STATINS















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%)
  • Atorvastatin (Lipitor®) 40 - 80 mg/day
  • Rosuvastatin (Crestor®) 20 - 40 mg/day
  • Atorvastatin (Lipitor®) 10 - 20 mg/day
  • Rosuvastatin (Crestor®) 5 - 10 mg/day
  • Simvastatin (Zocor®) 20 - 40 mg/day
  • Pravastatin (Pravachol®) 40 - 80 mg/day
  • Lovastatin (Mevacor®) 40 mg/day
  • Fluvastatin XL (Lescol XL®) 80 mg/day
  • Fluvastatin (Lescol®) 40 mg twice/day
  • Pitavastatin (Livalo®) 2 - 4 mg/day
  • Simvastatin (Zocor®) 10 mg/day
  • Pravastatin (Pravachol®) 10 - 20 mg/day
  • Lovastatin (Mevacor®) 20 mg/day
  • Fluvastatin (Lescol®) 20 - 40 mg/day
  • Pitavastatin (Livalo®) 1 mg/day


  • Ranges are from lowest dose of drug to highest
  • Ranges are derived from an average of the studies presented in each manufacturer's package insert
  • At higher doses, some statins have less of an effect on HDL so the "percent increase" may decrease
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%



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
LIPID study - Pravastatin vs Placebo for Secondary Prevention of Heart Disease, NEJM (1998) [PubMed abstract]
  • 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
  • The incidence of side effects including elevated liver enzymes, elevated CK, and myopathy were similar between the 2 groups
  • LDL cholesterol over the first 5 years of the study averaged 25% lower in the pravastatin group when compared to the placebo group
  • By the end of the study, 24% of the patients in the placebo group were taking cholesterol-lowering therapy [9]

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.
Heart Protection Study - Simvastatin vs Placebo for the Prevention of Heart Disease, Lancet (2002) [PubMed abstract]
  • 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
  • Over the course of the study, the average LDL was 39 mg/dl lower in the simvastatin group
  • There was no significant difference between the two groups for the incidence of elevated liver enzymes, elevated CK, and muscle aches
  • Over the course of the study, 17% of the patients in the placebo group used a statin [3]

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 guidelines
  • Statins are universally recommended for patients with heart disease by professional organizations



Primary prevention of CVD
  • 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.
AFCAPS - Lovastatin vs Placebo for the Primary Prevention of Heart Disease, JAMA (1998) [PubMed abstract]
  • 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
  • Average LDL after 1 year: Group 1 - 115 mg/dl, Group 2 - 156 mg/dl
  • There was no significant difference between the two groups for the incidence of elevated liver enzymes, elevated CK, and muscle aches leading to discontinuation [1]

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.
HOPE-3 trial - Rosuvastatin vs Placebo for Primary Prevention of CVD, NEJM (2016) [PubMed abstract]
  • 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
  • At 1 year, the average LDL was 39.6 mg/dl lower in Group 1 than Group 2
  • More patients in Group 1 complained of muscle pain or weakness (5.8% vs 4.7%, p=0.005)
  • More patients in Group 1 underwent cataract surgery (3.8% vs 3.1%, p=0.02)
  • There was no significant difference between the groups for new-onset diabetes (Group 1 - 3.9%, Group 2 - 3.8%, p=0.82)
  • There was no significant difference between the groups in liver function abnormalities or cancer incidence
  • Fewer patients in Group 1 than Group 2 had deep-vein thrombosis or pulmonary embolism (14 vs 31, hazard ratio, 0.45, 95% CI [0.24 to 0.84], p=0.01)

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 guidelines



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
SPARCL trial - Atorvastatin vs Placebo for Secondary Stroke Prevention, NEJM (2006) [PubMed abstract]
  • 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
Liver enzymes >3 X ULN on 2 consecutive labs: 2.2% 0.5% N/A
  • The average LDL level throughout the study was 73 mg/dl in Group 1 and 129 mg/dl in Group 2 [43]

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
  • In patients without known heart disease, statin therapy with "intensive lipid-lowering effects" is indicated if the stroke or TIA is presumed to be of atherosclerotic origin
  • In patients with known heart disease, therapy should follow the recommendations from the AHA lipid management guidelines [46]
StraightHealthcare analysis
  • 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).



