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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]; Raviteja Guddeti, M.B.B.S. [3]

Landmark Trials

VA-HIT Trial[1][2][3][4]

  • OBJECTIVE: To conclude if changes in plasma lipid levels due to gemfibrozil is the cause for reduction in major cardiovascular events in VA-HIT trial.
  • METHOD: VA-HIT (Veterans Affairs HDL Intervention Trial) trial is a multicentered, randomized, double-blinded, placebo-controlled trial wherein 2531 patients with CAD along with LDL levels ≤140 mg/dL (mean 111 mg/dL) and HDL ≤40 mg/dL (mean 32 mg/dL) were randomly assigned to treatment with gemfibrozil or placebo.
  • RESULTS: At one year the following findings were noted in the group treated with gemfibrozil:
    • Mean HDL-C level was higher by 6%
    • 31% lower mean TG concentration
    • Mean total cholesterol was 4% lower

At five years, the combined primary end point of cardiac death and non-fatal myocardial infarction occurred in 17.3% versus 21.7% in the placebo group. Acute coronary events reduced by 11% with gemfibrozil for every 5 mg/dL rise in HDL-C, but the reduction was independent of changes in LDL-C and triglyceride levels.

  • CONCLUSION: Low HDL-C levels strongly and independently predict the occurrence of coronary events which were reduced by treatment with gemfibrozil.

AIM-HIGH Trial[5][6][7][8][9][10]

  • OBJECTIVE: To assess if niacin + simvastatin combination is superior to simvastatin alone in raising low levels of high density lipoprotein (HDL).
  • METHOD: AIM-HIGH is a randomized trial wherein 3414 patients randomly received either extended release niacin (1500 to 2000 md per day) or a matching placebo. All patients received simvastatin 40 to 80 mg daily to maintain an LDL-C level in the range of 40-80 mg/dL. Ezetimibe 10 mg daily was added, if needed, to achieve the LDL goal. The primary end point was the first event of the composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, hospitalization for an acute coronary syndrome, or symptom-driven coronary or cerebral revascularization.
  • RESULTS: The trial was stopped prematurely for futility after a follow-up of 36 months. At two years compared to placebo, niacin increased HDL-C levels and reduced triglyceride and LDL-C levels but there was no reduction in the rate of primary endpoint or all-cause mortality with niacin. Moreover, there was a trend towards more ischemic strokes in the niacin group. This led to the decision to halt the trial prematurely.
  • CONCLUSION: No incremental clinical benefit was observed from addition of niacin to simvastatin during a 36 month follow-up. Also, elevations in HDL-C levels in the placebo group were higher than expected which may have reduced the competency of the trial to detect a real benefit with niacin therapy.

HATS Trial[11]

  • OBJECTIVE: To assess the effects of lipid-lowering drugs and/or antioxidant vitamins on progression or regression of coronary heart disease in patients with low HDL-C.
  • METHODS: HDL-Atherosclerosis Treatment Study (HATS) was a randomized, 2 x 2 factorial study wherein 160 patients, both men and women with low HDL cholesterol, with at least one 50% stenotic coronary lesion or three 30% stenotic coronary lesions were enrolled. All the patients were randomized to four groups which were simvastatin plus niacin, vitamins, simvastatin-niacin plus antioxidants; or placebos. The primary end points were arteriographic evidence of a change in coronary stenosis and the occurrence of a first cardiovascular event (death, myocardial infarction, stroke, or revascularization). Coronary angiograms were done at baseline and at three years to assess the change.
  • RESULTS:
    • In the simvastatin-niacin group mean LDL-C reduced by 42% and mean HDL-C increased by 26% while levels in the antioxidants and placebo groups remained unaltered.
    • Rate of progression of coronary stenoses was low with simvastatin-niacin group compared to the other groups.
    • Also, patients receiving simvastatin and niacin sustained lower cardiovascular events.
  • CONCLUSION: Addition of a drug that increases HDL-C levels to a statin proves to have additional protection over just statin alone.

ARBITER 2 Trial[12]

  • OBJECTIVE: To assess if treatment with extended release niacin when added to statin monotherapy slows progression of atherosclerosis among individuals with known coronary artery disease (CAD) and moderately low HDL-C.
  • METHOD: ARBITER (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol) 2 was a double blinded randomized placebo controlled study of once daily extended release niacin (1000 mg). 167 patients with known CAD and moderately low HDL-C were enrolled in this study and were assessed for the primary end-point carotid intima-media thickness (CIMT) at the end of one year.
  • RESULTS: At the end of 12 months mean CIMT significantly increased in the placebo group but not in the niacin group. Niacin significantly reduced the rate of IMT progression in patients without insulin resistance. Patients treated with niacin had a significant increase in HDL levels from a mean of 39 mg/dL to 47 mg/dL.
  • CONCLUSION: The addition of extended-release niacin to statin therapy slowed the progression of atherosclerosis among individuals with known coronary heart disease and moderately low HDL-C.

