- ACRONYMS AND DEFINITIONS
- ACS - Acute coronary syndrome defined as myocardial infarction or unstable angina
- AHA - American Heart Association
- CAD - Coronary artery Disease
- CK - Creatine kinase
- CVD - Cardiovascular disease
- DBP - Diastolic blood pressure
- GFR - Glomerular filtration rate
- LFTs - Liver function tests
- MI - Myocardial infarction
- RCT - Randomized controlled trial
- TIA - Transient ischemic attack
- ULN - Upper limit of normal
- SBP - Systolic blood pressure
- DRUGS IN CLASS
- Statins
- Atorvastatin (Lipitor®)
- Fluvastatin (Lescol®, Lescol XL®)
- Lovastatin (Mevacor®, Altoprev®)
- Pitavastatin (Livalo®, Zypitamag®)
- Pravastatin (Pravachol®)
- Rosuvastatin (Crestor®, Ezallor™ Sprinkle)
- Simvastatin (Zocor®, Flolipid®)
- Combination products with ezetimibe
- Roszet® (rosuvastatin + ezetimibe)
- Vytorin® (simvastatin + ezetimibe)
- Combination products with amlodipine
- Caduet® (atorvastatin + amlodipine)
- MECHANISM OF ACTION
- Cholesterol synthesis
- Humans synthesize cholesterol in the liver with an enzyme called HMG-CoA reductase
- Statins inhibit HMG-CoA reductase
- Inhibiting HMG-CoA reductase decreases cholesterol synthesis and leads to decreased blood levels of LDL
- See cholesterol transport diagram
- FDA-APPROVED INDICATIONS
- Atorvastatin (Lipitor®)
- Prevention of Cardiovascular Disease in Adults
- Hyperlipidemia
- Fluvastatin (Lescol®, Lescol XL®)
- Hypercholesterolemia (heterozygous familial and nonfamilial) and Mixed Dyslipidemia
- Heterozygous Familial Hypercholesterolemia in Pediatric Patients
- Secondary Prevention of Coronary Events
- Atherosclerosis
- Lovastatin (Mevacor®)
- Primary Prevention of Coronary Heart Disease
- Coronary Heart Disease
- Hypercholesterolemia
- Adolescent Patients with Heterozygous Familial Hypercholesterolemia
- Lovastatin (Altoprev®)
- Prevention of Coronary Heart Disease
- Hyperlipidemia
- Pitavastatin (Livalo®)
- Adult patients with primary hyperlipidemia or mixed dyslipidemia
- Pediatric patients aged 8 years and older with heterozygous familial hypercholesterolemia
- Pitavastatin (Zypitamag®)
- Primary Hyperlipidemia and Mixed Dyslipidemia
- Pravastatin (Pravachol®)
- Prevention of Cardiovascular Disease
- Hyperlipidemia
- Rosuvastatin (Crestor®)
- Hyperlipidemia and Mixed Dyslipidemia
- Pediatric Patients with Familial Hypercholesterolemia
- Hypertriglyceridemia
- Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia)
- Adult Patients with Homozygous Familial Hypercholesterolemia
- Slowing of the Progression of Atherosclerosis
- Primary Prevention of Cardiovascular Disease
- Rosuvastatin (Ezallor™ Sprinkle)
- Hypertriglyceridemia
- Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia)
- Adult Patients with Homozygous Familial Hypercholesterolemia
- Simvastatin (Zocor®, Flolipid®)
- Reductions in Risk of CHD Mortality and Cardiovascular Events
- Hyperlipidemia
- Adolescent Patients with Heterozygous Familial Hypercholesterolemia (HeFH)
- STATIN INTENSITY CHART
High-intensity statin therapy (lowers cholesterol by ≥50%) |
Moderate-intensity statin therapy (lowers cholesterol by 30 - 50%) |
Low-intensity statin therapy (lowers cholesterol by < 30%) |
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- CHOLESTEROL EFFECTS
- Overview
- All statins are effective at lowering cholesterol levels
- Statins differ in their effect on individual lipid parameters (LDL, HDL, Total Cholesterol, Triglycerides)
- The chart below presents the average percent reduction (except for HDL) in different lipid parameters for each statin
- Statins raise HDL levels
Medication | Total cholesterol | LDL | HDL (% increase) |
Triglycerides |
---|---|---|---|---|
Pravastatin (Pravachol®) |
28% | 34 - 37% | 8 - 3% | 20% |
Fluvastatin (Lescol®) |
17 - 27% | 22 - 36% | 5 - 8% | 15 - 21% |
Lovastatin (Mevacor®) |
18 - 32% | 26 - 41% | 6 - 9% | 10 - 23% |
Simvastatin (Zocor®) |
28 - 38% | 38 - 43% | 8 - 12% | 19 - 32% |
Pitavastatin (Livalo®) |
23 - 31% | 31 - 44% | 6% | 14 - 19% |
Atorvastatin (Lipitor®) |
29 - 49% | 29 - 51% | 8 - 7% | 26 - 47% |
Rosuvastatin (Crestor®) |
40 - 43% | 49 - 54% | 11 - 14% | 29 - 36% |
- PRIMARY PREVENTION OF CVD
- Overview
- Two large trials that evaluated the effects of statins in patients without a history of CVD are presented below
- In both trials, patients with common risk factors for CVD were enrolled. Based on the results of these trials and other similar trials, statins have become some of the most widely prescribed drugs in the world.
- The AFCAPS study enrolled 6605 patients with no prior history of cardiovascular disease (defined as heart attack, angina, stroke, TIA, or claudication)
Main inclusion criteria
- Total cholesterol 180 - 264 mg/dl
- LDL 130 - 190 mg/dl
- HDL ≤ 45 mg/dl for men and ≤ 47 mg/dl for women
- Triglycerides ≤ 400 mg/dl
Main exclusion criteria
- Uncontrolled hypertension
- Diabetes managed with insulin or HgA1C ≥ 10%
- Weight 50% greater than what is ideal for height
Baseline characteristics
- Average age 58 years
- Female sex - 15%
- Average BMI - 27
- Average SBP - 138, DBP - 78
- Average LDL - 150 mg/dl
- Average HDL - 36 mg/dl
Randomized treatment groups
- Group 1 (3304 patients) - Lovastatin 20 - 40 mg a day
- Group 2 (3301 patients) - Placebo
- Lovastatin was increased to 40 mg if LDL was > 110 mg/dl at 3 months
Primary outcome: Incidence of first acute major coronary events, defined as fatal or nonfatal myocardial infarction, unstable angina, or
sudden cardiac death
Results
Duration: After an average follow-up of 5.2 years, the trial was stopped early because lovastatin superiority | |||
Outcome | Lovastatin | Placebo | Comparisons |
---|---|---|---|
Primary outcome | 3.5% | 5.5% | RR 0.63, 95%CI [0.50 - 0.79], p<0.001 |
Fatal and nonfatal heart attack | 1.7% | 2.9% | RR 0.60, 95%CI [0.43 - 0.83], p=0.002 |
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Findings: Lovastatin reduces the risk for the first acute major coronary event in men and women with average TC and LDL-C levels and below-average HDL-C levels.
These findings support the inclusion of HDL-C in risk-factor assessment, confirm the benefit of LDL-C reduction to a target goal, and suggest the need for reassessment of the
National Cholesterol Education Program guidelines regarding pharmacological intervention.
