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Initiating and Monitoring Statin
Therapy
Kimberly K. Birtcher, MS, PharmD, BCPS
(AQ Cardiology), CDE, CLS
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NCEP Report Suggests the Need for
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.
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Statin Dosing Strategies
Achieve AT LEAST a 30% to 40% LDL-C reduction,
regardless of baseline LDL-C.
 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
LDL–C = low-density lipoprotein cholesterol
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.
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Doses of Currently Available Statins
Required for a 30% to 40% LDL-C Reduction
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%
LDL-C = low-density lipoprotein cholesterol
Grundy SM, et al. Circulation. 2004;110:227–239.
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LDL-C Reduction Significantly Reduces Coronary Events:
Primary and Secondary Prevention in Early Statin Trials
Primary
N
Risk Reduction in Major
Coronary Events (%)
LDL-C 
Secondary
AFCAPS/
TexCAPS
WOSCOPS
4S
LIPID
CARE
6605
6595
4444
9014
4159
−27%
−26%
−36%
−25%
−28%
−25
P<0.001
−25
P=0.002
0
-10
-20
-30
-40
−38
P<0.001
−31
P<0.001
−38
P<0.001
-50
LDL–C = low-density lipoprotein cholesterol
LaRosa JC, et al. JAMA. 1999;282:2340–2346.
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Start With the Dose Needed to Give
the Appropriate LDL-C Reduction
Some patients will need more than the initial starting dose:
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
LDL–C = low-density lipoprotein cholesterol
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The Initial Statin Dose Produces Most
of the LDL-C Lowering
10 mg
Atorvastatin
20 mg
30 mg
Rosuvastatin
40 mg
Simvastatin
Mean % Change in
LDL-C from Untreated
Baseline Value
0%
-10%
-20%
−37
−28
−46†
-30%
-40%
-50%
−6
−5
−3
14% with
3 titrations
−7
−4
−7
−6*
−3*
9% with
2 titrations
18% with
3 titrations
-60%
*P < 0.001 vs. atorvastatin 10 mg and simvastatin 20 mg and 40 mg
†P = 0.026 vs. atorvastatin 20 mg
LDL–C=low-density lipoprotein cholesterol
Jones PH, et al. Am J Cardiol. 2003;92:152–160.
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Combination Drug Strategies May
Be 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 nonHDL-C
– ↑ HDL-C
 Combination therapy may increase risk for drug interactions
LDL-C = low-density lipoprotein cholesterol
HDL-C = high-density lipoprotein cholesterol
Vasudevan AR, Jones PH. Curr Cardiol Rep. 2005;7:471–479.
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Statin Drug Interactions:
Labeled Contraindications for
Lovastatin and Simvastatin
Lovastatin and simvastatin are contraindicated with:
 Erythromycin
 Nefazodone
 Clarithromycin
 HIV protease
inhibitors
 Itraconazole
 Ketoconazole
 Grapefruit juice >1
quart/day
 Telithromycin
HIV = human immunodeficiency virus
Mevacor® [package insert]; 2008.
| Zocor® [package insert]; 2008.
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Statin Drug Interactions:
Labeled Dosing Restrictions for
Lovastatin and Simvastatin
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
Mevacor® [package insert]; 2008. | Zocor® [package insert]; 2008.
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Statin Dosing Considerations:
Use of Rosuvastatin in Specific
Populations
 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.
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Statin Drug Interactions: Rosuvastatin
 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)
Crestor® [package insert]; 2008.
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Statins: Monitoring
Headache or Dyspepsia
Initially
6–8 weeks after
starting therapy
At each followup visit
Muscle Soreness, Tenderness, or Pain
Initially
6–12 weeks after
starting therapy
Pasternak RC, et al. J Am Coll Cardiol. 2002;40:567–572.
At each followup visit
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Statins: Monitoring (Continued)
Lipid Panel
Baseline
6 weeks
3 months
Every 6 months
Liver Function Tests
Baseline
12 weeks after
starting/increasing
therapy
Annually, as needed
(when the patient reports
liver symptoms)
Creatine Kinase Test
Baseline
As needed (when patient reports muscle
soreness, tenderness, or pain)
Pasternak RC, et al. J Am Coll Cardiol. 2002;40:567–
572. | McKenney JM, et al. Am J Cardiol. 2006;97:89C–
94C.
