Risks, Benefits and Current Management Strategies of Statin

Therapy

Katherine Gambino, CRNP Erin Henry, CRNP

Teri Miller, CRNP

Objectives

• Participant will be able to verbalize the latest guidelines for statin therapy

• Participant will be able to state the benefits of statins in terms of reducing cardiovascular morbidity and mortality

• Participant will be able to state the adverse effects/intolerances related to statin use

• Participant will be able to describe the current practice patterns regarding the use of statin therapy in the Cleveland Clinic Preventive Cardiology.

The statins!!!!!!!

What are statins?

• Statins inhibit the HMG-CoA reductase enzyme therefore reducing the production of cholesterol in the liver.

• Metabolized in the liver

• Impact all components of a lipid panel (TC, TG, HDL, LDL) but mostly the LDL.

• Reduces LDL by 25-63%

FDA Indications • Labeled indications:

-Prevention of cardiovascular disease -Treatment of dyslipidemia -Treatment of heterozygous familial hypercholesterolemia.

• Primary prevention: Lipid reduction before disease occurs

• Secondary prevention: After the development of disease

What are the statins?

• Rosuvastatin (Crestor) – high potency

• Atorvastatin (Lipitor) – high potency

• Simvastatin (Zocor)

• Pravastatin (Pravachol)

• Lovastatin (Mevacor)

• Pitavastatin (Livalo)

• Fluvastatin (Lescol XL)

Trivia question!!

• Trivia question

• What was the first statin, and when was it FDA approved for use?

• Boring

• Award busies

Primary Prevention Trials

• EPIDEMIOLOGIC STUDIES

• WOSCOPS Pravastatin 40mg reduced non-fatal MI/CHD mortality in men with LDLs >155.

• AFCAPS/TEXCAPS Lovastatin 20-40mg reduced incidence 1st major CVE in low risk

male/females, average LDL 150s with lower HDLs.

• ASCOT LAA Atorvastatin 10mg reduced MI/ total CVE/Stoke in htn patients or those with 3+ risk factors.

• JUPITOR 15,000 patients multicenter trial, rosuvastatin 20mg in those with LDL<130 and CRP

>2.0 showed marked reduction 1st CVE : MI, CVA, need for CABG PTCA, all cause mortality. Those taking statin compared with placebo had 54% lower chance MI, 48% CVA, 46% PTCA/CABG/20% dying any cause. Stopped early. Normal LDL, inc CRP benefit.

• METEOR Rosuvastatin in low risk groups comparing CIMT; stat sign diff CIMT and LDL.

Secondary Prevention Trials • 4S Simvastatin 20-40mg reduced total mortality, coronary events, CHD deaths, need for revasc in 4444

subjects with recent MI/angina.

• CARE Pravastatin 40mg reduced coronary death, non fatal MI, need revasc, CVA/TIA in 4159

subjects with hx MI.

• LIPID Pravastatin reduced death from CHD, total mortality, CVA, bypass, fatal/non fatal MI in >9000

subjects with recent MI/UA. Stopped early.

• HPS Simvastatin 40mg reduced all cause mortality, death from ht or blood vessel disease, major CVE,

CVA in 20,536 subjects with hx CVD (cor/perip/cere), DM or Htn (mostly secondary prevention) . Red in events similar in all tertiles LDL (including all cause mortality, as well as low CRP and LDL).

• Post CABG Trial extended follow up period 1351

patients, lovasatin reduced composite endpt : death/MI/revasc stroke 18% end

trial; 24% at 7.5 years (significant p = .0.001).

Regression Trials Statins

• REGRESS Pravastatin 40mg delayed progression CAD, showed lower rate progression

periph/carotid disease, less CVEs, with 42% red non-fatal MI(not stat sig), red progression PVD.

• LCAS Fluvastatin reduced progression on angio; low HDL benefit most . 429 patients over

2.5yrs

• SCAT 460 patients double randomiz simvastatin vs plac; and/or enal vs plac; simv less

prgo/less PTCA. Normal cholesterol levels.

