduction. Statins therefore remain the cornerstone of lipid management in ATP IV.

7. Statin Benefit group
“the absolute reduction in ASCVD events is proportional to baseline absolute ASCVD risk. Therefore, statin therapy is recommended for individuals at increased ASCVD risk who are most likely to experience a net benefit in terms of the potential for ASCVD risk reduction and the potential for adverse effects."
In other words, the higher the risk, the greater the potential benefit.

8. Statin benefit group

9. Group 1: Clinical ASCVD Clinical ASCVD is defined as:
Acute coronary syndrome
Prior myocardial infarction
Stable/unstable angina
Prior coronary or arterial revascularization
Stroke
Transient ischemic attack
Peripheral arterial disease presumed to be of atherosclerotic origin
Not included is :
Asymptomatic atherosclerosis noted incidentally on imaging.
The presence of an abdominal aortic aneurysm.
We do not need to calculate 10-year ASCVD risk in this group of individuals who have clinical ASCVD, as they all warrant therapy with a statin.

10. Group 2: LDL-C >190mg/dl
Individuals with very high LDL-C (i.e., >190mg/dl) are known to be at significant risk of an ASCVD event regardless of other risk factors. As a result, primary LDL-C elevations >190mg/dl are an indication for statin treatment in all individuals 21 and older.
there is no need to calculate ASCVD risk in this group.
Before initiating treatment, secondary causes of LDL-C should be excluded.

11. Secondary causes of LDL-C elevation

12. Group 3: Diabetes
All patients aged with diabetes benefit from lipid lowering therapy.
Decisions on lipid lowering therapy in younger and older individuals outside this age range should be made on an individual basis.
Intensity of treatment is determined by their 10-year risk of an ASCVD event. Therefore, in patients with diabetes between 40-75, always calculate the 10- year risk of ASCVD to determine the intensity of management.
Minimum intensity (no other RFs): moderate

13. Group 4: ASCVD risk groups
Reminder, no need to perform this ASCVD risk calculation in those with clinical ASCVD or LDL-C>190mg/dl (secondary prevention with high intensity), but do use this calculation in other patients, including those with diabetes (determine moderate vs. high).
The guidelines limit their recommendations in this group to those aged , leaving to individual judgment the role of risk calculation for younger and older individuals. 
The only statin benefit group with specific recommendations on younger individuals is those with LDL-C>190mg/dl, in whom we start treatment at age 21.

14. No benefit groups
There were two clinical groups in whom the benefit of lipid lowering therapy was not demonstrated:
New York Heart Association (NYHA) Class II-IV heart failure .
those who were receiving hemodialysis.
The benefit of lipid-lowering drugs in these groups remains unclear.

15. Risk assessment for atherosclerosis
Risk assessment of an initial cardiovascular event has traditionally been done based on the data from the Framingham Study.
The Framingham risk calculation predicts the 10-year risk of an initial cardiovascular event, and was developed in a mostly male and white population.
Framingham risk calculation does not predict atherosclerotic cerebrovascular events. A new risk calculator was needed to predict the 10-year risk of fatal/non-fatal MI or CVA, to predict lifetime risk of ASCVD events, and to predict risk in non-white patients. 

16. ASCVD risk assessment guideline development
Concurrent with ATP IV guideline development was also a new guideline to better assess risk of ASCVD.
Similar to ATP IV, this new guideline was commissioned to evaluate two critical questions, listed in next Table .
In sum, these risk assessment guidelines were developed to better assess 10-year risk for a more diverse population, and to better assess lifetime risk to better counsel those patient with low short-term risk (i.e., young patients).

17. ASCVD risk assessment critical questions

18. Steps to assessing risk
There are two steps to assessing risk of an ASCVD event:
Assess risk using the ASCVD risk calculator
Modify that risk assessment if:
The patient is neither white or African American
Treatment is uncertain based on the results of Step 1 (including incorporating novel risk factors)
What follows is a discussion of each step.

19. Step 1
Step 1 uses a new risk calculator based on data from the Framingham Study and three additional studies (CARDIA; ARIC; the Cardiovascular Health Study).
This data included whites and African Americans for study; risks for other ethnic groups needs to be estimated based on the risk calculator results for a white person of the same gender.
The risk calculator provides not only the 10-year risk of an ASCVD event, but also provides risk assessment of a similar person but with each risk factor optimized. This may be used to guide discussion with patient on how to prioritize lowering cardiovascular risk. 

