1. Cholesterol Guidelines and Statin Initiation
Jinesh Shah
12/01/2014

2. Objectives
1. High cholesterol as a cardiovascular risk factor 2. Previous guidelines for cholesterol treatment 3. Current ACC/AHA guidelines from Statin initiation, management, safety, intolerance 5. Limitations

3. High Cholesterol as a CV Risk Factor
Early 1900’s - Russian scientist named Anitschkow discovered a link between cholesterol and vascular damage
40 years later – Gofman identified the components that make up total cholesterol (such as HDL and LDL)
1948 – National Heart Institute. followed people between the ages of 30 and 62 living in the town of Framingham, MA. Identified factors related to heart health, including smoking, high blood pressure, and high blood cholesterol
Ancel Keys – Nutritional scientist. Seven countries study linked high intake of dietary cholesterol to heart disease.
The Paul Leren Oslo Study (1966); The Wadsworth Veterans Administration Hospital Study(1969); and The Finnish Mental Hospitals Study (1968). Decreased saturated fat intake = lower blood cholesterol.
1973- Coronary Primary Prevention Trial (CPPT), randomized, double blind study showed lowering blood cholesterol =reduction in heart attacks.
Early 1900’s - Russian scientist named Anitschkow discovered a link between cholesterol and vascular damage (atherosclerosis) after feeding rabbits purified cholesterol.
40 years later – Gofman identified the components that make up total cholesterol (such as HDL and LDL)
Ancel Keys – Nutritional scientist Seven countries study. Flawed by todays standards but linked high intake of dietary cholesterol to heart disease.
1948 – National Heart Institute. following people between the ages of 30 and 62 living in the town of Framingham, MA. identified a number of factors related to heart health, including smoking, high blood pressure, and high blood cholesterol
More studies concluded that eliminating dietary saturated fats and replacing them with unsaturated fats has a profound effect on reducing blood cholesterol.  This finding was strengthened by the results of three pre-1970s clinical studies: The Paul Leren Oslo Study (1966); The Wadsworth Veterans Administration Hospital Study (1969); and The Finnish Mental Hospitals Study (1968).
Resistance due to unknown effect of cholestrol and low likelyhood for people to make dietary modifications
1970s and 1980s. Joe Goldstein teamed up with Michael Brown – a collaboration that would lead to the 1985 Nobel Prize in Physiology or Medicine –Brown and Goldstein showed how a critical enzyme involved in the generation of cholesterol was regulated, and showed that there is a genetic basis behind the inability to remove a pro-heart disease form of cholesterol called low density lipoprotein (LDL) from the blood.
1973- Coronary Primary Prevention Trial (CPPT), randomized, double blind study showed that lowering blood cholesterol leads to a reduction in heart attacks.

4. Journey of the ATP Guidelines

5. Adult Treatment Panel III National Cholesterol Education Panel
High risk for coronary heart disease (CHD) events (CHD risk equivalent):
n Clinical CHD
n Symptomatic carotid artery disease
n Peripheral arterial disease
n Abdominal aortic aneurysm.
Major Risk Factors (Exclusive of LDL Cholesterol) That Modify LDL Goals
n Note: in ATP III, diabetes is regarded as a CHD risk equivalent.
Cigarette smoking
Hypertension (BP >140/90 mmHg or on antihypertensive medication)
Low HDL cholesterol (<40 mg/dL)*
Family history of premature CHD (CHD in male first degree relative <55 years;
CHD in female first degree relative <65 years)
Age (men >45 years; women >55 years)
* HDL cholesterol >60 mg/dL counts as a “negative” risk factor; its presence removes one
risk factor from the total count.

6. 2013 ACC/AHA: Blood Cholesterol Guidelines for ASCVD Prevention
Key points
Focus on ASCVD Risk Reduction: 4 statin benefit groups.
A New Perspective on LDL-C and/or Non-HDL-C Treatment Goals.
Global Risk Assessment for Primary Prevention
Safety Recommendations
Future Updates to the Blood Cholesterol Guideline

7. 4 Statin Benefit Groups
1. Individuals with clinical ASCVD (ACS, Hx of MI, stable/unstable angina, stroke, TIA, PCI, PAD) 2. Individuals with primary elevations of LDL–C ≥190 mg/dL 3. Individuals 40 to 75 years of age with diabetes with LDL-C mg/dL 4. Individuals without clinical ASCVD or diabetes who are 40 to 75 years of age with LDL-C mg/ dL and an estimated 10-year ASCVD risk of 7.5% or higher

9. Treatment goals for LDL and HDL levels?
Secondary Prevention
19 RCT’s reviewed - no data identified regarding treatment or titration to a specific LDL–C goal in adults with clinical ASCVD.
No RCTs evaluated titration of all individuals in a treatment group to specific LDL–C targets <100 mg/dL or <70 mg/dL.
Primary Prevention
6 RCT’s reviewed - 4 studies confirming the efficacy of cholesterol reduction in improving clinical outcomes in patients without ASCVD.
No RCTs evaluated titration of all individuals in a treatment group to specific LDL–C <100mg/dL or <70 mg/dL.
Risk reduction of ASCVD seen in patients already with LDL<100 mg/dl