ARBITER 3 Trial[13]

  • OBJECTIVE: To study the effects of long term treatment with extended release niacin (ERN) on HDL levels and carotid intima- media thickness in patients who participated in ARBITER 2.
  • METHODS: 88% (149) of patients enrolled in ARBITER trial participated in ARBITER 3 trial, those who either were continued or crossed over to the placebo group. The long term effects of ERN on HDL cholesterol and carotid intima- media thickness were examined during 12- 24 months of treatment.
  • RESULTS:
    • The ERN group showed an increase in HDL-C levels along with modest reductions in LDL-C and triglycerides.
    • A net regression in CMIT was seen in patients treated with ENC for 12 months.
    • An additional regression was noted in patients treated with ENC for 24 months.
    • Changes in HDL-C were independently associated with regression of CIMT, controlling for changes in LDL and triglycerides.
  • CONCLUSIONS: ERN when added to statin therapy significantly increases HDL levels and induces atherosclerosis regression. Open label design and inability to correlate CIMT effects to clinical outcomes were the limitations of this study.

CLAS Trial[14][15][16][17]

  • OBJECTIVE: To determine whether combined therapy with the lipid lowering agents colestipol hydrochloride plus niacin would produce significant change in coronary, carotid, and femoral artery atherosclerosis and coronary bypass graft lesions as determined by angiography. Also, to determine possible correlations between lesion changes and plasma lipid and lipoprotein cholesterol levels and to explore interrelationships of atherosclerosis change in femoral, coronary, and carotid arteries.
  • METHOD: CLAS (Cholesterol Lowering Atherosclerosis Study) was a randomized, selectively blinded study wherein 188 men, with known previous coronary artery bypass grafts, were randomized to diet plus placebo or diet plus combined lipid lowering therapy consisting of colestipol and niacin and followed up at 2 years and 4 years.
  • RESULTS: The following results were noted:[18]
    • Treatment group had a 37% raise in HDL-C levels and a 43% reduction in LDL-C levels.
    • Regression of atherosclerosis, as measured by angiography, was greater with combined drug treatment at 2 years and at 4 years.
    • Reduction in the percentage of subjects with new atheroma formation in native coronary arteries.
    • Significantly reduced percentage of subjects with new lesions or any adverse change in bypass grafts.
    • Atherosclerosis regression occurred in 16.2% of colestipol-niacin treated vs 2.4% placebo treated
  • CONCLUSION: The benefit of combined nicotinic acid and colestipol therapy was most prominent in patients with baseline plasma cholesterol levels above 240 mg/dL.

FATS Trial[19][20][21][22][23][24][25]

  • OBJECTIVE: To compare the effects of two intensive lipid altering therapies in men with familial combined hyperlipidemia as assessed by arteriography.
  • METHOD: Familial Atherosclerosis Treatment Study (FATS) is a randomized, double blinded, placebo controlled study wherein 146 men with one coronary stenosis of greater than 50 percent or three lesions of greater than 30 percent were enrolled and randomized into three groups. The groups included:
    • Placebo plus low dose colestipol (if needed, to lower LDL)
    • Niacin (1 g QID) plus colestipol (10 g TID)
    • Lovastatin (20 mg BID) plus colestipol (10 g TID)

The primary endpoint was a measure of change in the severity of disease in the proximal coronary arteries as measured by quantitative arteriography.

  • RESULTS: Both the intensive lipid lowering therapies were equally effective. Both reduced the frequency of progression of coronary lesions (21% and 25% versus 46% in the control group), increased the frequency of regression (32% and 39% versus 11%), and reduced the incidence of cardiovascular events in men with coronary artery disease who were at high risk for cardiovascular events.

REGRESS Trial[26][27][28][29]

  • OBJECTIVE: To evaluate the effects of cholesterol lowering therapy, using a hydroxymethyl glutaryl coenzyme A reductase inhibitor (pravastatin) in symptomatic men with coronary artery disease (CAD).
  • METHOD: Regression Growth Evaluation Statin Study (REGRESS) was a multicentred, prospective, double-blinded, randomized, placebo-controlled trial that enrolled 885 men with established coronary artery disease with total cholesterol levels in the range of 155 and 310 mg/dL. The patients were randomized into two groups, treatment and control and followed up for two years. Effect of pravastatin on progression and regression of coronary atherosclerosis was assessed by quantitative coronary arteriography. All the patients received routine antianginal treatment for the duration of the trial.
  • RESULTS: Percent diameter stenosis before angioplasty was 78 +/- 14% (mean +/- SD) in the pravastatin group and 80 +/- 14% in the placebo group (p = 0.46). At follow-up, the percent diameter stenosis was 32 +/- 23% in the pravastatin group and 45 +/- 29% in the placebo group (p < 0.001). Clinical restenosis was significantly lower in the pravastatin group (7%) compared with the placebo group (29%) (p < 0.001).
  • CONCLUSIONS: In symptomatic men with significant coronary artery disease and normal to moderately elevated serum cholesterol, less progression of coronary atherosclerosis and fewer new cardiovascular events were observed in the group of patients treated with pravastatin than in the placebo group.