20. Adjusting risk by ethnic group

21. Incorporating novel risk factors
Evidence supported by the medical literature in which clinical outcomes (rather than surrogate markers) were included.
Other novel risk factors (e.g., carotid intima media thickness; GFR; microalbuminuria; apolipoprotein B; cardiorespiratory fitness) did not have enough supportive evidence to recommend their inclusion.
Incorporation of novel risk factors is not needed in all cases; its role is when there is management uncertainty after calculating risk.  For example, when 10-year ASCVD risk is calculated at 5-7.5% (i.e., it is borderline), other clinical risk factors may incorporated to determine the need for statin therapy. 

22. Next steps
When using the new risk calculator, two risk estimates are provided: 10-year risk and lifetime risk.
The role of lifetime risk assessment is to help guide patients who might have a low 10-year risk but a high lifetime risk. This is particularly common with younger patients, who are unlikely to have a risk of ASCVD event in the next 10 years, but who might have an elevated risk of an ASCVD when judged over 15 years or longer. By including this risk estimation, patients may be counseled on the modifiable risk factors that are contributing to this elevated risk.

23. Risk assessment algorithm

24. Lower-risk patient groups: JUPITER and HOPE-3
The risk of an ASCVD event is never zero. A significant portion of ASCVD events occur in individuals that fall outside of ATP recommendations. Two large studies have looked at using statins in individuals that fall outside of standard lipid-lowering guidelines: JUPITER and HOPE-3.
JUPITER: Treated men and women with LDL<130mg/dl but high-sensitivity CRP>2.0mg/dl with rosuvastatin 20mg/dl or placebo. Risk of ASCVD events cut nearly in half for those treated with rosuvastatin.
HOPE-3: Treated 'intermediate-risk' patients with rosuvastatin 10mg daily or placebo. Risk of ASCVD events was 25% lower in those treated with rosuvastatin relative to those treated with placebo.
Both of these studies show that statin therapy is likely to improve ASCVD outcomes in patients who otherwise do not have indications for a statin.
Deciding how to apply these studies to own patients should be based on an individualized approach.

25. lifestyle modification
Along with new guidelines on lipid management and ASCVD risk assessment, the NHLBI and ACC/AHA developed new guidelines on lifestyle modification and obesity/overweight. It bears repeating the obvious: lifestyle modification (specifically diet and exercise) should be addressed with every patient with or at risk for ASCVD, whether or not they are on lipid lowering therapy.
As management of cholesterol is begun, medical disorders and medications that cause secondary dyslipidemia should be considered. We've already reviewed those scenarios that can elevate LDL-C.

26. Secondary causes of LDL-C and TG elevation

27. Treatment: diet
The role of diet in CV risk first came to attention with the Seven Countries Study, an epidemiologic study of cardiovascular outcomes in the United States, Northern Europe, Southern Europe, and Japan.
CV outcomes were much lower in Southern Europe, and it was posited that the diet in Southern Europe (now referred to as the Mediterranean diet) was at least part of the explanation.
Many studies of variations of the Mediterranean diet have since confirmed the benefits of this diet on cholesterol and BP(eg,this study of individuals at high risk for CAD treated with a Mediterranean diet supplemented with olive oil and nuts had fewer heart attacks, strokes and death from CV causes).
The Mediterranean diet is moderate in total fat, low in saturated fat, high in fiber, and high in omega-3 fatty acids. The cumulative impact of these changes is to lower LDL-C.

28. The Mediterranean diet

29. Treatment: Exercise
Exercise is the other area of lifestyle management that impacts cholesterol (and hypertension, and cardiovascular risk).
Observational studies show that people who exercise have less ASCVD and live longer. One study suggested that if everyone in the world who was sedentary would start to exercise, world life expectancy would increase by 0.68 years.

30. Exercise
The two types of exercise that were reviewed by the expert panel were aerobic exercise and resistance training (e.g., weight training).
Studies in which lipids were assessed when these types of exercises were used alone (i.e., without diet changes or pharmacotherapy) were included. What was found comes as no real surprise: exercise (aerobic and resistance) lowers LDL-C. Slightly surprising was:
Lack of evidence that exercise improves HDL-C
Resistance training had greater impact on lipids than did aerobic training.

31. Exercise and lipids

32. ACC/AHA lifestyle management guidelines

33. 3 things to know when initiating lipid lowering therapy:
What are the goals of low-, moderate-, and high-intensity lipid management?
Which statins, at which dosages, are used for low-, moderate-, and high-intensity lipid management?
Which conditions are treated with low-, moderate-, and high- intensity lipid management?

34. Issue 1: Goals of low/moderate/high-intensity statin therapy
According to ATP IV guidelines, the actual statin used is not important. Rather, the intensity of therapy is the focus.
low-intensity statin therapy intends to reduce the LDL-C by less than 30%
moderate-intensity statin therapy intends to reduce the LDL-C by 30-50%
high intensity statin therapy intends to reduce the LDL-C by 50% or more.