- The HOPE-3 trial enrolled 12,705 patients with no prior history of cardiovascular disease
Main inclusion criteria
- Men ≥ 55 years | Women ≥ 65 years
- At least one of the following risk factors for CVD: - elevated waist-to-hip ratio, history of a low HDL, current or recent tobacco use, dysglycemia, family history of premature CAD, mild renal dysfunction
- Women ≥ 60 years old with 2 risk factors were also included
Main exclusion criteria
- Documented cardiovascular disease
- Chronic liver disease
- CrCl < 30 ml/min
Baseline characteristics
- Average age 66 years
- Female sex - 46%
- Average BMI - 27
- Average SBP - 138, DBP - 81
- Average LDL - 128 mg/dl
- Average HDL - 45 mg/dl
- Number of risk factors: 2 - 47% | ≥ 3 - 24%
Randomized treatment groups
- Group 1 (6361 patients) - Rosuvastatin 10 mg once daily
- Group 2 (6344 patients) - Placebo once daily
- Open-label statin could be prescribed in either group at the physician's discretion, but in those cases, the assigned regimen was discontinued. At 5 years, 5.6% of patients in Group 2 were taking open-label statins.
- The study had a 2 X 2 factorial design where half the patients also received candesartan 16 mg + HCTZ 12.5 mg
Primary outcome: The first coprimary outcome was the composite of death from cardiovascular causes, nonfatal myocardial
infarction, or nonfatal stroke, and the second coprimary outcome additionally included resuscitated cardiac arrest, heart failure, and revascularization
Results
Duration: Median of 5.6 years | |||
Outcome | Rosuvastatin | Placebo | Comparisons |
---|---|---|---|
First coprimary outcome | 3.7% | 4.8%, | HR 0.76, 95%CI [0.64 - 0.91], p=0.002 |
Second coprimary outcome | 4.4% | 5.7% | RR 0.75, 95%CI [0.64 - 0.88], p<0.001 |
Death from any cause | 5.3% | 5.6% | RR 0.93, 95%CI [0.80 - 1.08], p=0.32 |
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Findings: Treatment with rosuvastatin at a dose of 10 mg per day resulted in a significantly lower risk of cardiovascular events than placebo in an
intermediate-risk, ethnically diverse population without cardiovascular disease
- Professional recommendations
- See cholesterol treatment guidelines for recommendations from various professional organizations
- SECONDARY PREVENTION OF CVD
- Overview
- Statins have consistently been shown to improve outcomes in patients with heart disease regardless of their cholesterol levels
- Statins are universally recommended by professional associations for the secondary prevention of CVD. All patients with CVD should be offered a statin.
- Two of the larger randomized controlled trials that evaluated statins for secondary prevention of CVD are presented below
- The LIPID study enrolled 9014 patients with a history of heart attack or hospitalization for chest pain
Main inclusion criteria
- 31 - 75 years old
- ACS between 3 - 36 months before study entry
- Total cholesterol 155 - 271 mg/dl
- Fasting triglycerides < 445 mg/dl
Main exclusion criteria
- Heart failure
- Kidney or liver disease
- Taking any cholesterol lowering agent
Baseline characteristics
- Median age - 62 years
- Male sex - 83%
- Qualifying event, myocardial infarction - 64%, unstable angina - 36%
- Median time from event to randomization - 1.2 years
- CVD history: PCI only - 11% | CABG only - 27% | both - 3%
- Median total cholesterol - 218
- Median LDL - 150
- Median HDL - 36
Randomized treatment groups
- Group 1 (4512 patients) - Pravastatin 40 mg once daily
- Group 2 (4502 patients) - Placebo once daily
Primary outcome: Death from coronary heart disease defined as death due to fatal myocardial infarction, sudden death, death in the hospital after possible myocardial infarction, or death due to heart failure or another coronary cause
Results
Duration: Average 6.1 years | |||
Outcome | Pravastatin | Placebo | Comparisons |
---|---|---|---|
Primary outcome | 6.4% | 8.3% | RR 0.76, 95% CI [0.65 - 0.88], p<0.001 |
Overall mortality | 11% | 14.1% | RR 0.78, 95% CI [0.69 - 0.87], p<0.001 |
Myocardial infarction | 7.4% | 10.3% | RR 0.71, 95% CI [0.62 - 0.82], p<0.001 |
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Findings: Pravastatin therapy reduced mortality from coronary heart disease and overall mortality, as compared with the rates in the placebo group, as well
as the incidence of all prespecified cardiovascular events in patients with a history of myocardial infarction or unstable angina who had a broad range of initial cholesterol levels.
- The Heart Protection Study enrolled 20,536 patients with a history of vascular disease or diabetes
Main inclusion criteria
- Total cholesterol ≥ 135 mg/dl
- History of ≥ 1 of the following: CAD, Stroke, PAD, TIA, carotid artery stenosis, diabetes, male ≥ 65 years with treated hypertension
Main exclusion criteria
- Chronic liver disease or ALT > 67 IU/L
- Serum creatinine > 2.26 mg/dl
- CK > 750 IU/L
- Taking cyclosporine, fibrates, or niacin
- Severe heart failure
Baseline characteristics
- Qualifying criteria: CAD - 65% | Cerebrovascular disease - 9% | PAD - 13%
- Average total cholesterol - 227 mg/dl
- Average LDL - 131 mg/dl
- Average HDL - 41 mg/dl
Randomized treatment groups
- Group 1 (10,269 patients) - Simvastatin 40 mg once daily
- Group 2 (10,267 patients) - Placebo once daily
Primary outcome: Death from any cause and major vascular events
Results
Duration: Average of 5 years | |||
Outcome | Simvastatin | Placebo | Comparisons |
---|---|---|---|
Primary outcome (overall mortality) | 12.9% | 14.7% | RR 0.87, 95%CI [0.81 - 0.94], p=0.0003 |
Primary outcome (major vascular events) | 19.8% | 25.2% | RR 0.76, 95%CI [0.72 - 0.81], p<0.0001 |
Any stroke | 4.3% | 5.7% | RR 0.75, 95%CI [0.66 - 0.85], p<0.0001 |
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Findings: Adding simvastatin to existing treatments safely produces substantial additional benefits for a wide range of high-risk patients, irrespective
of their initial cholesterol concentrations. Allocation to 40 mg simvastatin daily reduced the rates of myocardial infarction, of stroke, and of revascularization by about one-quarter.
After making allowance for non-compliance, actual use of this regimen would probably reduce these rates by about one-third. Hence, among the many types of high-risk individual
studied, 5 years of simvastatin would prevent about 70-100 people per 1000 from suffering at least one of these major vascular events (and longer treatment should produce further
benefit). The size of the 5-year benefit depends chiefly on such individuals' overall risk of major vascular events, rather than on their blood lipid concentrations alone.