BECAIT Trial[30][31][32][33]

  • OBJECTIVE: To evaluate if bezafibrate could slow the progression of coronary stenoses in dyslipidemic male survivors of myocardial infarction who were younger than 45 years at the time of the event.
  • METHOD: The Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT) was a randomized, double-blinded, placebo-controlled trial over 5 years to assess the angiographic benefits of bezafibrate retard (400 mg a day) in 92 young (45 yrs), male, post-myocardial infarction (post-MI) patients with dyslipidemia (fasting serum cholesterol concentration above 240 mg/dL and triglyceride concentration above 141 mg/dL).
  • RESULTS:
    • Bezafibrate reduced the levels of LDL-C and triglycerides by 53% and 46% respectively
    • Plasma apolipoprotein (apo) B levels reduced by 9%
    • HDL3 levels rose by 9%
  • CONCLUSION: The effect of bezafibrate on progression of focal coronary atherosclerosis could be at least partly attributed to a rise in HDL3 cholesterol and a decrease in the total number of apo B-containing lipoproteins. Treatment with bezafibrate also significantly reduced the levels of insulin-like growth factor (IGF-1) which is one another factor associated with disease progression.

GAIN Trial[34]

  • This trial studied the effects of atorvastatin on the progression of atherosclerosis, assessed by intra-coronary ultrasound in 131 patients.
  • After a 12 month follow-up period, it was found that atorvastatin reduced the progression of mean plaque volume (1.2 versus 9.6 mm3 for placebo). Also, the drug increased the hyperechogenicity of the plaque which indicates a change in plaque composition from lipid-rich core to fibrotic or calcified. This change in composition of the plaque corresponds to increased plaque stability and a reduced tendency for rupture.

HARP Study[35][36][37][38]

  • OBJECTIVE: The Harvard Atherosclerosis Reversibility Project (HARP) aimed at studying the effect of intensive lipid lowering therapy in normocholesterolemic patients and its effect on angiographic progression of atherosclerosis.
  • METHOD: HAPR was a randomized placebo-controlled trial wherein 91 normocholesterolemic patients, with total serum cholesterol levels less than 250 mg/dL, were selected and treated with a stepwise regimen of diet, pravastatin, nicotinic acid, cholestyramine and gemfibrozil for 2.5 years. Repeat coronary angiograms were performed to assess the progression of coronary atherosclerosis.
  • RESULTS: The study found a significant improvement in total cholesterol, LDL-C and HDL-C levels, however repeat coronary angiograms did not show significant differences in the degree of coronary obstruction, progression of coronary stenosis, regression and clinical cardiac events.
  • CONCLUSION: This study concluded that intensive lipid lowering therapy does not alter the rate of progression of coronary stenoses in normocholesterolemic patients.

SCAT Trial[39][40][41]

  • OBJECTIVE: To assess the effects of cholesterol lowering and angiotensin-converting enzyme inhibition on coronary atherosclerosis in normocholesterolemic patients.
  • METHOD: The Simvastatin/Enalapril Coronary Atherosclerosis Trial (SCAT) was a multicentered, randomized, double blinded, placebo-controlled angiographic trial wherein a total of 460 normocholesterolemic patients were enrolled. 230 received simvastatin, 230 a simvastatin placebo, 229 enalapril and 231 an enalapril placebo. All the patients were followed up for an average time period of 47.8 months.
  • RESULTS and CONCLUSION: Less progression was observed in patients receiving simvastatin compared to those receiving placebo. On quantitative coronary angiography the change in mean diameter, minimum diameter, percentage stenosis and the need for angioplasty was less with simvastatin. No additional benefit was observed with enalapril therapy.

REVERSAL Trial[42]

  • OBJECTIVE: To compare the effects of pravastatin and atorvastatin on coronary artery plaque burden and progression by intensive lipid lowering.
  • METHOD: Reversal of Atherosclerosis with Aggressive Lipid Lowering [REVERSAL] was a multicentered, randomized, double- blinded trial wherein 654 patients received the study drug. IVUS examinations were performed at baseline and after 18 months of treatment in 502 patients. Patients randomly received either 40 mg pravastatin or 80 mg of atorvastatin.
  • RESULTS: The mean LDL-C levels reduced from 150 to 110 mg/dL in the pravastatin group and to 79 mg/dL in the atorvastatin. Percentage change in atheroma volume showed a significantly lower progression rate in the atorvastatin (intensive) group compared to the pravastatin group.
  • CONCLUSIONS: In patients with coronary artery disease, atorvastatin reduced progression of coronary atherosclerosis compared with pravastatin.

ASTEROID Trial[43]

  • OBJECTIVE: To assess if an extensive lipid lowering therapy with statins could regress coronary atherosclerosis as determined by IVUS imaging.
  • METHOD: A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden (ASTEROID) was a prospective open-label blinded end-points trial wherein 507 patients, who had a baseline IVUS examination, received at least 1 dose of the study drug rosuvastatin 40 mg/dL and were followed up for 24 months. At the end of 24 months 349 patients had evaluable serial IVUS examinations.
  • RESULTS: Mean baseline LDL-C reduced by 53.2% and mean HDL-C improved by 14.7%. Also mean atheroma volume for the entire vessel, as assessed by intravascular ultrasound, reduced by 0.98%.
  • CONCLUSION: The study showed that treatment with very high intensity statin therapy using rosuvastatin 40 mg/dL reduced LDL-C and improved HDL-C levels significantly resulting in regression of coronary atherosclerosis as measured by IVUS.

