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i. Twelve or 30 Months of Dual Antiplatelet Therapy After Drug-Eluting Stents (DAPT study)
(a) A total of 9961 patients were enrolled after drug-eluting stent (DES) placement. After
12 months of treatment with either clopidogrel or prasugrel plus aspirin, patients were
randomly assigned to continue either DAPT or aspirin monotherapy for an additional 18
(b) Co-primary efficacy end points: Stent thrombosis and major adverse CV and cerebrovascular events occurring between 12 to 30 months(c) Primary safety end point: Moderate or severe bleeding
(d) Patients in the DAPT group had a reduced rate of stent thrombosis (hazard ratio 0.29; 95%
CI, 0.17-0.48; p<0.001) and major adverse CV and cerebrovascular events (4.3% vs. 5.9%;
hazard ratio 0.71; 95% CI, 0.59-0.85; p<0.001).
(e) Moderate or severe bleeding was higher in the DAPT group (2.5% vs. 1.6%, p=0.001).
(f) All-cause mortality was 2.0% in the DAPT group versus 1.5% in the aspirin monotherapy
group (hazard ratio 1.36; 95% CI, 1.00-1.85; p=0.05).
(g) DAPT trial sub-analysis introduced the DAPT score, which weighs bleeding risk beyond
one year after PCI. (See Table 9)
(1) Score: -2 to 10
(2) Score of 2 or above: NNT to prevent ischemic event=34; NNH bleeding=272
(3) Limitations: modest discrimination, can only be applied to DAPT population, and
confirmation is needed.
ii. Long-term use of ticagrelor in patients with prior myocardial infarction (PEGASUS-TIMI 54)
(a) Evaluation of prolonged use of ticagrelor in patients older than 50 years who had a prior
MI 1 to 3 years before enrollment plus at least one additional risk factor (65 years of age
or older, diabetes mellitus requiring medication, second prior spontaneous MI, multivessel
CAD, chronic renal dysfunction)
(b) Patients were randomly assigned to one of two doses of ticagrelor (90 mg twice daily or 60
mg twice daily) or placebo; all patients received aspirin.
(c) Primary efficacy end point: CV death, MI, and stroke
(d) Primary safety end point: TIMI major bleeding
(e) The primary efficacy end point was significantly reduced in both ticagrelor groups
compared with placebo.
(1) Ticagrelor 90 mg twice daily versus placebo: 7.85% versus 9.04% (hazard ratio 0.85;
95% CI, 0.75-0.96, p=0.008)
(2) Ticagrelor 60 mg twice daily versus placebo: 7.77% versus 9.04% (hazard ratio 0.84;
95% CI, 0.75-.095, p=0.004)
(f) TIMI major bleeding events were higher with ticagrelor (2.60% with 90 mg twice daily vs.
2.30% with 60 mg twice daily vs. 1.06% with placebo; p<0.001 for each ticagrelor dose
vs. placebo)
a. Identified four groups that benefit from statin therapy to reduce ASCVD events for primary and
secondary prevention
i. Clinical ASCVD - Acute coronary syndromes, or a history of MI, stable or unstable angina,
coronary or other arterial revascularization, stroke, TIA, or atherosclerotic PAD
(a) Age 75 or younger - High-intensity statin recommended
(b) Older than 75 years - Moderate-intensity statin recommended
ii. Primary elevations of LDL-C greater than 190 mg/dL - High-intensity statin recommended
iii. Patients with diabetes, 40-75 years of age, with LDL-C of 70-189 mg/dL and without clinical
(a) Estimated 10-year risk of ASCVD at least 7.5% - High-intensity statin recommended
(b) Estimated 10-year risk of ASCVD less than 7.5% - Moderate-intensity statin recommended
iv. No clinical ASCVD or diabetes with LDL-C of 70-189 mg/dL and estimated 10-year ASCVD
risk greater than 7.5%, age 40-75 years - Moderate- to high-intensity statin recommended
(a) Can consider moderate-intensity statin therapy if ASCVD risk ranges from 5% to less than
(b) The potential for adverse effects may outweigh the potential for ASCVD risk reduction in the group with ASCVD risk of 5% to less than 7.5%.
b. ASCVD prevention benefit of statin therapy may be less clear in other groups.