• GAIN Intra u/s atorva red prog, inc hyperechogenicity of plaque (stable, less rupture) 131

pts 12

• REVERSAL Atorva 80mg vs pravasatin 40mg. Mean change atheroma vol by IVUS sign

lower atorvastatin group. (-0.4 vs 2.7); mean LDL significantly lower; 18 mos in 654 patients.

• ASTEROID Open label controlled study. Rosuv 40mg red LDL 53%, median %

atheroma vol decreased 0.79, most diseased segment -9.1%. 507 patients.

crp (c-reactive ultra sen)

Statins and usCRP

• JUPITOR Rosuvastatin 20mg LDL<130 and CRP >2.0 marked reduction 1st CVE : MI, CVA, need

for CABG PTCA, all cause mortality. Those taking statin compared with placebo had 54% lower chance MI, 48% CVA, 46% PTCA/CABG/20% dying any cause. Stopped early. Normal LDL, inc CRP benefit.

• AFCAPS Lovastatin reduced CRP 15%.

• PROVE IT-TIMI 22 Atorva 80mg vs prava 40mg in 4162 ACS patients.

Both treatment groups significant reductions CRP. Linear relationship between levels CRP achieved after statin therapy and risk reduction of MI/death. After adjusting for LDL and CRP, CRP explained residual benefit associated with atorva –death/MI from CHD after 30 days.

• REVERSAL Atorva 80mg vs pravastatin 40mg. Much greater % change CRP with atorva. Any

level LDL rate of progress lower in atorva group; suggesting factors other than LDL play role such as CRP.

• A to Z trial: 4497 patients ACS . Simvastatin 40mg 80mg vs conservative strategy.

• CRP at 30d and 4 months independently associated with long term survival • CRP >3.0 sig higher mort; higher statin with aggressive therapy more likely red CRP <1.3.

Lower LDLs the Better Trial Secondary Prevention

• TNT 10,000 patients atorva 10mg vs 80mg.

LDLs < 100 vs 75; significant reduction in primary endpoint MCVEs with aggressive targets for LDL.

• PROVE-IT TIMI 22 prava 40mg vs atorava 80g in 4182 patients ACS

LDLs <100 to LDLs <70 . Significant reduction primary endpt with HR 0.84 in aggressive therapy group. Primary endpoint death/MI/UA/revasc/CVA.

• REVERSAL Atorva 80mg vs pravastatin 40mg

Progression atheroma IVUS correlated with reduction LDL; each 10% red LDL correlated with 1% red in change of atheoma volume. Supports lower LDLs.

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Statins and Diabetes

• Cholesterol Treatment Trialists Collaborators Meta-analysis 18,686 DM patients revealed significant reductions of the following with statins:

major vasc events 21%, CVA 21%, major coronary event 22%,coronary revasc 25%

• HPS 3982 subjects . Simvastatin in subgroup with DM with no CVD reduced MI/CVA 28%.

• CARDS Atorva 10mg reduced CVEs in DM with no CVD 37%.

2838 patients with additional risk (prot, sm, ret , htn), stopped early. LDL < > 120.

• MEGA 8214 Japanese men/post men females study diet vs pravastatin 10-20 in primary or

DM reduced 1st occurrence CHD HR 0.67 Asian benefits similar to american.

Framingham Risk

Trials Adding Therapy to Statins

ACCORD fenofib + statin vs statin 5 yrs.; no diff primary endpoint

AIM HIGH niacin + simva vs simva stopped early; no diff primary endpoint

HPS Thrive niacin + simva vs simva 4 yrs. ; no diff primary endpoint

ARBITOR 2 niacin + statin HDL increased 21%; CIMT –not stat sig

CTEP INHIB TRIALS:

Dal Outcomes dalcetrapib + statin vs statin 40% inc HDL; increased prim outcome stopped early futility

Illuminate torcetrapib + atorva vs atorva 72% inc in HDL;stopped early adv events

ARBITOR 6-HALTS niacin + statin vs ezetimibe + statin

CHD or CHD risk equivalent with LDL<100; HDL < 50. Niacin red CIMT with fewer comp CV endpts (MI/revasc/ACS/death) p= 0.04.