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
PROVE-IT study - Atorvastatin vs Pravastatin in the Secondary Prevention of CVD, NEJM (2004) [PubMed abstract]
  • 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.
IDEAL study - Atorvastatin vs Simvastatin in the Secondary Prevention of CVD, JAMA (2005) [PubMed abstract]
  • 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
  • By the end of the study, 23% of patients in the simvastatin group were taking a dose of 40 mg

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.
SATURN study - Atorvastatin vs Rosuvastatin in the Secondary Prevention of CVD, NEJM (2011) [PubMed abstract]
  • 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



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.
TNT study - Atorvastatin 80 mg vs Atorvastatin 10 mg, NEJM (2005) [PubMed abstract]
  • 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 myocardial infarction 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
Liver enzymes >3 X ULN on two consecutive measurements 0.2% 1.2% p<0.001
Drug discontinuation due to adverse events 5.3% 7.2% p<0.001
  • There were no persistent elevations of CK in either group

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.
SEARCH trial - Simvastatin 80 mg vs Simvastatin 20 mg, Lancet (2010) [PubMed abstract]
  • 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
  • The average LDL in the 80 mg group was 13.5 mg/dl lower than Group 2 over the course of the study

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 significantly better outcomes in the TNT trial that were not seen 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)



Muscle pain (myalgias)
The AHA 2018 guidelines recommend the following for managing statin-induced myalgias: StraightHealthcare analysis

Muscle toxicity
Simvastatin (Zocor®) 80 mg AHA 2018 recommendations on statin-induced muscle toxicity StraightHealthcare analysis

Liver inflammation
AHA recommendations on statins and liver toxicity FDA recommendations:

Fatigue

Diabetes
AHA recommendations StraightHealthcare analysis

Cataracts
AHA statement

Cancer
AHA statement

Steroidogenesis
AHA statement

Photosensitivity

Proteinuria / hematuria with rosuvastatin





Kidney disease dosing recommendations
Creatinine clearance / GFR
Drug < 30 ml/min 30 - 59 ml/min ≥ 60 ml/min
Atorvastatin No change No change No change
Fluvastatin Has not been studied No change No change
Lovastatin For doses > 20 mg/d, use caution No change No change
Pitavastatin Start 1 mg/d | Max 2 mg/d Start 1 mg/d | Max 2 mg/d No change
Pravastatin Start 10 mg/d, use caution No change No change
Rosuvastatin Start 5 mg/d | Max 10 mg/d No change No change
Simvastatin Start 5 mg/d, monitor closely No change No change

Liver disease
AHA recommendations

Hemorrhagic stroke
AHA recommendations StraightHealthcare analysis

Asian patients
Manufacturer recommendations AHA recommendations

Pregnant or nursing
AHA recommendations



Drug interactions

All statins
  • Antacids (Tums®, Mylanta®, etc) - antacids may decrease the absorption of statins and they should be taken 2 hours apart
  • Bile acid sequestrants (Questran®, Welchol®, Colestid®) - cholestyramine may interfere with the absorption of statins. Statins should be taken one hour before or 4 hours after cholestyramine is consumed.
  • Colchicine (Colcrys®) - colchicine may raise levels of statins and increase the risk for 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®)
  • Clarithromycin (Biaxin®) - when combining atorvastatin and clarithromycin, use caution if atorvastatin dose exceeds 20 mg/day
  • Cyclosporine - DO NOT COMBINE atorvastatin with cyclosporine
  • 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]
  • HIV protease inhibitors (Lopinavir, ritonavir, atazanavir, etc) - atorvastatin dose should not exceed 20 mg/day when combining
  • Itraconazole (Sporanox®) - use caution if atorvastatin dose exceeds 20 mg/day
  • Oral contraceptives - rosuvastatin and atorvastatin may increase blood levels of ethinyl estradiol by 20 - 25% [60]
  • Simeprevir (Olysio®) - atorvastatin dose should not exceed 40 mg/day when combining
  • 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®)
  • Clarithromycin (Biaxin®) - 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®)
  • Cyclosporine - rosuvastatin dose should not exceed 5 mg/day when combining
  • Harvoni™ - DO NOT COMBINE. Combination may increase risk for muscle toxicity.
  • HIV protease inhibitors (Lopinavir, ritonavir, atazanavir, etc) - rosuvastatin dose should not exceed 10 mg/day when combining
  • Oral contraceptives - rosuvastatin and atorvastatin may increase blood levels of ethinyl estradiol by 20 - 25% [60]
  • Simeprevir (Olysio®) - rosuvastatin dose should not exceed 10 mg/day when combining
  • Teriflunomide (Aubagio®) - rosuvastatin dose should not exceed 10 mg/day when combining

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
  • 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
  • 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
  • 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.