Oxford Niaspan Study[44]

  • OBJECTIVE: To assess the effects of high dose niacin on the progression of atherosclerosis.
  • METHOD: Oxford Niaspan study was a double blinded, randomized, placebo-controlled study of 2 g daily modified-release in 71 patients with HDL-C levels less than 40 mg/dL and either: 1) type 2 diabetes with coronary heart disease; or 2) carotid/peripheral atherosclerosis. All the patients were on an additional statin therapy. The change in carotid artery wall area was assessed by magnetic resonance imaging after 1 year.
  • RESULTS: Niacin increased HDL-C by 23% and reduced low-density lipoprotein cholesterol by 19% and at 12 months niacin significantly reduced carotid wall area compared with placebo.
  • CONCLUSION: Compared with placebo, treatment with high-dose modified-release niacin along with statin therapy significantly reduced carotid atherosclerosis within 12 months.

SATURN Trial

  • OBJECTIVE: To compare the effects of two intensive lipid lowering treatment regimens (statins) on the progression of coronary atherosclerosis and to assess their safety and side-effect profiles.
  • METHOD: Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin Versus Atorvastatin (SATURN) trial was a randomized trial which enrolled 1049 patients with known coronary artery disease, to study the effects of rosuvastatin and atorvastatin on the progression of coronary atherosclerosis. Percent atheroma volume and total atheroma volume were assessed by intravascular ultrasound (IVUS) at baseline and after 104 weeks of treatment with either rosuvastatin 40 daily and atorvastatin 80 mg daily.
  • RESULTS: At the end of 104 weeks
    • Serum LDL-C levels were lower in the rosuvastatin group than atorvastatin group.
    • Similarly serum HDL-C levels were higher in the rosuvastatin group than in atorvastatin group.
    • Percent atheroma volume (PAV), decreased by 0.99% with atorvastatin and by 1.22% with rosuvastatin.
  • CONCLUSION: Maximal doses of rosuvastatin and atorvastatin resulted in significant regression of coronary atherosclerosis. Even though rosuvastatin achieved a lower LDL-C and higher HDL-C levels compared to atorvastatin, a similar degree of regression of PAV was observed in both the treatment groups.

4S Trial[45]

  • OBJECTIVE: To evaluate the effect of cholesterol lowering with simvastatin on mortality and morbidity in patients with coronary artery disease (CAD).
  • METHOD: The Scandinavian Simvastatin Survival Study (4S) enrolled 4444 patients with known CAD (angina pectoris or previous myocardial infarction) and serum cholesterol levels between 212 and 309 mg/dL. Patients were randomly assigned to either simvastatin (20 to 40 mg/day) or placebo and were followed-up for a median period of 5.4 years.
  • RESULTS:
    • Total cholesterol reduced by 25%
    • LDL-C levels reduced by 35%
    • Mean HDL-C improved by 8%
    • Mortality rate was lower in the simvastatin group compared with that in the placebo group (8% vs 12%)
    • Significant reductions in major coronary events (19 versus 28 percent)
  • CONCLUSION: The study showed that long-term treatment with simvastatin is safe and improves survival in CAD patients.

LIPID Study[46]

  • OBJECTIVE: To assess the efficacy of pravastatin in reducing mortality in known CAD patients.
  • METHOD: The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study was a randomized, double-blinded, placebo controlled trial wherein 9014 patients (young and old) with known CAD and total cholesterol levels in the range of 155 to 271 mg per deciliter were enrolled and randomly assigned to treatment with either 40 mg daily pravastatin or placebo. The patients were followed up for a mean period of 6.1 years.
  • RESULTS:
    • Pravastatin was associated with a lower rate of death from CAD compared with placebo (6.4% vs 8.3%)
    • Overall mortality rate was lower in the pravastatin group compared with that in the placebo group (11% vs 14.1%)
    • The incidence of all cardiovascular outcomes was consistently lower among patients assigned to receive pravastatin
  • CONCLUSION: Treatment with pravastatin 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.

TNT Trial[47]

  • OBJECTIVE: To compare the efficacy of 10 mg and 80 mg daily dose of atorvastatin in patients with stable CAD and baseline LDL-C between 130 mg/dL and 250 mg/dL.
  • METHOD: The Treating to New Targets (TNT) trial was a randomized trial that enrolled 10,001 patients with stable coronary artery disease to treatment with atorvastatin, 80 or 10 mg/d, and follwed them up for a median period of 4.9 years. The primary end point was a composite of cardiovascular death, myocardial infraction, resuscitated cardiac arrest, and stroke.
  • RESULTS: Compared to low dose, high dose atorvastatin was associated with
    • A significantly lower mean serum LDL-C concentration (77 vs 101 mg/dL)
    • Significant reductions in the rate of the primary end point (8.7 vs 10.9 percent)
    • No reduction in all-cause mortality. Higher doses of atorvastatin, although reduced mortality due to cardiac events, were associated with higher mortality rate due to noncardiovascular events.
  • CONCLUSION: Wider use of the 80-mg dose of atorvastatin in patients with stable coronary disease is safe, cost-effective, and provides an incremental reduction in coronary events.