Early Use of Statins After ACS Large Randomized Trials

• MIRACL 3086 patients with UA or non-Q wave MI

Atorva 80mg vs placebo.

Atorva 80mg reduced symptomatic ischemia requiring hospitalization;

not death, resucsciation after arrest or MI/ revascularization

• PROVE IT-TIMI 22:

compared atorvastatin 80mg with pravasatin 40mg in 4162 patients with ACS

LDL lower: 62 vs 96

combined endpoint (death any cause, MI, UA coronary revasc,CVA ) sign lower atorvastatin group with HR 0.84 CRP lower with atrovastatin.

Reduction in Stroke

• SPARCL: Atorvastatin reduced stroke, CAD events. No reduction in all cause mortality.

• HPS: Simvastatin reduced risk of first stroke (ischemic) compared to placebo.

• CARE: Pravastatin reduced risk of CAD event, CVA and CVA + TIA.

• ASCOTT-LLA: In high risk primary prev. patients with HTN and normal lipids, the risk of CVA was lower with Atorvastatin than placebo.

Pleiotropic benefits

• Plaque stabilization

• Reduces inflammation

• Improves endothelial function

• Promotes angiogenesis

• Repair endothelial injury

• Stabilizes arterial plaque

• Prevents cardiovascular and cerebrovascular events

Side Effects

Hepatic Dysfunction

• High aminotransferaces (ALT) • 0.5-3% occurrence of persistent elevations of

LFT’s in patients on statins. – Highest occurrence first 3-4 months of therapy

• Overall incidence of hepatic failure is no different than the incidence in the general population.

• FDA recommended in 2012 to check LFT’s prior to initiating statin therapy and when clinically indicated (fatty liver disease, statin intolerance, prior history of elevations).

• Routine LFT monitoring is not indicated. • Change or lower statin dose if ALT > 3x ULN

Myopathic Syndromes • Myalgia: Muscle discomfort (aches, soreness,

stiffness, tenderness) with a normal CK – 2-11% chance. Resolves days to weeks after

discontinuing

• Myopathy: Muscle weakness with or without CK elevation

• Myositis: Muscle inflammation (with elevated CK) – 0.5% chance

• Myonecrosis: Elevated CK compared with baseline – Clinically significant if CK is > 10 times normal with

muscle symptoms

– Occurs in < 0.5% of patients in clinical trials

Rhabdomyolysis

• Rhabdomyolysis: Myonecrosis with myoglobinuria or ARF.

– < 0.1% chance

• Rhabdomyolysis with ARF has primarily been seen when a statin is used with cyclosporine, gemfibrozil or protease inhibitors

Myopathic Syndromes

• Increased susceptibility with acute or chronic renal failure, obstructive liver disease and hypothyroidism

• Consider re-challenging or switching to another statin

• Pravastatin and fluvastatin - less muscle toxicity

CK elevation

• Other causes: hypothyroidism, trauma from athletics or high impact sports (running, hockey, etc)

• Discontinue statin if CK > 10 x ULN

• Consider switching statins

• Routine CK monitoring is not recommended

• Check baseline CK before statin therapy is initiated.

Renal Dysfunction

• Statins can cause proteinuria. Most reports are with Simvastatin and Rosuvastatin.

• Believed to be a benign finding

Memory Loss • Review of adverse events reported

to the FDA from 11/1997 – 2/2002 found 60 reports of memory changes. Most were with lipophilic statins (Atorvastatin and Simvastatin).

• Annals of Internal Medicine (2013) published a review of randomized trials and observational studies that did not suggest that statins harm cognition. Quality of evidence was low to moderate, especially with high-intensity therapy.

Prevention of Dementia

• Retrospective studies have shown that statins may prevent dementia.

• The Rotterdam study (n=6992) showed a decreased risk of Alzheimer's Disease

• Randomized controlled trials with dementia or cognitive decline as a primary endpoint are needed to determine this risk.