- Professional recommendations
- Statins are universally recommended for patients with CVD by professional organizations
- See cholesterol treatment guidelines for recommendations from various professional organizations
- STROKE PREVENTION
- Overview
- Statins have been shown to reduce the incidence of stroke in a number of cardiovascular disease prevention trials
- The SPARCL trial detailed below looked specifically at stroke prevention in patients with a history of stroke or TIA
- The SPARCL study enrolled 4731 patients who had experienced a stroke or TIA
Main inclusion criteria
- History of ischemic or hemorrhagic stroke or TIA within the past 1 - 6 months
- Modified Rankin score ≤ 3
- LDL of 100 - 190 mg/dl
Main exclusion criteria
- Atrial fibrillation
- History of subarachnoid hemorrhage
- History of coronary heart disease
Baseline characteristics
- Average age 63 years
- Average BP - 138/82
- Average LDL - 132 mg/dl
- Average HDL - 50 mg/dl
- Qualifying event: Ischemic stroke - 66% | TIA - 30% | Hemorrhagic stroke - 2%
Randomized treatment groups
- Group 1 (2365 patients) - Atorvastatin 80 mg once daily
- Group 2 (2366 patients) - Placebo once daily
Primary outcome: First nonfatal or fatal stroke
Results
Duration: Median of 4.9 years | |||
Outcome | Atorvastatin | Placebo | Comparisons |
---|---|---|---|
Primary outcome | 11.2% | 13.1% | HR 0.84, 95%CI [0.71 - 0.99], p=0.03 |
Stroke or TIA | 15.9% | 20.1% | HR 0.77, 95%CI [0.67 - 0.88], p<0.001 |
Hemorrhagic stroke | 2.32% | 1.4% | HR 1.66, 95%CI [1.08 - 2.55] |
Overall mortality | 9.1% | 8.9% | HR 1.0, 95%CI [0.82 - 1.21], p=0.98 |
Muscle aches | 5.5% | 6.0% | N/A |
Myopathy | 0.3% | 0.3% | N/A |
LFTs >3 X ULN on 2 consecutive labs | 2.2% | 0.5% | N/A |
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Findings: In patients with recent stroke or TIA and without known coronary heart disease, 80 mg of atorvastatin per day reduced the overall incidence
of strokes and of cardiovascular events, despite a small increase in the incidence of hemorrhagic stroke
- AHA recommendations
- Summary
- Statins reduce the risk of stroke in patients who have a history of stroke or TIA
- In the SPARCL trial, the risk of hemorrhagic stroke was increased in patients taking atorvastatin. It's unclear if this was a chance finding or significant risk (see hemorrhagic stroke below).
- HEAD-TO-HEAD STATIN TRIALS
- Overview
- A handful of trials have compared statins head-to-head for the secondary prevention of CVD
- These trials vary greatly in design, and in most trials, the statin doses were not comparable making it difficult to conclude if one statin is superior to another
- Three head-to-head trials are presented below
- The PROVE-IT study enrolled 4162 patients who had experienced acute coronary syndrome within the past 10 days
Main inclusion criteria
- Hospitalized for acute coronary syndrome (myocardial infarction or unstable angina) within past 10 days
- Total cholesterol ≤ 240 mg/dl if not being treated for high cholesterol and ≤ 200 mg/dl if treated
Main exclusion criteria
- Receiving 80 mg dose of any statin
- Taking CYP3A4 strong inhibitors
- Scheduled for CABG
- Serious liver disease
- Serum creatinine > 2.0 mg/dl
Baseline characteristics
- Average age 58 years
- Prior myocardial infarction - 18%
- Received PCI with qualifying event - 69%
- History of CABG - 11%
- Prior statin therapy - 25%
- Median LDL - 106 mg/dl
- Median HDL - 39 mg/dl
Randomized treatment groups
- Group 1 (2099 patients) - Atorvastatin 80 mg once daily
- Group 2 (2063 patients) - Pravastatin 40 mg once daily
Primary outcome: Composite of death from any cause, myocardial infarction, documented unstable angina requiring rehospitalization,
revascularization with either percutaneous coronary intervention or coronary-artery bypass grafting (if these procedures were performed at least 30 days after
randomization), and stroke
Results
Duration: Average of 2 years | |||
Outcome | Atorvastatin | Pravastatin | Comparisons |
---|---|---|---|
Primary outcome | 22.4% | 26.3% | HR 0.84, 95%CI [0.74 - 0.95], p=0.005 |
Overall mortality | 2.2% | 3.2% | p=0.07 |
Median LDL during study (mg/dl) | 62 | 95 | p<0.001 |
Liver enzymes >3 X ULN | 3.3% | 1.1% | p<0.001 |
Drug discontinuation | 30.4% | 33% | p=0.11 |
Drug discontinuation due to myalgias or elevated CK | 3.3% | 2.7% | p=0.23 |
Findings: Among patients who have recently had an acute coronary syndrome, an intensive lipid-lowering statin regimen provides greater protection against
death or major cardiovascular events than does a standard regimen. These findings indicate that such patients benefit from early and continued lowering of LDL cholesterol
to levels substantially below current target levels.
- The IDEAL study enrolled 8888 patients with a previous myocardial infarction
Main inclusion criteria
- Age 80 years or younger
- History of definite myocardial infarction
Main exclusion criteria
- Contraindication to statin
- Previous intolerance to statins
- Liver enzymes > 2 X ULN
- Triglycerides > 600 mg/dl
- NYHA class III or IV heart failure
- Treatment with other lipid-lowering drugs
- Treatment with statin at dose higher than the equivalent of 20 mg/d of simvastatin
Baseline characteristics
- Average age 61 years
- History of PCI only - 20%
- History of CABG only - 17%
- History of CABG and PCI - 3.3%
- Prior statin therapy - 76%
- Median time since last myocardial infarction - 22 months
- Average LDL - 121 mg/dl
- Average HDL - 46 mg/dl
Randomized treatment groups
- Group 1 (4449 patients) - Simvastatin 20 mg once daily
- Group 2 (4439 patients) - Atorvastatin 80 mg once daily
- Treatment was open-label
Primary outcome: Composite of coronary death, hospitalization for nonfatal acute myocardial infarction, or cardiac arrest with
resuscitation
Results
Duration: Median of 4.8 years | |||
Outcome | Simvastatin | Atorvastatin | Comparisons |
---|---|---|---|
Primary outcome | 10.4% | 9.3% | HR 0.89, 95%CI [0.78 - 1.01], p=0.07 |
Nonfatal myocardial infarction | 7.2% | 6% | HR 0.83, 95%CI [0.71 - 0.98], p=0.02 |
Overall mortality | 8.4% | 8.2% | HR 0.98, 95%CI [0.85 - 1.13], p=0.81 |
Stroke | 3.9% | 3.4% | HR 0.87, 95%CI [0.70 - 1.08], p=0.20 |
Average LDL during study (mg/dl) | 104 | 81 | N/A |
Myalgia leading to drug discontinuation | 1.1% | 2.2% | p<0.001 |
ALT >3 X ULN on 2 consecutive visits | 0.11% | 0.97% | p<0.001 |
Rhabdomyolysis | 0.07% | 0.05% | p>0.99 |
Drug discontinuation | 7% | 14% | N/A |
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Findings: In this study of patients with previous MI, intensive lowering of LDL-C did not result in a significant reduction in the primary outcome of major
coronary events, but did reduce the risk of other composite secondary end points and nonfatal acute MI. There were no differences in cardiovascular or all-cause mortality.
Patients with MI may benefit from intensive lowering of LDL-C without an increase in noncardiovascular mortality or other serious adverse reactions.