10. Statin Classification
High-Intensity Statin Therapy
Moderate-Intensity Statin Therapy
Low-Intensity Statin Therapy
Daily dose lowers LDL-C, on average, by approximately ≥50%
Daily dose lowers LDL-C, on average, by approximately 30% to <50%
Daily dose lowers LDL-C, on average, by <30%
Atorvastatin (40†)–80 mg
Rosuvastatin 20 (40) mg
Atorvastatin 10 (20 ) mg
Rosuvastatin (5 ) 10 mg
Simvastatin 20–40 mg‡
Pravastatin 40 (80 ) mg
Lovastatin 40 mg
Fluvastatin XL 80 mg
Fluvastatin 40 mg BID
Pitavastatin 2–4 mg
Simvastatin 10 mg
Pravastatin 10–20 mg
Lovastatin 20 mg
Fluvastatin 20–40 mg
Pitavastatin 1 mg

11. Intensity of Statin Therapy
-RCT’s showed High-intensity statin therapy reduced ASCVD risk more than moderate-intensity statin therapy
-Cholesterol Treatment Trialists (CTT) meta-analysis (2010)
Average reduction of LDL:
High-intensity statin therapy ≥50%,
Moderate-intensity statin therapy 30% to <50%,
Lower-intensity statin therapy <30%.
-LDL–C levels and percent reduction =markers for response to therapy and adherence, not to be used as performance standards.

12. Statin Safety Patient characteristics affecting statin safety
impaired renal or hepatic function, previous statin intolerance of muscle disorders, use of drugs affecting statin metabolism, history of hemorrhagic stroke, and >75 years of age.
Creatine Kinase
monitoring not required unless patient has symptoms.
Transaminases (ALT)
obtain baseline levels but monitoring not recommended.
Statin and Type 2 Diabetes
modest increased of developing Type 2 DM but CV risk reduction outweighs DM risk.
Pregnancy
Category X

13. Managing Statin Therapy

14. Statin Intolerance
Evaluate for pain, tenderness, stiffness, cramping, weakness, or fatigue
For unexplained severe muscle symptoms or fatigue, discontinue statin and rule out rhabdomyolysis.
Monitor for 2 months without statin therapy.
For mild-moderate symptoms: discontinue statin → evaluate for other causes, restart at same or lower dose after symptom resolution. If causal relationship, then change statin and start at lower dose.

15. Non Statins for ASCVD risk reduction?
No data supporting the routine use of non-statin drugs + statin therapy to reduce further ASCVD events.
Add non statin therapy in high risk individuals who do not have therapeutic response with highest tolerated intensity statin.
High-risk individuals = those with ASCVD, LDL–C ≥190 mg/dL and individuals with diabetes

16. What we do not know What about the others? Other therapies?
RCT evidence lacking in younger adults with high lifetime risk for ASCVD
Lacking evidence in patients with serious comorbidities and increased ASCVD risk(HIV, rheumatologic or IF diseases, or organ transplant recipients)
Other therapies?
No RCTs comparing titration to specific cholesterol or apolipoprotein goals versus fixed-dose statin therapy in high-risk patients.
Do submaximal statin therapy combined with non statin therapies reduce ASCVD?
New Lipid modifying agents in addition to fixed statin therapy

17. Morris PB1, Ballantyne CM2, Birtcher KK3, Dunn SP4, Urbina EM5.
J Am Coll Cardiol Jul 15;64(2): doi: /j.jacc
Review of clinical practice guidelines for the management of LDL-related risk.
Morris PB1, Ballantyne CM2, Birtcher KK3, Dunn SP4, Urbina EM5.
Abstract
Managing risk related to low-density lipoprotein (LDL) is vital in therapy for patients at risk for atherosclerotic cardiovascular disease (ASCVD) events given its important etiologic role in atherogenesis. Despite decades of research showing reduction of ASCVD risk with multiple approaches to lowering of LDL cholesterol, there continue to be significant gaps in care with inadequate numbers of patients receiving standard of care lipid-lowering therapy. Confusion regarding implementation of the multiple published clinical practice guidelines has been identified as one contributor to suboptimal management of LDL-related risk. This review summarizes the current guidelines for reduction of LDL-related cardiovascular risk provided by a number of major professional societies, which have broad applicability to diverse populations worldwide. Statements have varied in the process and methodology of development of recommendations, the grading system for level and strength of evidence, the inclusion or exclusion of expert opinion, the suggested ASCVD risk assessment tool, the lipoproteins recommended for risk assessment, and the lipoprotein targets of therapy. The similarities and differences among important guidelines in the United States and internationally are discussed, with recommendations for future strategies to improve consistency in approaches to LDL-related ASCVD risk and to reduce gaps in implementation of evidence-based therapies.

18. Concerns related to the new guidelines
Review of Clinical Practice Guidelines for the Management of LDL-Related Risk
State-Of-The-Art Review of current lipid guidelines
Multiple studies showing the CV Risk Calculator overestimated observed risks by %.
Applicability of the algorithm for other ethinic groups.
Should almost every adult male be on a statin?
Adherence to high intensity statins. Further reduction of compliance.
ESC/EAS continues to recommend LDL as target of therapy due to above concerns

19. References
Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS,Shero ST, Smith SC Jr, Watson K, Wilson PW; American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol Jul 1;63(25 Pt B):
J Am Coll Cardiol Jul 15;64(2): doi: /j.jacc
Review of clinical practice guidelines for the management of LDL-related risk.
Morris PB1, Ballantyne CM2, Birtcher KK3, Dunn SP4, Urbina EM5.
NCEP, ATP III Executive Summary. National Cholesterol Education Program
National Heart, Lung, and Blood Institute National Institutes of Health
NIH Publication No (May 2001)
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), Executive Summary.

20. The End Questions?