Diabetes Mellitus

• Jupiter Trial, IDEAL, TNT, A to Z, PROVE IT – TIMI 22, SEARCH raised concern for new onset diabetes

• Increased incidence with higher dose statin therapy vs. moderate dose therapy

• One case DM for every 500 patients treated with intensive rather than moderate statin therapy

• Benefit of statins on cardiovascular events and mortality outweigh risks.

Pregnancy

• Category X

• Discontinue prior to conception

• Risk is likely small with statin use

– Increase in congenital CNS and limb abnormalities with exposure of lipophilic statins in the 1st trimester.

• Use discouraged while breastfeeding

Cancer

• 4S – 10 year follow up

• West of Scotland Coronary Prevention Study (WOSCOPS) – 10 year follow up

• Heart Protection Study (HPS) – 11 year follow up

Statins have no effect on cancer incidence or mortality

Cataracts

• Large cohort studies from England, Wales and US military health system found association of statins and increased cataracts

• Randomized trial in the British Journal of Ophthalmology (1995) showed no increase in risk of cataracts.

– Most case control and cohort studies also support this.

Possible Risks

• Neuropathy – causal association with statin use

• Lupus – drug induced by statins

• Androgen synthesis

– Men: Not clinically significant

– Women: May reduce androgen levels

Special Populations

Chronic liver disease + statin

• Used to decrease cardiovascular risk

• Abstinence from alcohol

• Low dose Pravastatin (preferred)

• No increased risk with baseline aminotransferace elevation + statin

• Safe with Gilbert’s syndrome

• Primary biliary cirrhosis + Atorvastatin showed significant elevation in transaminases

– Avoid statins with significant cholestasis

CKD + Statin

• Atorvastatin and Fluvastatin do not require dose adjustment in severe CKD

– Pravastatin may be safer than other remaining options

• Dose adjustment is warranted with other statins with CrCl < 30 mL/min

Interactions • CYP3A4: Cyclosporine, macrolide antibiotics,

HIV protease inhibitors, CCB’s, Amiodarone, Antifungal agents

– Grapefruit juice: 8-oz glass or one-half of a grapefruit or less is unlikely to cause a problem

• Fibrates: ex. Gemfibrozil, fenofibrate

• Niacin

NEW STATIN GUIDELINES

11/12/2013: New guidelines for cholesterol to reduce risk of ASCVD (atherosclerotic cardiovascular disease) in adults Joint task force from the ACC (American College Of Cardiology) and AHA (American Heart Association) 12 years ago guidelines from ATP III- (Adult Treatment Panel, previous gold standard) with emphasis on LDL lowering for high risk patients

33,000 more

people on

STATINS!!!!

What’s known, what’s new

KNOWN:

• LDL matters- increased “bad” cholesterol leads to heart disease

NEW:

• 4 different “Statin Benefit Groups”:

• ID whose at the highest risk for having CVD and prescribe statin therapy

What’s different with new guidelines?

• Only evidence based randomized controlled trials used to provide the most compelling data

• New cardiovascular risk calculator

• Paradigm shift

4 Groups

• ACS (acute coronary syndrome)

• CAD, MI, CABG, stent

• PAD or history of arterial revascularization

• Stroke, TIA (new)

Statin Benefit Groups

• Whose with established ASCVD or established heart disease (secondary prevention)

• No history of heart disease, but LDL-C levels of >190 mg/dl or higher (primary prevention)

• Diabetics: 40-75 y/o with LDL 70-189 mg/dl without heart disease

• 40-75 y/o with LDL-C levels 70-189 with a 10 year risk of 7.5% or higher (no diabetes)

Not in the Recommended Group?

• Elevated high-sensitivity CRP 2 mg/L or higher- marker of inflammation

• Familial hyperlipidemia

• Family history – ASCVD onset in 1st degree male >55 or female >65

• Elevated coronary artery calcium score

• Elevated LP(a)

Guidelines Include:

• CAD

• STROKE

• PAD (peripheral arterial disease)

• DIABETES

Dislikes

• New risk assessment calculator to identify 10 year risk of CV disease likelihood- untested

• No recommendations for lowering triglycerides

• No benchmark for LDL goals

• Emphasis on high or moderate dose statins challenging with statin intolerance

2013 Risk Calculator • The calculator uses nine pieces of

information—sex, age, race, total cholesterol, HDL cholesterol, systolic blood pressure, current treatment for high blood pressure, diagnosis of diabetes, smoking habits.