- The SATURN study enrolled 1039 patients with coronary artery disease
Main inclusion criteria
- ≥ 1 vessel with 20% stenosis on clinically indicated coronary angiography and a target vessel for imaging with < 50% obstruction
- LDL > 100 mg/dl if not treated with statin and LDL > 80 mg/dl if receiving statin
Main exclusion criteria
- Received intensive lipid-lowering therapy for > 3 months within previous year
- Uncontrolled hypertension
- Heart failure
- Kidney or liver disease
Baseline characteristics
- Average age 57 years
- Previous myocardial infarction - 24%
- Previous PCI - 23%
- Prior statin use - 60%
- Average LDL - 120 mg/dl
- Average HDL - 45 mg/dl
Randomized treatment groups
- Group 1 (519 patients) - Atorvastatin 80 mg once daily
- Group 2 (520 patients) - Rosuvastatin 40 mg a once daily
Primary outcome: Progression of coronary atherosclerosis as measured by intravascular coronary ultrasound
Results
Duration: 104 weeks | |||
Outcome | Atorvastatin | Rosuvastatin | Comparisons |
---|---|---|---|
Primary outcome (decrease in percent atheroma volume) | 0.99% | 1.22% | p=0.17 |
Disease regression (percent of patients) | 63.2% | 68.5% | p=0.07 |
Average LDL during treatment | 70 mg/dl | 63 mg/dl | p<0.001 |
Average HDL during treatment | 48 mg/dl | 50 mg/dl | p=0.01 |
ALT >3 X ULN | 2.1% | 0.7% | p=0.04 |
New proteinuria | 1.7% | 3.8% | p=0.02 |
Drug discontinuation | 20.6% | 21% | N/A |
CK >5 X ULN | 0.7% | 0.3% | N/A |
Findings: Maximal doses of rosuvastatin and atorvastatin resulted in significant regression of coronary atherosclerosis. Despite the lower level of LDL
cholesterol and the higher level of HDL cholesterol achieved with rosuvastatin, a similar degree of regression of PAV was observed in the two treatment groups.
- Summary and recommendations
- The PROVE-IT and IDEAL studies did not use comparable doses of statins, so a conclusion cannot be drawn regarding superiority of one statin over another
- The SATURN trial used comparable doses, but it measured a surrogate endpoint and found no difference
- There are no good head-to-head trials that have used comparable doses of statins and measured significant clinical outcomes
- LDL goals should be the main focus of statin therapy
- There is no evidence that one statin is more beneficial than another when patient LDL values are comparable
- HIGH VERSUS LOW DOSE STATINS
- Overview
- Two large trials have compared the effects of taking high versus low doses of the same statin. The TNT trial compared 80 mg of atorvastatin to 10 mg. The SEARCH study compared 80 mg of simvastatin to 20 mg. Both studies are detailed below.
- The TNT study enrolled 10,001 patients with coronary heart disease
Main inclusion criteria
- Clinically evident coronary heart disease defined by one or more of the following: previous myocardial infarction, previous or current angina with objective evidence of coronary artery disease, history of coronary revascularization
Baseline characteristics
- Average age 61 years
- Previous myocardial infarction - 58%
- Previous PCI - 54%
- Previous CABG - 46%
- Average LDL (after washout period) - 152 mg/dl
Randomized treatment groups
- Group 1 (5006 patients) - Atorvastatin 10 mg once daily
- Group 2 (4995 patients) - Atorvastatin 80 mg once daily
- All patients went through a washout period of 1 - 8 weeks where all lipid-lowering drugs were held. Patients with an LDL of 130 - 250 mg/dl after the washout period were then given atorvastatin 10 mg for 8 weeks. Patients with an LDL < 130 mg/dl on atorvastatin 10 mg were then randomized to treatment.
Primary outcome: Composite of death from coronary heart disease, nonfatal non–procedure-related myocardial infarction,
resuscitation after cardiac arrest, or fatal or nonfatal stroke
Results
Duration: Median of 4.9 years | |||
Outcome | 10 mg | 80 mg | Comparisons |
---|---|---|---|
Average LDL during study | 101 mg/dl | 77 mg/dl | N/A |
Primary outcome | 10.9% | 8.7% | HR 0.78, 95%CI [0.69 - 0.89], p<0.001 |
Nonfatal, non–procedure-related MI | 6.2% | 4.9% | HR 0.78, 95%CI [0.66 - 0.93], p=0.004 |
Stroke | 3.1% | 2.3% | HR 0.75, 95%CI [0.59 - 0.96], p=0.02 |
Overall mortality | 5.6% | 5.7% | HR 1.01, 95%CI [0.85 - 1.19], p=0.92 |
Myalgia | 4.7% | 4.8% | p=0.72 |
LFTs >3 X ULN on two consecutive labs | 0.2% | 1.2% | p<0.001 |
Drug discontinuation due to adverse events | 5.3% | 7.2% | p<0.001 |
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Findings: Intensive lipid-lowering therapy with 80 mg of atorvastatin per day in patients with stable CHD provides significant clinical benefit
beyond that afforded by treatment with 10 mg of atorvastatin per day. This occurred with a greater incidence of elevated aminotransferase levels.
- The SEARCH trial enrolled 12,064 patients with a history of myocardial infarction
Main inclusion criteria
- History of previous myocardial infarction
- Total cholesterol ≥ 135 mg/dl if on a statin and ≥ 173 if not
Baseline characteristics
- Average age 64 years
- Previous revascularization - 33%
- Taking statin at entry - 72%
Randomized treatment groups
- Group 1 (6031 patients) - Simvastatin 80 mg once daily
- Group 2 (6033 patients) - Simvastatin 20 mg once daily
- All participants went through a run-in phase where they took simvastatin 20 mg once daily
- Average LDL at the end of the run-in phase was 97 mg/dl
Primary outcome: Composite of major vascular events defined as coronary death, myocardial infarction, stroke, or arterial revascularization
Results
Duration: Average of 6.7 years | |||
Outcome | 80 mg | 20 mg | Comparisons |
---|---|---|---|
Primary outcome | 24.5% | 25.7% | RR 0.94, 95%CI [0.88 - 1.01], p=0.10 |
Stroke | 4.2% | 4.6% | RR 0.91, 95%CI [0.77 - 1.08], p=0.30 |
Overall mortality | 16% | 16.1% | RR 0.99, 95%CI [0.91 - 1.09], p=0.90 |
ALT >2 X ULN | 4.1% | 2.7% | N/A |
CK >5 X ULN | 2.4% | 0.7% | N/A |
Rhabdomyolysis | 7 cases | 0 cases | N/A |
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Findings: The 6% (SE 3.5%) reduction in major vascular events with a further 0.35 mmol/L reduction in LDL cholesterol in our trial is consistent with
previous trials. Myopathy was increased with 80 mg simvastatin daily, but intensive lowering of LDL cholesterol can be achieved safely with other regimens.
- Summary and recommendations
- The efficacy of statins is directly related to their effect on cholesterol levels. In the TNT trial, a larger difference in LDL (24 mg/dl) was achieved between groups than in the SEARCH trial (13.5 mg/dl). This led to better outcomes in the TNT trial than in the SEARCH trial.
- In the SEARCH trial, the 80 mg dose of simvastatin was associated with a significantly greater number of myopathy cases. This led to restrictions being placed on the 80 mg simvastatin dose.
- Statin dosing or "statin intensity" recommendations are now a part of all cholesterol treatment guidelines. See cholesterol treatment guidelines for more.