i. May consider other risk factors for ASCVD risk
ii. Primary LDL-C of 160 mg/dL or greater or other evidence of genetic hyperlipidemias
iii. Family history of premature ASCVD with onset before 55 years of age in a first-degree male
relative or before 65 years of age in a first-degree female relative
iv. hs-CRP greater than 2 mg/L
v. Coronary artery calcium score of 300 Agatston units or greater or 75th percentile or greater for
age, sex, and ethnicity
vi. ABI less than 0.9
vii. Elevated lifetime risk of ASCVD
(1) Prevention of CHD with pravastatin in men with hypercholesterolemia (WOSCOPS trial)
(A) Pravastatin 40 mg versus placebo for 5 years in 6595 male patients
(B) Reduction in acute coronary event: 31%; reduction in death from CV causes: 32%;
reduction in all-cause mortality not statistically significant
(2) Pravastatin in elderly individuals at risk of vascular disease (PROSPER trial)
(A) Pravastatin 40 mg versus placebo for 3.2 years in 5804 older patients (about 45%
had preexisting vascular disease)
(B) Reduction in coronary events/stroke: 15%; reduction in CHD mortality: 24%(3) Major outcomes in moderately hypercholesterolemic, hypertensive patients randomly
assigned to receive pravastatin versus usual care: The Antihypertensive and LipidLowering
Treatment to Prevent Heart Attack Trial (ALLHAT-LLT)
(A) Pravastatin 40 mg versus usual care for 4.8 years in 10,355 hypertensive patients
(B) No difference in mortality or coronary events
(4) Prevention of coronary and stroke events with atorvastatin in hypertensive patients
who have average or lower-than-average cholesterol concentrations, in the AngloScandinavian
Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA) trial
(A) Atorvastatin 10 mg versus placebo for 3.3 years in 19,342 hypertensive patients
(B) Reduction in coronary events: 29%; no difference in all-cause mortality
(5) Rosuvastatin to prevent vascular events in men and women with elevated CRP
(JUPITER trial)
(A) Rosuvastatin 20 mg versus placebo in healthy men and women with LDL-C less than 130 mg/dL and CRP greater than 1.9 mg/L
(B) Primary end points: Composite of MI, stroke, revascularization, hospitalization for UA, or death from CV causes
(C) Reduction in composite end point (MI, stroke, arterial revascularization, hospitalization for UA, or death from CV causes): 44%; number needed to treat: 25
(D) Reduction in all-cause mortality: 20%
(E) Study was terminated early because of the observed treatment benefit, as well as
the effects on death rates and other secondary end points.
(F) The FDA approved the expanded indication.
(1) Randomized trial of cholesterol lowering in 4444 patients with CHD: The Scandinavian
Simvastatin Survival Study (4S) trial
(A) Simvastatin 10-40 mg versus placebo for 5.4 years in 4444 patients
(B) Reduction in coronary events: 34%; reduction in all-cause mortality: 30%
(2) Prevention of CV events and death with pravastatin in patients with CHD and a broad
range of initial cholesterol concentrations (Long-Term Intervention with Pravastatin in
Ischaemic Disease [LIPID] trial)
(A) Pravastatin 40 mg versus placebo for 6 years in 9014 patients
(B) Reduction in coronary events (fatal CHD or nonfatal MI): 24%; reduction in allcause
mortality: 22%
(3) MRC/BHF (British Heart Foundation) Heart Protection Study of cholesterol lowering
with simvastatin in 20,536 high-risk individuals: A randomized placebo-controlled
trial (HPS trial)
(A) Simvastatin 40 mg versus placebo for 5 years in 20,536 patients
(B) Reduction in major vascular events: 24%; reduction in all-cause mortality: 13%
(C) Statin therapy is beneficial for high-risk patients with low-normal cholesterol
concentrations as well as for patients older than 70 years.
(D) Consider statin therapy for anyone who is at increased risk of vascular disease,
regardless of cholesterol concentrations.
(4) Intensive versus moderate lipid lowering with statins after ACSs (PROVE-IT - TIMI
22 trial)
(A) Within 10 days of MI, patients randomly assigned to receive 40 mg of pravastatin
(median achieved LDL-C 95 mg/dL) versus 80 mg of atorvastatin (median achieved
LDL-C 62 mg/dL)(B) Compared with the pravastatin group, 16% reduction in primary end point (allcause
mortality, MI, revascularization) in the atorvastatin group. Absolute risk
reduction of 3.9% in the atorvastatin group.
(C) Initiate statin therapy immediately after ACS event, regardless of lipid status.
(D) Consider a lower LDL-C goal, especially in very high-risk patients.
(5) Intensive lipid lowering with atorvastatin in patients with stable coronary disease
(Treating to New Targets [TNT] trial)
(A) Atorvastatin 10 mg versus 80 mg for 4.0 years in 10,001 patients
(B) Mean LDL-C concentrations were 77 mg/dL during treatment with 80 mg of
atorvastatin and 101 mg/dL during treatment with 10 mg of atorvastatin.
(C) Reduction in major vascular events: 22%; no difference in reduction of mortality
(A) The FDA's review of the Study of the Effectiveness of Additional Reductions in
Cholesterol and Homocysteine (SEARCH) trial and other data prompted label
changes for simvastatin.