IDEAL Trial[48][49]

  • OBJECTIVE: To compare the effects of two lipid lowering strategies (high dose atorvastatin [80 mg] and simvastatin 20 mg) on the risk of cardiovascular disease among patients with a previous myocardial infarction (MI).
  • METHOD: The Incremental Decrease in End Points through Aggressive Lipid Lowering (IDEAL) trial was a prospective, randomized, open-label, blinded end-point evaluation trial which enrolled 8888 patients with past history of acute myocardial infarction, who were randomly assigned to treatment with high dose atorvastatin (80 mg) or simvastatin 20 mg. The primary endpoint was a major coronary event, defined as coronary death, confirmed nonfatal acute MI, or cardiac arrest with resuscitation.
  • RESULTS: After a median follow-up time of 4.8 years, compared with patients in simvastatin group those in atorvastatin group were associated with
    • Lower mean LDL-C levels (81 vs 104 mg/dL)
    • Lowered primary end point rate (9.3% vs 10.4%)
    • Lowered occurrence of any coronary event (898 vs 1059)
  • CONCLUSIONS: 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.

SEARCH Study[50][51]

  • OBJECTIVE: To study the efficacy and safety of prolonged use of more intensive cholesterol-lowering therapy in patients at high cardiovascular risk.
  • METHOD: Study of the effectiveness of additional reductions in cholesterol and homocysteine (SEARCH) was a randomized, double blinded study which enrolled 12,064 men and women aged 18-80 years with a history of myocardial infarction. In addition these patients were randomly assigned to homocysteine lowering with folic acid 2 mg plus vitamin B12 1 mg daily versus matching placebo. The primary endpoint was major vascular events, defined as coronary death, myocardial infarction, stroke, or arterial revascularization.
  • RESULTS:
    • Major vascular events occurred in 24·5% of patients receiving 80 mg simvastatin versus 25·7% of those receiving 20 mg.
    • An average of 0.35 mmol/L greater reduction in LDL-C was observed in the group receiving 80 md simvastatin compared to those receiving 20 mg.
    • Overall 6% reduction in major vascular events was observed in the 80 mg group compared with the 20 mg group.
    • Myopathy occurred in 0.9% patients taking 80 mg simvastatin compared with 0.03% patients in the 20 mg simvastatin group.
  • CONCLUSION: The SEARCH study failed to find a benefit with more intensive therapy as a significant number of patients in the 20 mg simvastatin group took an additional statin off protocol as more intensive LDL-C goals were promulgated.

BIP Trial[52]

  • This double blinded clinical trial studied the effects of bezafibrate on incidence of cardiovascular events.
  • Bezafibrate raised the HDL levels and decreased the triglyceride levels in patients with a previous myocardial infarction or stable angina. An overall reduction in the risk of cardiovascular events was noted.

CARE Trial[53][54]

  • OBJECTIVE: To assess if pravastatin would reduce the sum of fatal coronary artery disease (CAD) and nonfatal myocardial infarction (MI) in patients who had a previous MI and a total cholesterol value < 240 mg/dl.
  • METHOD: Cholesterol and Recurrent Events trial was a double blinded, randomized study wherein 4159 patients with a history of a myocardial infarction in the previous two years who had a total cholesterol value < 240 mg/dl were enrolled and treated with either 40 mg pravastatin or a placebo.
  • RESULTS and CONCLUSION: The following results were obtained after a median follow-up time of 5 years:
    • Reduced combined end point of coronary death and nonfatal MI (10.2 versus 13.2 percent)
    • Reduced need for revascularization with CABG or PTCA (14.1 versus 18.8 percent)
    • Reduced frequency of stroke (2.6 versus 3.8 percent) and of stroke plus transient ischemic attacks (4.4 versus 6.0 percent)

Heart Protection Study[55]

  • OBJECTIVE: To study the effect of simvastatin therapy that lowers LDL levels in reducing cardiovascular disease risk.
  • METHODS: 20,536 patients with history of coronary artery disease, peripheral arterial disease or diabetes, were randomly allocated to receive either simvastatin (40 mg daily). These patients were followed up over a period of 5 years for occurrence of any fatal or non- fatal events, along with incidence of cancer and other causes of major mortality.
  • RESULTS: The results of this study are tabulated as follows:
    • All cause mortality significantly reduced in the simvastatin group compared to the placebo group. A highly significant proportional reduction in the coronary death rate, marginally significant reduction in other vascular deaths and a non-significant reduction in non-vascular deaths was noted in the simvastatin group.
    • A highly significant reduction in first event rate for non-fatal/fatal myocardial infarction or coronary death, non-fatal/fatal stroke, and for coronary/ non-coronary revascularization was noted in the simvastatin group compared to the placebo group.
    • This reduction in first event rate was not significant in the first year, whereas found to be highly significant in subsequent years during each separate year.
    • The annual excess risk of myopathy with simvastatin 40 mg daily was about 0.01 %.
  • CONCLUSION: Long term treatment with simvastatin in addition to the existing treatment protocols safely gives an additional benefit to a wide range of high risk patients by reducing mortality.

MEGA Trial[56][57]

  • OBJECTIVE: To assess whether evidence for treatment of hypercholesterolemia with statins derived from western populations can be extrapolated to the Japanese population.
  • METHOD: Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study) was a prospective, randomized, open-labelled, blinded study which enrolled 8214 Japanese men and postmenopausal women aged 40 to 70 years and with a serum total cholesterol concentration of 220 to 270 mg/dL. All the patients were randomly assigned to receive either diet therapy alone or diet therapy plus pravastatin 10 to 20 mg daily and followed-up for a mean period of 5.3 years.
  • RESULTS: The following results were obtained at the end of follow-up period:
    • Mean total cholesterol was reduced by 2.1% and 11.5% in the patients treated with diet alone and diet plus pravastatin respectively.
    • Similarly mean LDL-C reduced by 3.2% and 18.0%.
    • Significantly lower CAD in patients treated with diet plus pravastatin than in those treated with diet alone.
  • CONCLUSION: Treatment with a low dose of pravastatin reduces the risk of CAD in Japan by much the same amount as higher doses have shown in Europe and the USA.