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Statins: Liver Issues
 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
Pasternak RC, et al. J Am Coll Cardiol. 2002;40:567–572.
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Statins: Liver Issues (Continued)
Modest increases* in liver transaminases
are not a contraindication to:
 Initiate statins
 Continue statins
 Increase the dose of statins
*Increases <3  the upper limits of normal.
Pasternak RC, et al. J Am Coll Cardiol. 2002;40:567–572. |
McKenney JM, et al. Am J Cardiol. 2006;97:89C–94C.
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Statins: Liver Issues (Continued)
When an elevation* in liver transaminases is isolated
and asymptomatic:
 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.
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Statins: Liver Issues (Continued)
Patients with these conditions may
receive statins:
 Chronic liver disease
 Nonalcoholic fatty liver disease
 Nonalcoholic steatohepatitis
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.
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Statins: Liver Issues (Continued)
 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
Reprinted from McKenney JM, et al. Am J Cardiol. 2006;
97:89C–94C, with permission from Elsevier.
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Statins: Muscle Issues
 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
IV = intravenous; ULN = upper limits of normal
Reprinted from McKenney JM, et al. Am J Cardiol. 2006;
97:89C–94C, with permission from Elsevier.
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Statins: Muscle Issues (Continued)
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
Pasternak RC, et al. J Am Coll Cardiol. 2002;40:567–572.
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Statins: Muscle Issues (Continued)
The risk of myopathy increases with certain
medications:
 Fibrates, especially
gemfibrozil
 Niacin
 Cyclosporine
 Erythromycin
 Clarithromycin
 Itraconazole
 Ketoconazole
 Protease inhibitors
 Verapamil
 Amiodarone
 Nefazodone
Pasternak RC, et al. J Am Coll Cardiol. 2002;40:567–572.
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Statins: Muscle Issues (Continued)
 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
Reprinted from McKenney JM, et al. Am J Cardiol. 2006;
97:89C–94C, with permission from Elsevier.
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Statins: Muscle Issues (Continued)
 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
Reprinted from McKenney JM, et al. Am J Cardiol. 2006;
97:89C–94C, with permission from Elsevier.
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Statins: Muscle Issues (Continued)
When rhabdomyolysis occurs:
 Stop statin therapy
 Provide intravenous hydration
 After recovery, weigh the risks and
benefits of restarting statin therapy
Reprinted from McKenney JM, et al. Am J Cardiol. 2006;
97:89C–94C, with permission from Elsevier.
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Statins: Kidney Issues
 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
Reprinted from McKenney JM, et al. Am J Cardiol 2006;
97:89C–94C, with permission from Elsevier.
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Statins: Neurology Issues
 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
AIDS = acquired immunodeficiency syndrome
Reprinted from McKenney JM, et al. Am J Cardiol. 2006;
97:89C–94C, with permission from Elsevier.
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Statins: Neurology Issues (Continued)

If no other cause is found for peripheral neuropathy
symptoms, stop statin use for 3 to 6 months


With symptom
improvement
Without
symptom improvement


Consider diagnosis of
statin-induced neuropathy
Rule out statin-induced
neuropathy


Consider using a
different statin
Restart statin therapy,
weighing risks and benefits
Reprinted from McKenney JM, et al. Am J Cardiol. 2006;
97:89C–94C, with permission from Elsevier.
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Statins: Neurology Issues (Continued)
When a patient has impaired cognition,
the clinician should:
 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
Reprinted from McKenney JM, et al. Am J Cardiol. 2006;
97:89C–94C, with permission from Elsevier.
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Summary
 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
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