Slide Source: Lipids Online Slide Library Initiating and Monitoring Statin Therapy Kimberly K....

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Initiating and Monitoring Statin Initiating and Monitoring Statin TherapyTherapy

Kimberly K. Birtcher, MS, PharmD, BCPS (AQ Kimberly K. Birtcher, MS, PharmD, BCPS (AQ Cardiology), CDE, CLSCardiology), CDE, CLS


NCEP Report Suggests the Need NCEP Report Suggests the Need for More Intensive Therapyfor More Intensive Therapy Based on statin trials published since 2001

Key points:

– Treat according to global risk level, not only cholesterol value

– Achieve at least a 30% to 40% reduction in low-density lipoprotein cholesterol (LDL-C)

– Initiate therapeutic lifestyle changes (TLC) in all patients with lifestyle-related risk factors regardless of LDL-C level

NCEP = National Cholesterol Education Program

Grundy SM, et al. Circulation. 2004;110:227-239. | NCEP ATP III. JAMA. 2001;285:2486-2497.


Statin Dosing StrategiesStatin Dosing Strategies

Start with dose needed to give appropriate LDL-C reduction (some patients will need more than 30% to 40% LDL-C reduction to achieve LDL-C goal)

Doubling the statin dose provides up to 6% to 7% additional LDL-C reduction

May need combination therapy to achieve goals

Monitor for efficacy and safety

Achieve AT LEAST a 30% to 40% LDL-C reduction, regardless of baseline LDL-C.

Grundy SM, et al. Circulation. 2004;110:227–239. | Pasternak RC, et al. J Am Coll Cardiol. 2002;40:567–572. | Jones P, et al. Am J Cardiol. 1998;81:582–587.

LDL–C = low-density lipoprotein cholesterol


In clinical trials: 40 mg daily of lovastatin has shown an LDL-C reduction of

31% 40 mg daily of pravastatin has shown an LDL-C reduction of

34% 40–80 mg daily of fluvastatin has shown an LDL-C reduction

of 25–35% 20–40 mg daily of simvastatin has shown an LDL-C reduction

of 35–41% 10 mg daily of atorvastatin has shown an LDL-C reduction of

39% 5–10 mg daily of rosuvastatin has shown an LDL-C reduction

of 39–45%

Grundy SM, et al. Circulation. 2004;110:227–239.

LDL-C = low-density lipoprotein cholesterol

Doses of Currently Available Statins Doses of Currently Available Statins Required for a 30% to 40% LDL-C Reduction Required for a 30% to 40% LDL-C Reduction


SecondaryPrimary

LDL-C Reduction Significantly Reduces Coronary Events: LDL-C Reduction Significantly Reduces Coronary Events: Primary and Secondary Prevention in Early Statin TrialsPrimary and Secondary Prevention in Early Statin Trials

LaRosa JC, et al. JAMA. 1999;282:2340–2346.

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ts (

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−38P<0.001

−31P<0.001

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−25P=0.002

CARE

4159

−28%

LIPID

9014

−25%

4S

4444

−36%

WOSCOPS

6595

−26%

AFCAPS/TexCAPS

6605

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LDL-C



Start With the Dose Needed to Give the Appropriate LDL-C Reduction

Baseline LDL-C 160 mg/dL

Target LDL-C <70 mg/dL

Needed LDL-C reduction 160 − 69 = 91 mg/dL

To achieve the target LDL-C, this patient needs a:

57% LDL-C reduction = (160−69 mg/dL)/160 mg/dL 100

Medications and doses that will achieve this reduction are:– Atorvastatin 80 mg– Rosuvastatin 20 mg– Ezitimibe/simvastatin 10/40 mg

Some patients will need more than the initial starting dose:



Jones PH, et al. Am J Cardiol. 2003;92:152–160.

*P < 0.001 vs. atorvastatin 10 mg and simvastatin 20 mg and 40 mg†P = 0.026 vs. atorvastatin 20 mg

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Mean %

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ange in

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rom

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Atorvastatin Rosuvastatin Simvastatin

14% with14% with3 titrations3 titrations



10 mg 20 mg 30 mg 40 mg

−28

−7

−4−7

−46†

−6*−3*

−37

−6−5−3

LDL–C=low-density lipoprotein cholesterol

The Initial Statin Dose Produces Most The Initial Statin Dose Produces Most of the LDL-C Loweringof the LDL-C Lowering


Combination Drug Strategies May Combination Drug Strategies May Be an Option for Some PatientsBe an Option for Some Patients Consider combination therapy if:

– Higher statin doses are not well tolerated– Lipid goals are not met

Statins + bile acid resins or ezetimibe: – ↓ LDL-C >50%

Fibrates, niacin, omega-3 fatty acids: – ↓ Triglycerides and nonHDL-C– ↑ HDL-C

Combination therapy may increase risk for drug interactions

Vasudevan AR, Jones PH. Curr Cardiol Rep. 2005;7:471–479.