MIRACL Study[58][59]

  • OBJECTIVE: To assess whether early initiation of treatment with a statin can reduce the occurrence of these early events.
  • METHOD: The Myocardial Ischemia Reduction with Acute Cholesterol Lowering (MIRACL) trial was a randomized, double-blinded trial wherein 3086 adults (18 years and above) with unstable angina or non-Q-wave MI were randomly assigned to receive treatment with atorvastatin (80 mg/day) or placebo between 24 and 96 hours after hospital admission and followed-up through 16 weeks. Primary predefined end point event was defined as time to death, nonfatal acute MI, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia with objective evidence and requiring emergency re-hospitalization.
  • RESULTS:
    • Primary end point occurred in 14.8% in patients treated with atorvastatin compared with 17.4% in the placebo group.
    • No significant differences in risk of death, nonfatal myocardial infarction, or cardiac arrest between the two groups.
    • Atorvastatin group had a lower risk of symptomatic ischemia with objective evidence and requiring emergency re-hospitalization.
  • CONCLUSION: After an acute coronary event early treatment with 80 mg/day atorvastatin reduces recurrent ischemic events in the first 16 weeks, mostly recurrent symptomatic ischemia requiring re-hospitalization.

PROVE IT-TIMI 22 Trial[60][61][62][63][64]

  • OBJECTIVE: To determine whether intensive LDL-C lowering with atorvastatin 80 mg/day was more efficacious than standard LDL-C lowering with pravastatin 40 mg/day in reducing the incidence of cardiovascular events in patients hospitalized with acute coronary syndrome (ACS) within the preceding 10 days.
  • METHOD: Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial was a randomized comparative study where in 4162 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days were enrolled and randomly assigned to treatment with either 40 mg a day pravastatin or 80 mg a day atorvastatin. The primary end point was a composite of death from any cause, myocardial infarction, documented unstable angina requiring re-hospitalization, revascularization (performed at least 30 days after randomization), and stroke.
  • RESULTS:
    • High-dose atorvastatin group achieved a mean LDL-C level of 62 mg per deciliter compared to 95 mg per deciliter in the standard-dose pravastatin group.
    • The composite end point at 30 days occurred in 3.0% of patients receiving atorvastatin 80 mg versus 4.2% of patients receiving pravastatin 40 mg.
  • CONCLUSION: 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-C to levels substantially below current target levels.

FLORIDA Trial[65]

  • OBJECTIVE: To assess the effect of fluvastatin on residual ischemia after acute myocardial infarction.
  • METHOD: FLuvastatin On Risk Diminishment after Acute myocardial infarction (FLORIDA) trial was a randomized, placebo-controlled, double-blinded, parallel study that enrolled 540 patients with an acute myocardial infarction and serum cholesterol <251 mg/dL. The trial used ambulatory electrocardiographic (AECG) monitoring to measure ischemia over 48-h at baseline, after 6 weeks and at 12 months. All the patients were randomized to treatment with either fluvastatin or placebo.
  • RESULTS: The following were the results of the trial:
    • At 12 months, the serum total cholesterol (TC) level was reduced by 13% and LDL-C by 21% in the fluvastatin treatment group compared to a 9% rise in the placebo group.
    • AECG monitoring at baseline showed ischemia in 11% of the patients. After 6 weeks, 32/48 (67%), and 12 months 35/46 (76%) of the patients with ischemia on the baseline AECG, no longer showed signs of ischemia.
  • CONCLUSION: As compared to placebo, Fluvastatin treatment did not affect ischemia on AECG, nor the occurrence of any major clinical events.

Phase Z of A-Z Trial[66][67]

  • OBJECTIVE: To compare early initiation of an intensive statin regimen with delayed initiation of a less intensive regimen in patients with ACS.
  • METHOD: The Z phase of A-Z trial was a multicentered, randomized, double blinded which enrolled 4497 patients with acute coronary syndrome who had an initial total cholesterol level ≤250 mg/dL. All the patients were randomized to treatment with either 40 mg/d of simvastatin for 1 month followed by 80 mg/d thereafter or placebo for 4 months followed by 20 mg/d of simvastatin. All the patients were followed-up for 6 months to 24 months. Primary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, readmission for ACS, and stroke.
  • RESULTS:
    • In the less intense treatment group median LDL-C level achieved while taking placebo was 122 mg/dL at 1 month and was 77 mg/dL at 8 months while taking 20 mg/d of simvastatin. Corresponding values in the simvastatin only group were 68 mg/dL at 1 month while taking 40 mg/d of simvastatin and 63 mg/dL at 8 months while taking 80 mg/d of simvastatin.
    • Primary endpoint was reached in 16.7% in the placebo plus simvastatin group compared with 14.4% in the simvastatin only group.
    • Cardiovascular death occurred in 5.4% and 4.1% patients in the 2 groups but no differences were observed in other individual components of the primary end point.
  • CONCLUSION: Pre-specified end point was not achieved by the trial. However the early initiation of an aggressive simvastatin regimen, in patients with ACS, resulted in a favorable trend toward reduction of major cardiovascular events.