- SIDE EFFECTS
- Muscle pain (myalgias)
- In randomized controlled trials, the reported incidence of myalgias with statin therapy is typically between 1 - 5%
- While it is a widely held belief that statins cause muscle pain (myalgia), most large clinical trials have found no significant difference in the incidence of muscle pain between statins and placebo [1,4,5,8,9,10,11,12,13,14]. A large review of statin trials that encompassed 74,102 patients also found no significant difference. [PMID 17159064]. Furthermore, a handful of studies have randomized patients who reported statin intolerance to another statin or placebo. In these studies, patient-reported myalgia outcomes were not significantly different between statins and placebo. [62,63,64,65]
- The AHA 2018 guidelines recommend the following for managing statin-induced myalgias
- Discontinue statin. If symptoms resolve, retry statin to develop a causal relationship.
- If causal relationship exists, try lower dose of same statin or change statins. Consider combination therapy (e.g. statin + ezetimibe) to achieve LDL goals.
- Coenzyme Q10 is not recommended for routine use in patients treated with statins or for the treatment of statin-associated muscle symptoms [61]
- Summary
- While muscle pain is a highly publicized side effect of statins, in trials, the incidence is not significantly different than placebo
- Muscle toxicity
- Muscle toxicity from statins may involve myositis (muscle inflammation, elevated CK value) or its more severe form, rhabdomyolysis (muscle breakdown, CK value > 10,000 IU/L). Statins have also been associated with a rare autoimmune myopathy called immune-mediated necrotizing myopathy (IMNM). IMNM is marked by proximal muscle weakness, elevated CK that persists despite statin discontinuation, anti-HMG CoA reductase antibodies, and necrotizing myopathy on muscle biopsy. Immunosuppressants improve IMNM, and statins should be permanently discontinued.
- As a whole, the risk of muscle toxicity with statins is very low. A study that reviewed a large number of statin trials (35 trials encompassing 74,102 subjects) found no increased risk of muscle toxicity when compared to placebo [PMID 17159064].
- A recent paper from the AHA that reviewed side effects of statins found that the excess risk of myopathy (defined as muscle pain with CK > 10 X ULN) with statins when compared to placebo is < 0.1%. The risk of rhabdomyolysis (defined as CK > 40 X ULN) was found to be around 0.01%. The risk was greater during the first year of therapy, after dose increases, and with the addition of an interacting drug. [62]
- Simvastatin (Zocor®) 80 mg
- In 2011, the FDA issued a warning against using simvastatin at a dose of 80 mg because of an increased risk for muscle toxicity, particularly in the first year of treatment
- The warning stated that patients should not be prescribed simvastatin 80 mg unless they have been taking it for ≥ 1 year without problems
- In a clinical trial database that included 41,413 patients, the incidence of muscle toxicity with simvastatin was as follows:
- Simvastatin 20 mg - 0.03%
- Simvastatin 40 mg - 0.08%
- Simvastatin 80 mg - 0.61% [47]
- AHA 2018 recommendations on statin-induced muscle toxicity
- Statin-induced muscle toxicity is rare
- Routine measurements of creatine kinase (CK) are not useful
- During statin therapy, it is reasonable to measure CK in individuals with severe muscle pain, objective muscle weakness, dark urine, and/or decreased urine output
- Coenzyme Q10 is not recommended for routine use in patients treated with statins or for the treatment of statin-associated muscle symptoms [61]
- Summary
- Statin-induced muscle toxicity is rare
- When statins are taken with certain medications (e.g. gemfibrozil), the risk is increased
- Simvastatin dosed at 80 mg may confer a slightly higher risk of muscle toxicity
- Hepatotoxicity
- Statins can cause liver inflammation resulting in elevated liver enzymes. The risk is greater with higher doses and concomitant hepatotoxins (e.g. alcohol, medications). Liver damage or failure from statins is rare, and statin-induced liver enzyme elevations typically return to normal after discontinuation. A study that pooled the results of 28 statin trials and encompassed over 62,000 patients found that the overall incidence of elevated liver enzymes was 1.4% in statin-treated patients and 1.1% in placebo-treated patients. [PMID 17159064]
- Routine monitoring of liver enzymes used to be recommended with statin therapy, but now the AHA and FDA recommend a selective approach outlined below.
- AHA recommendations on statins and liver toxicity
- Patients with no liver disease
- Routine measurements of liver function tests are not useful
- During statin therapy, it is reasonable to measure hepatic function if symptoms suggesting hepatotoxicity arise (e.g. unusual fatigue or weakness, loss of appetite, abdominal pain, dark colored urine or yellowing of the skin or sclera)
- Patients with stable liver disease including non-alcoholic fatty liver disease and hepatitis C
- There is no need to avoid statin therapy in patients with stable chronic liver disease and normal or modestly elevated transaminases (up to 3 X ULN)
- Obtain baseline measurements, and monitor liver functions periodically depending on the severity of liver disease
- Measure hepatic function if symptoms suggestive of worsening liver disease arise (e.g. unusual fatigue or weakness, loss of appetite, abdominal pain, dark colored urine or yellowing of the skin or sclera) [62]
- FDA recommendations
- The FDA no longer recommends routine monitoring of liver enzymes in patients on statins
- The FDA recommends that liver enzymes be checked before therapy, and as clinically indicated thereafter
- Statins should be stopped or the dose decreased when liver enzymes are greater than 3 times the upper limits of normal
- Fatigue
- Statins may cause fatigue in some patients
- A randomized controlled trial published in the Archives of Internal Medicine compared fatigue outcomes in patients randomized to placebo, simvastatin 20 mg, or pravastatin 40 mg. At 6 months, patients in the simvastatin group reported significantly more fatigue than placebo. [PMID 22688574]
- Diabetes
- In several large clinical trials, statin-treated patients had a higher incidence of diabetes than placebo-treated patients
- A Lancet meta-analysis that pooled 13 trials encompassing over 91,000 patients found the following effect:
- For every 255 patients taking a statin for 4 years, there will be one additional case of diabetes compared to 255 patients not taking statins [23]
- AHA recommendations
- Statin therapy modestly increases the risk of developing diabetes mellitus via mechanisms not yet understood
- The absolute risk of statin-induced diabetes mellitus in major trials has been ∼0.2% per year
- The increased risk of diabetes mellitus should not deter statin use in patients considered to be at sufficiently high CVD risk to warrant statin treatment, although it is prudent both to increase efforts at diabetes mellitus prevention and to screen for the development of diabetes mellitus in patients at elevated risk for diabetes mellitus, especially in those on intensive statin therapy [62]
- Cataracts
- In some animal studies, statins have been shown to induce cataracts
- In humans, some studies have suggested an increased risk of cataracts with statins while others have suggested a decreased risk [24 - 27]
- AHA statement
- The preponderance of the evidence indicates that statins in clinical use do not increase the risk of cataracts [62]
- Cancer
- In trials, statins have been associated with both an increase and decrease in the risk for certain cancers
- Overall, there is no conclusive evidence that statins affect cancer risk [28,29]
- AHA statement
- To the extent that the question can be answered given the constraint that trials longer than 5 to 7 years are not feasible, statins do not cause cancer
- The quantity and quality of cancer incidence data available for statins from trials is probably unmatched by any other drug class [62]
- Steroidogenesis
- Cholesterol is a precursor for the formation of all hormones (e.g. testosterone, glucocorticoids, estrogen)
- Because statins inhibit cholesterol synthesis, there is a theoretical concern that statins may affect steroid production
- Studies have consistently found that statins do not affect steroid hormone production [62]
- AHA statement
- Statins have minimal if any effects on steroidogenesis, and none are clinically relevant
- They might slightly reduce plasma testosterone, but they do not cause hypogonadism, and their effect on erectile function is not adverse and could be beneficial [62]
- Photosensitivity
- Certain statins (simvastatin, atorvastatin, lovastatin, pravastatin) have been associated with photosensitivity
- Some patients may need to limit sun exposure and/or wear sunscreen to prevent reactions [58]
- Proteinuria / hematuria with rosuvastatin
- Rosuvastatin at a dose of 40 mg may cause proteinuria and hematuria. The mechanism of this effect is unknown, but it is typically transient and not associated with worsening kidney function.