35. Low/moderate/high-intensity goals

36. Issue 2: Dosing statins to attain goals Options for statin dosing

37. Issue 3: Determining intensity of statin therapy
High-intensity statin therapy
Clinical ASCVD < 75 years
LDL-C > 190mg/dl (regardless of age)
Diabetes and 10-year risk of ASCVD of 7.5% or greater.
Moderate-intensity statin thrapy
Diabetes and 10-year risk of ASCVD of less than 7.5%.
Aged with a 10-year risk of ASCVD of 7.5% or higher without diabetes.
Low-intensity statins are typically not first-line therapy in the four treatment groups we have identified. However, they may be your first choice in a patient who is elderly, or in whom side effects from statins is a concern. 

38. Statin therapy review

39. Assess whether or not statins are appropriate for the patient.
Lipid panel done prior to treatment
Should the pre-treatment LDL-C be >190mg/dl or the serum TG>500mg/dl, secondary causes of hyperlipidemia should be considered.
If the diabetes status of the patient is unknown, a hemoglobin A1C should be checked.
An ALT should be checked to screen for liver disease, and if normal, no further monitoring for hepatotoxicity is indicated unless symptoms are suggestive.
If the patient is at risk for myositis from statins (e.g., positive family history; muscle symptoms), a pre-treatment creatine kinase should be checked.

40. Assessing response to therapy
Response to therapy should be assessed 4-12 weeks after initiation of therapy with a statin.
Should the desired drop in LDL-C occur, the dose of statin should be continued and lipids should be reassessed no less than annually.
If the LDL-C has not decreased by the desired amount,
Adherence should be assessed,
Lifestyle changes should be reinforced, and
Secondary causes of hyperlipidemia should be considered.
Rather than intensify therapy at this first follow up, lipids should be assessed a second time 4-12 weeks later, and if the LDL-C remains above goal, then intensification of treatment is indicated.

41. Assessing response to therapy

42. Assessing response to therapy
If LDL-C<40mg/dl for two consecutive readings while on statin therapy, the intensity of treatment should be lowered.
If baseline LDL-C is unknown, patients on high-intensity statins should be treated to LDL-C<100mg/dl. However, this treat-to-target alternative is inferior to the intensity of treatment approach.
There will be times when an individual on maximally-tolerated statins does not have the goal reduction in LDL-C. After assessing adherence and considering secondary causes of hyperlipidemia, non-statin therapy may be considered, especially in those with clinical ASCVD, LDL-C>190mg/dl, or diabetes. In each case, the maximally-tolerated statin should be continued as the non-statin therapy is added.

43. Statin-intolerant patients
When a certain intensity of statins is indicated (e.g., high-intensity) but not tolerated, the next lower intensity statin therapy should be tried (e.g., moderate-intensity).
Those most likely to have statin intolerance include :
Those with impaired renal or hepatic function, ALT > 3X the upper limit of normal.
age >75.
Asian ancestry.
On drugs that affect statin metabolism. 
Although the four treatment groups start with moderate- or high-intensity statins, clinical factors (e.g., advanced age; statin intolerance) low-intensity statin may prompted.

44. Statin intolerance
Because of the long history of proven reduction in ASCVD events in patients treated with statins as primary prevention or secondary prevention, patients who develop myalgias on a statin should be tried on either a lower dose of the same statin or a different statin, or even dosing the statin once or twice weekly.
Most patients (i.e., more than 90%) who are rechallenged in such a way ultimately tolerate statins, and many will tolerate the initial statin at its indicated dose.

45. Non-statin therapy
The evidence for clinical benefit for most non-statin therapy is weak. For the rare patient who does not tolerate any dose of any statin, or in whom further LDL lowering is indicated, non-statin therapy may be considered.

46. PCSK9
new non-statin agents in use are the proprotein convertase subtilisin/kexin type 9 ('PCSK9') inhibitors.
MoAb that prevent PCSK9 from binding to LDL receptors in the liver, resulting in 50% or more reductions in LDL-C levels.
PCSK9 inhibitors approved for use :
evolocumab (Repatha; 140mg subcut
every 2 wks or 420mg subcut every
month)
alirocumab (Praluent; mg subcut
every 2 weeks). 

47. PCSK9 indications
Although receiving a lot of attention, these agents have not been shown to improve ASCVD outcomes, and are only indicated in the following types of patients:
Patients with familial hypercholesterolemia
Patients with documented ASCVD who require additional LDL-C lowering.

48. Non-statin therapy

49. Thank You