AFREGS Trial[68]

  • OBJECTIVE: To study the angiographic and clinical effects of increasing HDL levels with pharmacologic treatment.
  • METHOD: This was a randomized, double- blinded, placebo controlled trial with 143 patients younger than 76 years of age with low HDL levels and angiographically evident coronary artery disease. These patients were randomly allocated to the gemfibrozil, niacin, cholestyramine and corresponding placebo, with aggressive dietary and lifestyle intervention at baseline. They were then followed up for a period of 30 months for clinical events which includes hospitalization for angina, mwocardial infacrtion, transient ischemic attack and stroke, death and other cardiovascular procedures.
  • RESULTS:
    • The pharmacologically treated group had a 20% decrease in total cholesterol, 36% increase in HDL cholesterol, 26% decrease in LDL cholesterol and a 50% reduction in triglyceride levels compared to the placebo group.
    • Focal coronary stenosis showed an increase of 1.4% in the placebo and a decrease of 0.8% in the drug group.
    • 26% of patients in the placebo group reached a composite cardiovascular event end point whereas the same was seen in 13% of patients in the drug group.
  • CONCLUSION: Pharmacologic regimen aimed at raising HDL cholesterol levels improved the cholesterol levels, retards progressing of stenosis and prevent cardiovascular events in some who exercise regularly and are on a low-fat diet.

ARBITER 6-HALTS Trial[69]

  • OBJECTIVES: To study the effects of extended-release niacin or ezetimibe added to statin monotherapy on carotid intima-media thickness.
  • METHOD: This was an open labeled randomized trial. The study subjects consisted of patients who had coronary artery disease or equivalent on long standing statin therapy with LDL cholesterol levels above 100 mg/dl and HDL cholesterol levels below 50 mg/dl for men and 55 mg/dl in women. The patients were randomly assigned to extended-release niacin (target dose 2000 mg) or ezetimibe (10 mg daily). The primary end point was a change in the carotid intima-media thickness from baseline in both study groups. This trial was terminated early because of side-effects of the drugs which affected compliance.
  • RESULT:
    • A significant increase in HDL levels, and a decrease in LDL and triglyceride levels was noted in the niacin group.
    • Niacin group showed a significant change in terms of CMIT, leading to a reduction in both mean and maximal carotid intima-media thickness.
    • A paradoxical increase in the CMIT was noted along with a reduction in LDL levels in the ezetimibe group. There was also a fall in both HDL and triglyceride levels.\
  • CONCLUSION: Extended release niacin causes statistically significant reduction in the carotid intima-media thickness and is superior to ezetimibe.

SPARCL Study[70]

  • OBJECTIVE: To study the effects of statins on incidence of recurrent stroke after a recent episode of stroke or transient ischemic attack
  • METHOD: Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) was a double blinded study with subjects who had at least one episode of stroke in the last one to six months and LDL levels of 100 to 190 mg/dl with no history of coronary artery disease. These patients were randomly assorted to receive 80 mg of atorvastatin daily or placebo. The primary end point for the study was first fatal or non-fatal stroke.
  • RESULTS:
    • During the mean follow up period of 4.9 years, 11.2% of patients from the atorvastatin group and 13.1% of patients from the placebo experienced fatal/ non-fatal stroke, with a 5 year absolute risk reduction of 2.2%.
    • The 5 year absolute risk reduction in major cardiovascular events was 3.5%.
    • The overall mortality rates were similar in both the groups.
  • CONCLUSION: Atorvastatin (80 mg daily) reduced the incidence of recurrent stroke and cardiovascular events in patients with a recent episode of stroke or transient ischemic attacks. However, the incidence of hemorrhagic stroke increased in the atorvastatin group.

AVERT Trial[71][72]

  • OBJECTIVE: To compare the outcome of aggressive lipid lowering to that of angioplasty in stable coronary artery disease patients, relatively normal left ventricular function, asymptomatic or mild-to-moderate angina, and a serum level of LDL-C of at least 115 mg/dL who were referred for percutaneous revascularization.
  • METHOD: Atorvastatin versus Revascularization Treatment (AVERT) trial was a randomized comparative study that enrolled 341 patients with stable CAD. All the patients were randomly assigned to treatment with either atorvastatin 80 mg per day or percutaneous revascularization procedure (angioplasty) followed by usual care. The follow-up period was 18 months.
  • RESULTS: At the end of follow-up period atorvastatin was associated with 36% lower incidence of ischemic events compared to angioplasty. Also, patients who received atorvastatin had a significantly longer time to the first ischemic event.
  • CONCLUSION: Aggressive lipid lowering therapy with atorvastatin is at least as effective as angioplasty in reducing the incidence of ischemic events in low-risk patients with stable CAD.