- Other statins do not appear to have this effect [62]
- CONTRAINDICATIONS
- Atorvastatin (Lipitor®)
- Acute liver failure or decompensated cirrhosis
- Pregnant or nursing (see pregnant or nursing below)
- Fluvastatin (Lescol®, Lescol XL®)
- Active liver disease
- Pregnant or nursing
- Lovastatin (Mevacor®, Altoprev®)
- Active liver disease
- Pregnant or nursing
- Concomitant therapy with strong CYP3A4 inhibitors
- Pitavastatin (Livalo®, Zypitamag®)
- Acute liver failure or decompensated cirrhosis
- Pregnant or nursing
- Coadministration with cyclosporine
- Pravastatin (Pravachol®)
- Acute liver failure or decompensated cirrhosis
- Rosuvastatin (Crestor®)
- Acute liver failure or decompensated cirrhosis
- Simvastatin (Zocor®)
- Active liver disease
- Pregnant or nursing
- Concomitant therapy with strong CYP3A4 inhibitors
- Concomitant administration of gemfibrozil, cyclosporine, or danazol
- PRECAUTIONS
- Kidney disease
- Atorvastatin (Lipitor®)
- No dose adjustment necessary in kidney disease
- Fluvastatin (Lescol®)
- CrCl ≥ 30 ml/min: no dose adjustment necessary
- CrCl < 30 ml/min: has not been studied at doses greater than 40 mg; use caution
- Lovastatin (Mevacor®)
- CrCl ≥ 30 ml/min: no dose adjustment necessary
- CrCl < 30 ml/min: dosage increases above 20 mg /day should be carefully considered and, if deemed necessary, implemented cautiously
- Pitavastatin (Livalo®)
- CrCl < 60 ml/min: recommended starting dose is 1 mg once daily; do not exceed 2 mg/day
- Pravastatin (Pravachol®)
- CrCl < 30 ml/min: starting dose of 10 mg is recommended
- Rosuvastatin (Crestor®)
- CrCl < 30 ml/min: recommended starting dose is 5 mg once daily; do not exceed 10 mg/day
- Simvastatin (Zocor®)
- CrCl < 30 ml/min: recommended starting dose is 5 mg once daily
- Liver disease
- Statins have been linked to rare cases of hepatotoxicity, and liver enzyme elevations are seen in about 1.4% of patients. All statins used to list active liver disease as a contraindication, but recently, some labels have been updated to say acute liver failure or decompensated cirrhosis, as studies have found statins to be safe and possibly beneficial in some forms of stable liver disease. Recommendations from the AHA on statin use in liver disease are provided below. Guidance on monitoring liver enzymes is covered here - statins and hepatotoxicity. [32,33]
- AHA recommendations
- Statins appear to be safe to use and do not cause progression of liver disease in patients with fatty liver disease or chronic hepatitis C. On that basis, there is no need to avoid statin therapy in patients with stable chronic liver disease and normal or modestly elevated transaminases (up to 3 X ULN)
- There are no reliable data showing that statins are safe in advanced or decompensated liver disease [62]
- Hemorrhagic stroke
- In the SPARCL trial, patients treated with atorvastatin 80 mg had a higher incidence of hemorrhagic stroke than placebo-treated patients (2.3% vs 1.4%); however, the overall stroke risk was lower with atorvastatin (11.2% vs 13.1%). Several observational studies have compared outcomes between statin users and nonusers before and after hemorrhagic strokes; these studies have found no adverse effects of statins on stroke severity or recurrence. [48, 49, 50]
- The Lipitor PI states that providers should consider the risks and benefits of atorvastatin 80 mg in patients with recent hemorrhagic stroke. Recommendations from the AHA are provided below.
- AHA recommendations
- The available data in aggregate show no increased risk of brain hemorrhage with statin use in primary stroke prevention populations. An increased risk in secondary stroke prevention populations is possible, but the absolute risk is very small, and the benefit in reducing overall stroke and other vascular events generally outweighs that risk. [62]
- Asian patients
- Blood levels of some statins run higher in Asians compared to other races. Genetic differences in drug metabolism are likely the cause, and the prescribing information for rosuvastatin and simvastatin recommend lower doses in Asian patients. [52]
- Manufacturer recommendations
- Rosuvastatin: Pharmacokinetic studies have demonstrated an approximate 2‑fold increase in median exposure to rosuvastatin in Asian subjects when compared with Caucasian controls. When treating Asian patients, use a starting dose of 5 mg/day, and consider the risks and benefits of rosuvastatin in patients not adequately controlled at doses up to 20 mg/day.
- Simvastatin: Chinese patients may be at higher risk for myopathy and should be monitored appropriately. In a study of simvastatin 40 mg, the incidence of myopathy was approximately 0.05% for non-Chinese patients (n=7367) compared with 0.24% for Chinese patients (n=5468). Coadministration of simvastatin with lipid-modifying doses (≥ 1 g/day niacin) of niacin-containing products is not recommended in Chinese patients. It is unknown if this risk applies to other Asian patients.
- AHA recommendations
- Pharmacokinetic studies suggest greater plasma concentrations of some statins or their active metabolites in subjects of East Asian ethnicity compared with whites
- Chinese patients appear to be more susceptible to myopathy induced by simvastatin
- Lower doses of statins in East Asians have been recommended by some organizations, as well as in the prescribing information of rosuvastatin and simvastatin. [62]
- Pregnant or nursing
- Some statins list pregnancy as a contraindication based on studies that showed teratogenicity in animals at very high doses. There is also concern that disrupting cholesterol synthesis can affect fetal and newborn development.
- Small observational studies evaluating an association between statins and birth defects have had mixed results. In 2015, a large cohort study (N=886,996) was published that found no significant link. [PMID 25784688]
- In 2019, the AHA published the following statement on statins in pregnancy
- AHA statement on statins in pregnancy
- The available evidence does not suggest any major hazard but also does not prove that statins are safe in pregnancy. All statins therefore remain contraindicated in pregnancy, but a woman exposed to a statin during pregnancy can be reassured that the risk of a fetal abnormality is unlikely to be much greater than the background risk, if it is increased at all.
- Because a definitive answer is not possible, careful screening for congenital abnormalities in utero using ultrasound and other techniques is appropriate in the event of statin exposure in early pregnancy and might provide some assurance to a woman deciding whether to carry the pregnancy to term [62]
- MONITORING STATIN THERAPY
- Lipid profile
- Recheck lipid profile 4 - 12 weeks after initiating or changing statin therapy and every 3 - 12 months thereafter, depending on need [5]
- Liver function tests
- See liver inflammation above
- Creatine kinase
- See muscle toxicity above
- DRUG INTERACTIONS
- NOTE: The drug interactions presented here are NOT all-inclusive. Other interactions may exist. Drug interaction checkers provide the most efficient and practical way to check for interactions among multiple medications. A free interaction checker is available from Drugs.com (see Drugs.com interactions checker).