(B) SEARCH was a 7-year, randomized, double-blind clinical trial comparing the
efficacy and safety of simvastatin 80 mg with simvastatin 20 mg in survivors of MI.
• Safety
Myopathy: Fifty-two patients (0.9%) in the 80-mg group versus one patient
(0.02%) in the 20-mg group
Rhabdomyolysis: Twenty-two patients (0.4%) in the 80-mg group versus no
patient in the 20-mg group
The risks of myopathy and rhabdomyolysis with simvastatin 80 mg were
highest in the first 12 months of treatment.
The findings from the SEARCH trial are supported by analyses of the
FDA's Adverse Event Reporting System database.
• Efficacy
Nonsignificant 0.6% absolute risk reduction in the primary end point of CV
death, MI, stroke, or arterial revascularization (24.5% vs. 25.7%; RR 0.94;
95% CI, 0.88-1.01) with 80 mg versus 20 mg of simvastatin treatment for a mean of 6.7 years
Nonfatal MI reduced from 7.7% to 6.6% with high-dose simvastatin (RR 0.85; 95% CI, 0.75-0.99)(3) Myalgias usually occur without CK elevation.
(A) Manage by holding drug for a few weeks to see whether symptoms improve.
(B) Consider a retrial (with a lower dose of original statin or a different statin).
Hydrophilic statins (e.g., pravastatin and rosuvastatin) theoretically decrease statin
entry into the skeletal muscle and may be tried in patients with a history of myalgias.
However, hydrophilic statins have not been studied in a direct comparison with
more lipophilic statins to determine whether this theory holds.
(a) Lipid panel
(1) Check 4-12 weeks after statin initiation or titration.
(2) Check every 3 to 12 months thereafter, mainly to assess for adherence.
(3) Decrease in statin dose may be considered when two consecutive LDL-C values are
below 40 mg/dL.
(b) LFTs (usually ALT): The FDA revised labels in February 2012 to remove the need for
routine periodic monitoring of liver enzymes in patients taking statins.
(1) LFTs performed before starting statin therapy and as clinically indicated thereafter
(2) Serious liver injury with statins is rare and unpredictable in individual patients,
and routine periodic monitoring of liver enzymes does not appear to be effective in
detecting or preventing serious liver injury.
(3) If liver enzymes are elevated, important to exclude other etiologies such as viral
hepatitis, alcohol consumption, steatosis, or other drug-related causes
(c) Creatine kinase (CK)
(1) Baseline levels not necessary unless patient is at risk of myopathy (renal or hepatic
dysfunction; concomitant agent that affects statin metabolism; personal or family
history of statin intolerance or muscle disease)
(2) Routine monitoring not necessary in asymptomatic patients. Most CK elevations
during statin therapy are benign and caused by other factors, such as physical exertion,
infection, long periods of immobility, seizures, drugs/toxins, trauma, electrolyte
abnormalities, and low thyroid hormone concentration.
(3) Monitor CK in symptomatic patients, in addition to evaluating thyroid function, renal
and hepatic function, rheumatologic disorders, vitamin D deficiency, and exacerbating
factors (drug-drug interactions, including OTC medications [red yeast rice] and foods
[grapefruit juice]). If patient has intolerable muscle symptoms, do the following:
(A) Hold statin regardless of CK value until patient is asymptomatic. If symptoms do
not resolve within a few weeks, then they are not likely caused by statin therapy.
(B) Once the symptoms have resolved (or a few weeks have passed without change in
symptoms), the same statin (at a lower dose) or another statin can be reinitiated to
test the reproducibility of symptoms.
(C) Recurrence of symptoms with many statins and statin doses requires the use of
other lipid-lowering agents.
(4) If patient has no muscle symptoms or if muscle symptoms are tolerable and CK
elevation is mild (less than 10 times the ULN), statin therapy can be continued at the
same or reduced dose.
(5) If the CK elevation is moderate or severe or if rhabdomyolysis occurs, statin therapy
should be discontinued, and the risk-benefit of statin therapy should be weighed.
(d) Other laboratory values to consider: Renal function (see Chronic Kidney Disease section
(a) Simvastatin with or without ezetimibe in familial hypercholesterolemia (ENHANCE trial)
(1) Simvastatin 80 with or without ezetimibe for 2 years in 720 patients with familial dyslipidemia
(2) Primary end point was the change in carotid artery intima-media thickness.
(3) Baseline LDL-C 319 mg/dL(4) LDL-C reduced by 39% with simvastatin monotherapy and 56% with ezetimibe/simvastatin
(5) No statistically significant difference found for primary end point
(b) Intensive lipid lowering with Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial
(1) Ezetimibe/simvastatin 10/40 mg versus placebo
(2) A total of 1873 older patients with aortic valve stenosis
(3) Primary end point: Aortic stenosis and CV events
(4) LDL-C reduced by 4% in the placebo group and 54% with ezetimibe/simvastatin
(5) No statistically significant difference found in primary end point. Cancer occurred
statistically more often in the ezetimibe/simvastatin group (likely incidental finding).