• The new guidelines recommend a statin for seemingly healthy people with a risk of 7.5% or higher

Risk Calculator

• http://myamericanheart.org/professional/ • “Something is terribly wrong,” Dr. Nissen said.

Using the calculator’s results, he said, “your average healthy Joe gets treated, virtually every African-American man over 65 gets treated.”

- EMPHASIS ON AGE AND SEX. DOES NOT INCLUDE FAMILY HISTORY, TRIGS, CRP, LP(A)

65 year old male s/p MI at age 56, not active, no special diet

• TG : 365

• HDL-C : 35

• LDL-C : 78

• Glucose: :144

• What would you do first? Hint: new guidelines don’t address triglyceride levels

Average Jane

• 30 year old female, father died of MI at age 45

• total cholesterol of 270 mg/dL

• Triglycerides: 360 mg/dL

• HDL- 45

• LDL-180

• Due to her young age, risk calculator doesn’t apply. Should we wait 10 years to treat??

AVERAGE JOE

65 y/o AA male, primary prevention, no history of CAD, DM, HPTN. LP(a) normal. Fasting lipids: Total cholesterol 190 mg/dL HDL: 64 Triglycerides: 125 LDL-76 BP 130 systolic New calculator: 10 year risk score of CV disease= 7.5% Recommend moderate intensity statin treatment (overtreatment)

Do I really need a statin? Individualize!

Statin

All Statins are NOT Created Equal

• Generic:

• Pravastatin (gentle)

• Simvastatin (restrictions past 40 mg)

• Atorvastatin (lipitor)

• Not Generic:

• Rosuvastatin (crestor)

• Pitavastatin

Lipophilic vs. Hydrophilic statins

Preventive Cardiology Jb-1

• Clear LDL goals: may be as high as 130 mg/dL or as low as 70 mg/dL

• Lifestyle management is addressed: diet, weight, exercise, co-morbidities, risk factors

- start statin lowest dose and increase as tolerated

Statin Intolerance

• Literature suggests statin related events 5-10% in RCT

• Clinical practice: 20% or more of patients experience subjective intolerance

• Muscle aches, weakness, constant, often bilateral. Symptoms relieved within days after stopping statins

Therapies for statin intolerance

• Co-enzyme Q-10

• Treating vitamin D deficiency

• Switching statins

• Adding non-statin therapy

• Drug holiday- re-challenge

Statin Dose Equivalency

Caution: FDA warning

• Simvastatin: limit dosing to no > than 40 mg daily

• No more than 10 mg simvastatin if patient on amiodarone, diltiazem, verapamil: FDA alert 2011 (considered low dose statin)due to risk of myopathy

• Amlodipine, ranexa- no more than simvastatin 20 mg

• Simva contraindicated: antifungal –azole, antimicrobials-mycins, HIV protease inhibitors

Intermittent dosing

Rosuvastatin (Crestor) in particular can effectively be dosed as low as 2.5 mg twice weekly due to:

– Long half-life

– High potency

72 y/o male with CAD tolerated atorvastatin for > 3 years before progressive muscle fatigue

CK elevation

• While on statins if CK> 2.5 times normal stop the statin and monitor symptoms

If CK back down to normal after stopping statin, can re-challenge with different drug or dose

Cleveland Clinic Experience

• PC analyzed EMR of 1,605 patients with documented intolerance to at least two statins (between 1995-2010)

• Study showed most patients can tolerate some statin as opposed to none at all

3 groups analyzed

Daily statins, intermittent statin, no statin use

LDL lowering and all cause mortality analyzed

Trend toward a survival benefit for those who could tolerate some statin vs. no statin group

An Apple A Day?

• 150 year old proverb has withstood the test of time

• Apple + statin to >50 age group for primary prevention in the UK theorized

• BMJ 2013: 347, p. 1-6

It’s Complicated:

• 3/14/2014 YouTube Dr. Oz

Apple vs. Statin

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