- All statins
- Antacids (Tums®, Mylanta®, etc) - antacids may decrease statin absorption. Separate statin and antacid dosing by at least 2 hours.
- Bile acid sequestrants (Questran®, Welchol®, Colestid®) - cholestyramine may interfere with the absorption of statins. Statins should be taken one hour before or four hours after cholestyramine is consumed.
- Colchicine (Colcrys®) - colchicine may raise statin levels and increase the risk of toxicity. Consider alternative therapy.
- Fibrates other than gemfibrozil - use caution when combining statins with fibrates. Risk of myopathy may be increased. Do not combine statins with gemfibrozil.
- Gemfibrozil (Lopid®) - DO NOT COMBINE. Gemfibrozil may raise levels of statins and increase the risk for toxicity.
- Niacin - both niacin and statins have been shown to cause muscle toxicity. When taken together, the risk may be greater. Use caution when combining niacin with statins.
- OATP inhibitors - when statins are taken with OATP inhibitors, the risk of muscle toxicity is increased. OATP inhibitors include gemfibrozil (Lopid®), cyclosporine, erythromycin, clarithromycin, etc.
- Warfarin (Coumadin®) - statins may affect warfarin levels. Patients on warfarin should monitor INR levels after starting a statin.
- Atorvastatin (Lipitor®)
- Antifungals (e.g. itraconazole, ketoconazole, and voriconazole) - azole antifungals may increase atorvastatin levels. Atorvastatin doses should not exceed 20 mg/day when taken with itraconazole. Consider the risk/benefit of concomitant use of azole antifungals with atorvastatin. Monitor all patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.
- Cyclosporine - DO NOT COMBINE. Cyclosporine raises atorvastatin levels and may increase the risk of toxicity.
- CYP3A4 inhibitors - combination may increase risk for muscle toxicity
- Digoxin - atorvastatin may increase levels of digoxin. Monitor digoxin levels when starting or changing therapy. [59]
- Grapefruit juice - large quantities of grapefruit juice (> 1.2 liters/day) can raise atorvastatin levels and increase the risk of toxicity. Avoid large intakes of grapefruit juice while taking atorvastatin.
- Harvoni® (ledipasvir and sofosbuvir) - Harvoni can increase blood levels of atorvastatin. Monitor patients closely for statin-related adverse events such as myopathy and rhabdomyolysis when taken together.
- HIV medications - In patients taking lopinavir plus ritonavir, consider the risk/benefit of concomitant use with atorvastatin. In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, or letermovir, atorvastatin dose should not exceed 20 mg/day. In patients taking nelfinavir, atorvastatin dose should not exceed 40 mg/day.
- Letermovir (Prevymis®) - letermovir increases exposure to atorvastatin. Doses of atorvastatin should not exceed 20 mg/day if prescribed concomitantly. In patients receiving cyclosporine and letermovir, atorvastatin is not recommended.
- Macrolide antibiotics (e.g. erythromycin, clarithromycin) - macrolide antibiotics may increase atorvastatin levels. Atorvastatin dose should not exceed 20 mg/day when taken with clarithromycin. Consider the risk/benefit of concomitant use of macrolide antibiotics with atorvastatin. Monitor all patients for signs and symptoms of myopathy particularly during initiation of therapy and during upward dose titration of either drug.
- Mavyret® (Glecaprevir and pibrentasvir) - DO NOT COMBINE. Mavyret may raise atorvastatin levels and increase the risk of toxicity.
- Oral contraceptives - atorvastatin may increase blood levels of ethinyl estradiol by 20 - 25% [60]
- Posaconazole (Noxafil®) - DO NOT COMBINE. Posaconazole is a CYP3A4 strong inhibitor, and it increases atorvastatin exposure.
- Rifampin - rifampin is a CYP3A4 inducer and OATP1B1 inhibitor. When atorvastatin is taken after rifampin, atorvastatin levels may be reduced. To avoid this interaction, atorvastatin and rifampin should be taken simultaneously.
- Tipranavir plus ritonavir - DO NOT COMBINE. Tipranavir plus ritonavir may raise atorvastatin levels and increase the risk of toxicity.
- Zepatier® (Elbasvir and grazoprevir) - atorvastatin dose should not exceed 20 mg/day when combining
- Fluvastatin (Lescol®)
- Cyclosporine - fluvastatin dose should not exceed 20 mg/day when combining
- CYP2C9 substrates and inhibitors - CYP2C9 inhibitors can increase the risk for muscle toxicity, and fluvastatin can increase blood levels of CYP2C9 substrates
- Fluconazole (Diflucan®) - fluvastatin dose should not exceed 20 mg twice a day when combining
- Lovastatin (Mevacor®)
- Amiodarone (Cordarone®) - lovastatin dose should not exceed 40 mg/day when combining
- Conivaptan (Vaprisol®) - DO NOT COMBINE. Conivaptan may raise lovastatin levels and increase risk for toxicity.
- Cyclosporine (Neoral®, etc.) - DO NOT COMBINE cyclosporine with lovastatin. Cyclosporine may raise levels of these statins and increase the risk for toxicity. [59]
- CYP3A4 strong inhibitors - DO NOT COMBINE lovastatin with CYP3A4 strong inhibitors
- Danazol (Cyclomen®) - Lovastatin starting dose should be 10 mg/day. lovastatin dose should not exceed 20 mg/day when combining.
- Diltiazem (Cardizem®) - lovastatin starting dose should be 10 mg/day. Lovastatin dose should not exceed 20 mg/day when combining.
- Dronedarone (Multaq®) - lovastatin starting dose should be 10 mg/day. Lovastatin dose should not exceed 20 mg/day when combining.
- Erythromycin - DO NOT COMBINE lovastatin with erythromycin
- Fibrates other than gemfibrozil - lovastatin dose should not exceed 20 mg/day when combining.
- Niacin - lovastatin dose should not exceed 20 mg/day when combining
- Tacrolimus (Prograf®) - DO NOT COMBINE tacrolimus with simvastatin, lovastatin, and pitavastatin. Tacrolimus may raise levels of statins and increase the risk for toxicity. [59]
- Ranolazine (Ranexa®) - lovastatin dose should not exceed 20 mg/day when combining
- Ticagrelor (Brilinta®) - lovastatin dose should not exceed 40 mg/day when combining
- Verapamil (Calan®, etc.) - lovastatin starting dose should be 10 mg/day. Lovastatin dose should not exceed 20 mg/day when combining.
- Pitavastatin (Livalo®)
- Cyclosporine (Neoral®, etc.) - DO NOT COMBINE cyclosporine with pitavastatin. Cyclosporine may raise levels of these statins and increase the risk for toxicity. [59]
- Erythromycin - pitavastatin dose should not exceed 1 mg/day when combining
- Rifampin - pitavastatin dose should not exceed 2 mg/day when combining
- Tacrolimus (Prograf®) - DO NOT COMBINE tacrolimus with simvastatin, lovastatin, and pitavastatin. Tacrolimus may raise levels of these statins and increase the risk for toxicity. [59]
- Pravastatin (Pravachol®)
- Bempedoic acid (Nexletol®) - bempedoic acid increases pravastatin exposure. Doses of pravastatin should not exceed 40 mg when combining.