  • Reference: [Manufacturer's PI, CYP and transporter pages, 62]
  • OATP - Organic anion transporting polypeptide
Statin metabolism and clearance
Drug CYP3A4 CYP2C8 CYP2C9 P-glycoprotein OATP1B1 OATP1B3
Atorvastatin Substrate - - Substrate and inhibitor Substrate Substrate
Fluvastatin Minor substrate Minor substrate Major substrate and weak inhibitor Substrate and inhibitor - Substrate
Lovastatin Sensitive substrate - - Substrate and inhibitor Substrate -
Pitavastatin - Minor substrate Substrate Substrate Substrate -
Pravastatin - - - Substrate Substrate Substrate
Rosuvastatin - - Minor substrate - Substrate Substrate
Simvastatin Substrate Substrate and inhibitor - Substrate and inhibitor Substrate -










Kidney disease

ACE inhibitors and statins in adolescents with type 1 diabetes, NEJM (2017) [PubMed abstract]
  • Design: Randomized, 2X2 factorial, placebo-controlled trial (N=443, length=2.6 years)
  • Treatment: ACE inhibitor vs Statin vs ACE inhibitor + Statin vs Placebo
  • Primary outcome: Change in albumin excretion, assessed according to the albumin-to-creatinine ratio calculated from three early-morning urine samples obtained every 6 months over 2 to 4 years, and expressed as the area under the curve.
  • Findings: The use of an ACE inhibitor and a statin did not change the albumin-to-creatinine ratio over time

Simvastatin + ezetimibe in patients with chronic kidney disease, Lancet (2011) [PubMed Abstract]
  • Design: Randomized controlled trial comparing heart disease outcomes in patients with chronic kidney disease taking Vytorin® versus placebo
  • Findings: Vytorin® group had absolute risk reduction of 2.1% for major atherosclerotic event. There was no significant difference in overall mortality. (median follow-up 4.9 years)

Rosuvastatin in patients on dialysis, NEJM (2009) [PubMed Abstract]
  • Design: Randomized controlled trial of rosuvastatin versus placebo in patients receiving dialysis
  • Findings: Rosuvastatin had no significant effect on cardiovascular outcomes or mortality (median follow-up 3.8 years)

Perioperative studies

Perioperative rosuvastatin in cardiac surgery, NEJM (2016) [PubMed Abstract]
  • Design: Randomized, placebo-controlled trial
  • Findings: In this trial, perioperative statin therapy did not prevent postoperative atrial fibrillation or perioperative myocardial damage in patients undergoing elective cardiac surgery

High-dose perioperative atorvastatin and acute kidney injury following cardiac surgery, JAMA (2016) [PubMed Abstract]
  • Design: Randomized, placebo-controlled trial
  • Findings: Among patients undergoing cardiac surgery, high-dose perioperative atorvastatin treatment compared with placebo did not reduce the risk of AKI overall, among patients naive to treatment with statins, or in patients already taking a statin. These results do not support the initiation of statin therapy to prevent AKI following cardiac surgery.

Respiratory disease

Simvastatin in adult respiratory distress syndrome (ARDS), NEJM (2014) [PubMed Abstract]
  • Design: Randomized controlled trial of simvastatin vs placebo in patients with ARDS
  • Findings: Simvastatin therapy, although safe and associated with minimal adverse effects, did not improve clinical outcomes in patients with ARDS

Simvastatin for the prevention of exacerbations in moderate-to-severe COPD, NEJM (2014) [PubMed Abstract]
  • Design: Randomized controlled trial of simvastatin vs placebo in patients with COPD
  • Findings: Simvastatin at a daily dose of 40 mg did not affect exacerbation rates or the time to a first exacerbation in patients with COPD who were at high risk for exacerbations.

Rosuvastatin for sepsis-associated acute respiratory distress syndrome, NEJM (2014) [PubMed Abstract]
  • Design: Randomized controlled trial of rosuvastatin vs placebo in patients with ARDS
  • Findings: Rosuvastatin therapy did not improve clinical outcomes in patients with sepsis-associated ARDS and may have contributed to hepatic and renal organ dysfunction

Simvastatin and ventilator-associated pneumonia (VAP), JAMA (2013) [PubMed Abstract]
  • Design: Randomized controlled trial of simvastatin vs placebo in patients with VAP
  • Findings: Simvastatin did not improve 28-day mortality

Alzheimer's disease

Simvastatin in Alzheimer's disease, Neurology (2011) [PubMed Abstract]
  • Design: Randomized controlled trial of simvastatin versus placebo in slowing the progression of Alzheimer's disease
  • Findings: Simvastatin had no significant effect on Alzheimer's disease progression