LDL-C = low-density lipoprotein cholesterolHDL-C = high-density lipoprotein cholesterol


Statin Drug Interactions:Labeled Contraindications for Lovastatin and Simvastatin

Erythromycin

Clarithromycin

Itraconazole

Ketoconazole

Telithromycin

Mevacor® [package insert]; 2008. | Zocor® [package insert]; 2008.

Lovastatin and simvastatin are contraindicated with:

Nefazodone

HIV protease inhibitors

Grapefruit juice >1 quart/day

HIV = human immunodeficiency virus


Lovastatin

20 mg/day maximum with cyclosporine, danazol, fibrates, niacin >1 g/day

40 mg/day maximum with amiodarone, verapamil

Simvastatin

10 mg/day maximum with cyclosporine, danazol, gemfibrozil

20 mg/day maximum with amiodarone, verapamil

Use with caution with other fibrates, niacin > 1 g/day

Statin Drug Interactions:Statin Drug Interactions:Labeled Dosing Restrictions forLabeled Dosing Restrictions for Lovastatin and SimvastatinLovastatin and Simvastatin

Mevacor® [package insert]; 2008. | Zocor® [package insert]; 2008.


Statin Dosing Considerations:Statin Dosing Considerations:Use of Rosuvastatin in Specific Use of Rosuvastatin in Specific PopulationsPopulations

Asians– May have higher blood concentrations and

more risk of side effects than Caucasians– Start with 5 mg daily; maximum of 20 mg daily

Patients with renal impairment– Start with 5 mg daily; maximum of 10 mg daily

Patients who are predisposed to myopathy– Start with 5 mg daily

Crestor® [package insert]; 2008.


Give a 10 mg/day maximum dose when taken with gemfibrozil or with lopinavir/ritonavir

Give a 5 mg/day maximum dose when taken with cyclosporine

Give antacids containing aluminum or magnesium >2 hours after rosuvastatin

Remember that this statin may increase the levels of ethinyl

estradiol and norgestrel

Remember that this statin may increase the effects of warfarin; monitor international normalized ratio

Use cautiously with other drugs that may decrease the levels or activity of endogenous steroid hormones (i.e., ketoconazole, spironolactone, cimetidine)

Statin Drug Interactions: Statin Drug Interactions: RosuvastatinRosuvastatin

Crestor® [package insert]; 2008.


Statins: Statins: MonitoringMonitoring

Headache or Dyspepsia

Initially6–8 weeks after starting therapy

At each follow-up visit

Muscle Soreness, Tenderness, or Pain

Initially6–12 weeks after starting therapy

At each follow-up visit

Pasternak RC, et al. J Am Coll Cardiol. 2002;40:567–572.


Statins: Statins: Monitoring (Continued)Monitoring (Continued)

Pasternak RC, et al. J Am Coll Cardiol. 2002;40:567–572. | McKenney JM, et al. Am J Cardiol. 2006;97:89C–94C.

Lipid Panel

Baseline 6 weeks 3 months Every 6 months

Liver Function Tests

Baseline12 weeks after

starting/increasing therapy

Annually, as needed (when the patient reports

liver symptoms)

Creatine Kinase Test

BaselineAs needed (when patient reports muscle

soreness, tenderness, or pain)


Statins are well tolerated by most people

Some people experience problems with liver function. Elevations in liver transaminases:

– Occur in 0.5% to 2.0% of statin users

– Are dose-dependent

– Are usually reversed with a lowered statin dose

– Usually do not recur with rechallenge or use of another statin

– Rarely progress to liver failure

Statins: Statins: Liver IssuesLiver Issues



Initiate statins

Continue statins

Increase the dose of statins

Statins: Statins: Liver Issues (Continued)Liver Issues (Continued)

Pasternak RC, et al. J Am Coll Cardiol. 2002;40:567–572. |McKenney JM, et al. Am J Cardiol. 2006;97:89C–94C.

Modest increases* in liver transaminases are not a contraindication to:

*Increases <3 the upper limits of normal.


Repeat liver function tests

– If values are still high, rule out other causes

Based on clinical judgment, consider:

– Continuing the statin

– Reducing the dose of the statin

– Discontinuing statin therapy


*Increased <3 the upper limits of normal.

Reprinted from McKenney JM, et al. Am J Cardiol. 2006;97:89C–94C, with permission from Elsevier.

When an elevation* in liver transaminases is isolated and asymptomatic:



Reprinted from McKenney JM, et al. Am J Cardiol. 2006;97:89C–94C, with permission from Elsevier. | Pasternak RC, et al.J Am Coll Cardiol. 2002;40:567–572.