- Clarithromycin (Biaxin®) - pravastatin dose should not exceed 40 mg/day when combining
- Erythromycin - pravastatin dose should not exceed 40 mg/day when combining
- Cyclosporine - pravastatin starting dose should be 10 mg/day. Pravastatin dose should not exceed 20 mg/day when combining.
- Rosuvastatin (Crestor®)
- Capmatinib (Tabrecta®) - capmatinib increases rosuvastatin exposure more than 2.1-fold. Rosuvastatin dosing should not exceed 10 mg/day when combining.
- Cyclosporine - cyclosporine increases rosuvastatin exposure 7-fold. Rosuvastatin dosing should not exceed 5 mg/day when combining.
- Darolutamide (Nubeqa®) - darolutamide increases rosuvastatin exposure more than 5-fold. Rosuvastatin dosing should not exceed 5 mg/day when combining.
- Epclusa® (sofosbuvir and velpatasvir) - Epclusa increases rosuvastatin exposure. Use a starting dose of 5 mg/day and do not exceed 10 mg/day when combining.
- Febuxostat (Ullori®) - febuxostat increases rosuvastatin exposure more than 1.9-fold. Rosuvastatin dosing should not exceed 20 mg/day when combining.
- Fostamatinib (Tavalisse®) - fostamatinib increases rosuvastatin exposure more than 2-fold. Rosuvastatin dosing should not exceed 20 mg/day when combining.
- Harvoni™ (ledipasvir and sofosbuvir) - DO NOT COMBINE. Harvoni increases rosuvastatin exposure.
- HIV protease inhibitors (lopinavir or atazanavir + ritonavir) - rosuvastatin exposure is increased. Use a starting dose of 5 mg/day and do not exceed 10 mg/day.
- Mavyret® (glecaprevir and pibrentasvir) - rosuvastatin exposure is increased. Use a starting dose of 5 mg/day and do not exceed 10 mg/day.
- Oral contraceptives - rosuvastatin and atorvastatin may increase blood levels of ethinyl estradiol by 20 - 25% [60]
- Regorafenib (Stivarga®) - regorafenib increases rosuvastatin exposure. Rosuvastatin dosing should not exceed 10 mg/day when combining.
- Tafamidis (Vyndaqel®) - tafamidis can cause myopathy, and it increases rosuvastatin exposure. Concomitant use should be avoided if possible. If taken together, initiate rosuvastatin at 5 mg/day and do not exceed 10 mg/day.
- Teriflunomide (Aubagio®) - teriflunomide increases rosuvastatin exposure more than 2.5-fold. Rosuvastatin dose should not exceed 10 mg/day when combining.
- Viekira pak™ (ombitasvir, paritaprevir, dasabuvir, ritonavir) - Viekira pak increases rosuvastatin exposure. Use a starting dose of 5 mg/day and do not exceed 10 mg/day.
- Vosevi™ (sofosbuvir, velpatasvir, voxilaprevir) - DO NOT COMBINE. Rosuvastatin exposure is increased.
- Warfarin - rosuvastatin may increase the anticoagulant effect of warfarin. Monitor INR values closely when combining, particularly during initiation, dose changes, and discontinuation.
- Zepatier® (elbasvir and grazoprevir) - Zepatier increases rosuvastatin exposure. Use a starting dose of 5 mg/day and do not exceed 10 mg/day.
- Simvastatin (Zocor®)
- Amiodarone (Cordarone®) - simvastatin dose should not exceed 20 mg/day when combining
- Amlodipine (Norvasc®) - simvastatin dose should not exceed 20 mg/day when combining
- Bempedoic acid (Nexletol®) - bempedoic acid increases simvastatin exposure. Doses of simvastatin should not exceed 20 mg when combining.
- Conivaptan (Vaprisol®) - DO NOT COMBINE. Conivaptan may raise simvastatin levels and increase risk for toxicity.
- Cyclosporine (Neoral®, etc.) - DO NOT COMBINE cyclosporine with simvastatin. Cyclosporine may raise levels of these statins and increase the risk for toxicity. [59]
- CYP3A4 strong inhibitors - DO NOT COMBINE simvastatin with CYP3A4 strong inhibitors
- Danazol (Cyclomen®) - DO NOT COMBINE. Danazol may raise simvastatin levels and increase the risk of toxicity.
- Daptomycin - DO NOT COMBINE. Both drugs can cause rhabdomyolysis and myopathy, and the risk may be greater when taken together. Temporarily suspend simvastatin if daptomycin must be given.
- Diltiazem (Cardizem®) - simvastatin dose should not exceed 10 mg/day when combining. Diltiazem dose should not exceed 240 mg/day when combining.
- Dronedarone (Multaq®) - simvastatin dose should not exceed 10 mg/day when combining.
- Erythromycin - DO NOT COMBINE simvastatin with erythromycin
- Lomitapide (Juxtapid®) - lomitapide increases simvastatin exposure two-fold, raising the risk of myopathy. Reduce simvastatin dose by 50% when starting lomitapide and do not exceed 20 mg daily (or 40 mg daily for patients who have previously taken an 80 mg daily dosage of simvastatin chronically).
- Niacin - DO NOT COMBINE niacin (≥ 1 gram/day) with simvastatin in Chinese patients. See Asian patients above.
- Ranolazine (Ranexa®) - simvastatin dose should not exceed 20 mg/day when combining
- Tacrolimus (Prograf®) - DO NOT COMBINE tacrolimus with simvastatin, lovastatin, and pitavastatin. Tacrolimus may raise levels of these statins and increase the risk for toxicity. [59]
- Ticagrelor (Brilinta®) - simvastatin dose should not exceed 40 mg/day when combining
- Verapamil (Calan®, etc.) - simvastatin dose should not exceed 10 mg/day when combining.
- Metabolism and clearance
- Atorvastatin (Lipitor®)
- CYP3A4 - Substrate
- P-glycoprotein - Substrate and inhibitor
- OATP1B1 and OATP1B3 - Substrate
- Fluvastatin (Lescol®)
- CYP2C9 - Major substrate and weak inhibitor
- CYP3A4 - Minor substrate
- CYP2C8 - Minor substrate
- P-glycoprotein - Substrate and inhibitor
- OATP1B3 - Substrate
- Lovastatin (Mevacor®)
- CYP3A4 - Sensitive substrate
- P-glycoprotein - Substrate and inhibitor
- OATP1B1 - Substrate
- Pitavastatin (Livalo®)
- CYP2C9 - Substrate
- CYP2C8 - Minor substrate
- P-glycoprotein - Substrate
- OATP1B1 - Substrate
- Pravastatin (Pravachol®)
- P-glycoprotein - Substrate
- OATP1B1 and OATP1B3 - Substrate
- Rosuvastatin (Crestor®)
- Simvastatin (Zocor®)
- CYP3A4 - Substrate
- CYP2C8 - Substrate and inhibitor
- P-glycoprotein - Substrate and inhibitor
- OATP1B1 - Substrate
- DOSING
- See statin dosing
- LONG-TERM SAFETY
- Statins have been in use since 1987
- They have been prescribed to millions of people and their safety has been evaluated in a large number of trials
- Statins have consistently been shown to be safe in long-term use
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