North Bay Educational Symposium CANP North Bay Chapter January 30, 2016 Gregg Hopkins, MD, FACC Sutter Medical Group of the Redwoods
2013 ACC/AHA Guidelines on Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults
What has Changed Compared to ATP-III Guidelines (2001)? Initiate either moderate-intensity or high-intensity statin therapy for patients who fall into the four treatment categories Unlike ATP-III, do not titrate to a specific LDL cholesterol target Measure lipids during follow-up to assess adherence to treatment, not to achieve a specific LDL target
Intensity of Statin Therapy in Primary and Secondary Prevention
Recommended LDL goal is <100 mg/dL – An LDL goal of <70 mg/dL is a therapeutic option on the basis of available clinical trial evidence, especially for patients at very high risk Grundy, S. et al., Circulation 2004;110: High-Risk Persons Recommendations for Modifications to Footnote the ATP III Treatment Algorithm for LDL Levels
Four Major Statin Benefit Groups 1)Clinical ASCVD 2)LDL >190 3)Diabetics, y/o, with LDL but no clinical ASCVD 4)10-year ASCVD risk >7.5% without clinical ASCVD or diabetes
Definition of Clinical ASCVD Clinical ASCVD is defined by the inclusion criteria of secondary prevention statin RCTs: –acute coronary syndromes –history of MI –stable or unstable angina –coronary or other arterial revascularization –stroke or TIA –peripheral arterial disease
“Don’t Give More Patients Statins” -- Rita Redberg’s Opinion in NYTimes Lowering ASCVD risk threshold from 10% to 7.5% increases number of “healthy people” treated with statins by 70%. NNT of 140 in primary prevention, with 18% experiencing side effects Skeptical that Big Pharma has influenced guideline recommendations
2010 ACC/AHA Guidelines on Screening for CAD CAC scoring is reasonable (level of evidence B) in asymptomatic adults with intermediate Framingham risk (10-20% chance of CV event in 10 yrs) CAC scoring “may be reasonable” in those at low-intermediate risk (6-10% chance of CV event in 10 yrs)
CAC Scoring to Predict Coronary Events in Asymptomatic Patients Most coronary events occur from rupture of “vulnerable” plaque, not fixed lesions Unstable plaque tends to co-localize with areas of coronary calcification Patients with high CAC scores have a high likelihood of vulnerable plaque rupture
Adding CAC Score to Framingham Risk Scoring Re-Classified 1/4 of the 6814 Patients in MESA 298 patients (5%) were re-classified as high risk based on the CAC –Their CV event rate was 16% 744 patients (16%) were re-classified as low risk –Their CV event rate was 2%
Combination Therapy “Clinicians treating high risk patients who have a less than anticipated response to statins, who are unable to tolerate a less than recommended intensity of a statin or who are completely statin intolerant, may consider the addition of non-statin cholesterol lowering therapy”
Recommended LDL goal is <100 mg/dL – If a high-risk person has high triglycerides or low HDL, consideration can be given to combining a fibrate or nicotinic acid with an LDL-lowering drug Grundy, S. et al., Circulation 2004;110: High-Risk Persons Recommendations for Modifications to Footnote the ATP III Treatment Algorithm for LDL Levels
Niacin—AIM-HIGH ASCVD pts with low HDL, elevated triglycerides (150–400 mg/dL), and LDL 40–80 mg/dL compared simvastatin (+/- ezetimibe) plus niacin-SR 1,500–2,000 mg vs. simvastatin (+/- ezetimibe) plus placebo. Niacin lowered LDL levels an additional 6%, increased HDL by an additional 14%, reduced triglycerides by an additional 23%. Yet there was no change in rates of CV events in subgroups by age, sex, diabetes, metabolic syndrome or previous myocardial infarction status. There were similar rates of adverse events.
Ezetimibe—IMPROVE-IT RCT of high risk ACS patients comparing simvastatin 40 mg alone vs. simvastatin 40 mg + ezetimibe 10 mg Ezetimibe + simvastatin group showed a 17% reduction in LDL levels (53 vs 70 mg/dL) c/w simvastatin alone. After 7-year follow-up period, a “modest” benefit was seen: – 2% absolute reduction and 6% relative reduction in rates of CV death, MI, ACS, revascularization, and ischemic stroke (p<.05) –All-cause mortality was not affected.
Statin Safety Recommendations Check baseline ALT prior to initiating the statin Check LFTs if patient develops symptoms of hepatic dysfunction If 2 consecutive LDL <40, consider decreasing the statin dose (Grade C, weak recommendation) Simvastatin 80mg dose may be harmful Conditions that could predispose pts to statin side effects: o Impaired renal or hepatic function o History of previous statin intolerance or muscle disorder o Age >75 o Unexplained ALT elevation > 3x ULN o History of hemorrhagic stroke o Asian ancestry
Statin Drug Interactions(CYP3A4) Lovastatin/Simvastatin> Atorvastatin>Pravastatin/Rosuvastatin Amiodarone and dronedarone Antifungals (fluconazole, ketoconazole) Ca++ channel Blockers Colchicine Cyclosporine Erythromycin, clarithromycin, telithromycin Protease inhibitors Ranolazine Ticagrelor Grapefruit juice
Risk of Diabetes from Statins Very modest excess risk of new onset diabetes in RCTs and meta-analyses of RCTs (1 excess case per 1000 treated x 1 year with moderate-intensity statins; 3 excess cases per 1000 treated with high- intensity statins) Risk confined to those with risk factors for diabetes--also at higher risk of ASCVD Statin therapy still indicated
Risk of Memory Loss from Statins The panel found NO evidence that statins had an adverse effect on cognitive changes or risk of dementia. Despite initial promising results from observational studies, 2 RCTs in Alzheimer’s disease showed no benefit from statins in protecting against cognitive decline.
Rhabdomyolysis With the exception of simvastatin 80 mg, intensive- and moderate-dose statins did not increase the risk for rhabdomyolysis. In RCTs of statin therapy, rhabdomyolysis occurred rarely (<0.06% over a mean 5-year treatment period). In adults with CHD, the rate of CK>3 times ULN occurs at a similar rate in those treated with intensive- or moderate-dose statin therapy.
Myalgias In adults with and without CVD, statin-treated individuals in 14 clinical trials are not more likely to discontinue treatment than placebo-treated individuals. In adults with and without CVD in clinical trials, low- to moderate-dose statins do not increase the risk for myalgias or muscle pain. No evidence to support the use of Coenzyme Q10 Switching statins, alternate-day or once-weekly dosing regimens are best approach.
PCSK9 is a Key Regulator of LDLR Recycling PCSK9 mediates degradation of the LDLR by interacting with the extracellular domain and targeting the receptor for degradation 1 1. Horton JD, et al. J Lipid Res. 2009;50:S172-S Qian YW, et al. J Lipid Res. 2007;48: Zhang DW, et al. J Biol Chem. 2007;282: LDL = low-density lipoprotein; LDLR = low-density lipoprotein receptor LDLR/PCSK9 routed to lysosome Lysosomal degradation PCSK9 secretion Decreased LDLR surface concentration 24
PCSK9 Inhibition by Evolocumab or Alirocumab SQ administered monoclonal antibody given twice per month ($14,600/yr) 70% LDL-C reduction within weeks FDA approved this summer Safety profile encouraging Alternative to statin intolerant or resistant patients, particularly with FH No outcomes trial results
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