Patients with these conditions may receive statins:

Chronic liver disease

Nonalcoholic fatty liver disease

Nonalcoholic steatohepatitis


Teach patients to report jaundice, malaise, fatigue, and lethargy

Suspect hepatotoxicity when jaundice, hepatomegaly, increased indirect bilirubin, or increased prothrombin time occur

Discontinue statin therapy with objective evidence of significant liver injury

– Seek cause

– Consider referral to a gastroenterologist or hepatologist




Myopathy

– Patient reports muscle pain, soreness, weakness, and/or cramps with elevated creatine kinase (>10 ULN)

Rhabdomyolysis

– Creatine kinase >10,000 IU/L, or

– Creatine kinase >10 ULN with an elevation in serum creatinine or requiring medical intervention with IV hydration therapy

Statins: Statins: Muscle IssuesMuscle Issues

IV = intravenous; ULN = upper limits of normal



The risk of myopathy increases with respect to:

Age (>80 years; especially in women)

Multisystem diseases (chronic renal failure, especially due to diabetes)

Multiple medications

Perioperative periods

Alcohol abuse

Grapefruit juice >1 quart/day

Statins: Statins: Muscle Issues (Continued)Muscle Issues (Continued)



Statins: Muscle Issues (Continued)

Fibrates, especially gemfibrozil

Niacin

Cyclosporine

Erythromycin

Clarithromycin

Itraconazole

Ketoconazole

Protease inhibitors

Verapamil

Amiodarone

Nefazodone


The risk of myopathy increases with certainmedications:


Teach patients to report muscle symptoms

When muscle symptoms or elevations in creatine kinase occur, the clinician should rule out common causes:

– Exercise, trauma, falls, accidents, seizures, shaking chills, hypothyroidism, infections, carbon monoxide poisoning, polymyositis, dermatomyositis, alcohol abuse, illicit drug abuse (cocaine, amphetamines, heroin, PCP)

– A patient will be at increased risk when starting vigorous, sustained endurance-exercise or when undergoing surgery



PCP = phencyclidine hydrochloride


When there are tolerable muscle symptoms or creatine kinase is elevated (<10 the upper limits of normal) in the absence of such symptoms:

– Continue statin therapy at the same or a reduced dose

– Use the patient’s symptoms to guide statin therapy

When there are intolerable muscle symptoms that cannot be attributed to other causes and may or may not be accompanied by an elevation in creatine kinase:

– Discontinue statin therapy

– Restart the (same or different) statin at the same or a reduced dose when a patient is asymptomatic

– Try other lipid-lowering medications when muscle symptoms recur after treatment with various statins




When rhabdomyolysis occurs:

Stop statin therapy

Provide intravenous hydration

After recovery, weigh the risks and benefits of restarting statin therapy




Assess renal function before initiating statin therapy

Statin therapy may be used in patients with chronic kidney disease (some statins may need dose adjustments)

No need to routinely monitor serum creatinine or proteinuria

Statins: Statins: Kidney IssuesKidney Issues

Reprinted from McKenney JM, et al. Am J Cardiol 2006;97:89C–94C, with permission from Elsevier.


Routine neurologic monitoring is not needed

With symptoms consistent with peripheral neuropathy, the clinician should rule out common causes:

– Diabetes – Cancer

– Renal insufficiency – Hypothyroidism

– Alcohol abuse – AIDS

– Vitamin B12 deficiency – Lyme disease

– Heavy metal intoxication

Statins: Statins: Neurology IssuesNeurology Issues

AIDS = acquired immunodeficiency syndrome



Statins: Statins: Neurology Issues (Continued)Neurology Issues (Continued)

With symptom improvement

Without symptom improvement

Consider diagnosis of

statin-induced neuropathyRule out statin-induced

neuropathy

Consider using a different statin

Restart statin therapy, weighing risks and benefits

If no other cause is found for peripheral neuropathy symptoms, stop statin use for 3 to 6 months



Rule out common causes

Stop statin therapy for 1 to 3 months if no other cause of the impairment is found

Restart statin therapy if there is no symptom improvement, weighing the risks and benefits

Statins: Statins: Neurology Issues (Continued)Neurology Issues (Continued)


When a patient has impaired cognition, the clinician should:


SummarySummary Treat according to the patient’s global risk, not

only cholesterol value

Statins are safe and effective

Achieve at least a 30% to 40% reduction in low-density lipoprotein cholesterol (LDL-C) with initial statin therapy

May need to use higher initial doses of statins or combination therapy in some patients to reach LDL-C goals

Use established guidelines to monitor for and manage potential adverse drug reactions

Slide Source: Lipids Online Slide Library Initiating and Monitoring Statin Therapy Kimberly K....

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