(c) The effects of lowering LDL-C with simvastatin plus ezetimibe in patients with CKD
(Study of Heart and Renal Protection [SHARP] trial): A randomized placebo-controlled
(1) Simvastatin 20 mg plus ezetimibe 10 mg/day versus matching placebo
(2) A total of 9270 patients with CKD (3023 on dialysis and 6247 not) with no known
history of MI or coronary revascularization
(3) Outcome was the first major atherosclerotic event (nonfatal MI or coronary death,
nonhemorrhagic stroke, or any arterial revascularization procedure).
(4) Seventeen percent proportional reduction in major atherosclerotic events (526 [11.3%]
simvastatin plus ezetimibe versus 619 [13.4%] placebo; RR 0.83; 95% CI, 0.74-0.94;
log-rank p=0.0021)
(5) In November 2011, FDA advisers recommended Vytorin for CVD prevention at predialysis
for patients with CKD.
(d) The IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVEIT):
A multicenter randomized controlled trial
(1) Simvastatin 40 mg plus ezetimibe 10 mg/day versus simvastatin 40 mg/day
(2) A total of 18,144 high-risk patients who were enrolled within 10 days after
hospitalization for ACS. Patients were followed up an average of 7 years.
(3) The primary outcome (composite CV death, MI, UA, and coronary rization)
was reduced in the ezetimibe/simvastatin group as compared with the simvastatinalone
group (32.7% vs. 34.7%; hazard ratio 0.94; 95% CI, 0.89-0.99; p=0.016).
(4) Compared with simvastatin alone, the simvastatin/ezetimibe group had a 6.4% lower
risk of all CV events, 14% lower risk of heart attack or stroke, and a 21% lower risk of ischemic stroke. There was no significant difference in CV death between the two groups.
(5) This is the first trial to show a decrease in CV outcomes when adding a nonstatin lipidlowering
agent to statin therapy.
(a) Clofibrate and niacin in the Coronary Drug Project
(1) IR niacin versus placebo in 8341 patients with a history of MI
(2) The niacin treatment arm had an 11% decrease in coronary mortality.
(b) Extended-release (ER) niacin or ezetimibe and carotid intima-media thickness
(ARBITER-6 trial)
(1) Niaspan 2 g/day versus ezetimibe in 363 patients with CHD or a CHD risk equivalent
(2) Baseline LDL-C less than 100 mg/dL; HDL-C less than 50 mg/dL when taking statins
(3) Niaspan significantly reduced carotid artery intima-media thickness progression
compared with ezetimibe when used in combination with statins. (Unknown whether
improvement in carotid artery intima-media thickness or as revealed by intravascular
ultrasound translates to improved clinical outcomes.)
(c) Niacin for patients with low HDL-C concentrations receiving intensive statin therapy
(AIM HIGH trial)
(1) A total of 3414 patients with established heart disease, low HDL-C concentrations,
and raised TG values were randomly assigned to receive ER niacin (1500-2000 mg/
day) or placebo. All patients received simvastatin 40-80 mg/day, plus ezetimibe 10
mg/day, if needed, to maintain an LDL-C concentration of 40-80 mg/dL.
(2) Trial terminated early after a mean follow-up of 3 years because niacin showed no
additional benefits over placebo, and there was also a small, insignificant increase in
ischemic stroke in the niacin group.
(3) At 2 years, niacin therapy had increased HDL-C values from a median of 35-42 mg/
dL, lowered TG values from 164 mg/dL to 122 mg/dL, and lowered LDL-C values
from 74 mg/dL to 62 mg/dL.
(4) The primary end point, the first event of a composite of CHD death, nonfatal MI,
ischemic stroke, hospitalization for ACS, or symptom-driven coronary or cerebral
revascularization, was similar in the two groups, occurring in 282 patients (16.4%)
in the niacin group versus 274 patients (16.2%) receiving placebo.
(d) Heart Protection Study 2 - Treatment of HDL to Reduce the Incidence of Vascular Events
[HPS2-THRIVE] trial(1) More than 38,000 patients were assessed for adherence to a regimen of ER niacin 2 g
plus laropiprant 40 mg daily; about one-third were excluded largely because of niacin
adverse effects.
(2) A total of 25,673 patients were randomly assigned to receive ER niacin plus laropiprant
daily or placebo and followed up for a median of 3.9 years.
(3) There was no significant benefit of ER niacin/laropiprant on the primary outcome of
major vascular events when added to effective statin-based LDL-C-lowering therapy.
(4) Significant excesses of serious niacin-related adverse events occurred (about 30
patients per 1000).