CORONA Trial[73][74][75][76]

  • OBJECTIVE: To study the effects of rosuvastatin 10 mg daily in patients with congestive heart failure.
  • METHOD: Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) was a double-blinded, randomized, placebo controlled trial wherein 5011 patients with congestive heart failure NYHA Class II, III or IV ischemic, systolic heart failure. The primary outcome was death from cardiovascular causes, non-fatal MI or non-fatal stroke.
  • RESULTS and CONCLUSION: Compared to placebo, rosuvastatin reduced the LDL levels and raised the HDL and triglyceride levels. However, there was no significant reduction in mortality rates from cardiovascular causes, coronary events and all-cause mortality.

Trials on Investigational Therapies

ERASE Trial[77]

  • OBJECTIVE: To study the effects of reconstituted HDL on atheromatous plaque volume.
  • METHOD: This was a randomized placebo-controlled trial conducted in 17 centers across Canada. An intravascular ultrasound was performed at baseline and at 2 to 3 weeks after the last infusion to assess plaque burden.
  • RESULTS: The group with higher doses of reconstituted HDL (CSL-111) was eliminated from the study because of mild liver function test abnormalities. The results of the study are briefed below:
    • Percentage change in plaque volume: -3.4% with CSL-111 and -1.6% with placebo (P= 0.48 between the groups, P< 0.001 vs baseline for CSL-111)
    • Nominal change in plaque volume: -5.3% with CSL-111 and -2.3% with placebo (P= 0.39 between the groups, P< 0.001 vs baseline for CSL-111)
    • Mean changes in plaque characterization on IVUS: −0.0097 for CSL-111 and 0.0128 with placebo (P = .01)
    • Mean changes in coronary score on quantitative coronary angiography: −0.039 mm for CSL-111 and −0.071 mm with placebo (P= 0.03)
  • CONCLUSIONS: Short term infusions of reconstituted HDL (CSL-111) resulted in:
    • No significant reductions in percentage change and nominal change in plaque volume compared to placebo.
    • Statistically significant improvement in mean changes in plaque characterization on IVUS and coronary score on quantitative coronary angiography, compared to placebo.

Infusion of Apo A-1 Milano[78]

  • OBJECTIVE: To study the effects of Apo A-1 Milano on plaque burden on arteries.
  • METHOD: Apo A-1 was infused in cholesterol fed rabbits and showed a decreased intimal thickness and macrophage content after balloon injury in femoral and iliac arteries. Based on these results, another pilot trial was designed using recombinant Apo A-1 Milano phospholipid complex (ETC-216) in 57 patients within two weeks of the onset of acute coronary syndrome. Subjects were randomly assigned to the ETC 216 infusion group at 15 mg/kg or 45 mg/kg or to placebo group. IVUS was performed at baseline and repeated at the completion of the study.
  • RESULTS: Treatment with ETC-216 (in both doses) resulted in a significant decrease in mean percentage of coronary artery volume occupied by atheroma as well as the total atheroma volume. Whereas the placebo group did not show any significant change.
  • CONCLUSIONS: Although Apo A-1 Milano infusions resulted in decrease in plaque burden, further study is required assess efficacy, safety and cost-effectiveness.

CETP Inhibitors

Torcetrapib

  • Clinical research on torcetrapib stopped because of increased incidence of cardiovascular events as an adverse effect of the drug[79].
  • This drug is thought to cause its side effects because of a significant increase in systolic blood pressure and a significant reduction in serum potassium levels.

Anacetrapib

Dalcetrapib

  • Research studies on dalcetrapib were stopped due to lack of clinically and statistically meaningful efficacy of the drug on interim analysis[82].
  • The Dal-Outcomes study[83] assessed dalcetrapib at various dose ranges. This study showed a significant rise in HDL levels, but there was no significant difference between the drug and the placebo group.

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  60. ↑ Cannon CP, Braunwald E, McCabe CH; et al. (2004). "Intensive versus moderate lipid lowering with statins after acute coronary syndromes". The New England Journal of Medicine. 350 (15): 1495–504. doi:10.1056/NEJMoa040583. PMID 15007110. Unknown parameter |month= ignored (help)
  61. ↑ Rouleau J (2005). "Improved outcome after acute coronary syndromes with an intensive versus standard lipid-lowering regimen: results from the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial". The American Journal of Medicine. 118 Suppl 12A: 28–35. doi:10.1016/j.amjmed.2005.09.014. PMID 16356805. Unknown parameter |month= ignored (help)
  62. ↑ Murphy SA, Cannon CP, Wiviott SD; et al. (2007). "Effect of intensive lipid-lowering therapy on mortality after acute coronary syndrome (a patient-level analysis of the Aggrastat to Zocor and Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 trials)". The American Journal of Cardiology. 100 (7): 1047–51. doi:10.1016/j.amjcard.2007.04.053. PMID 17884359. Unknown parameter |month= ignored (help)
  63. ↑ Ray KK, Cannon CP, McCabe CH; et al. (2005). "Early and late benefits of high-dose atorvastatin in patients with acute coronary syndromes: results from the PROVE IT-TIMI 22 trial". Journal of the American College of Cardiology. 46 (8): 1405–10. doi:10.1016/j.jacc.2005.03.077. PMID 16226162. Unknown parameter |month= ignored (help)
  64. ↑ Giraldez RR, Giugliano RP, Mohanavelu S; et al. (2008). "Baseline low-density lipoprotein cholesterol is an important predictor of the benefit of intensive lipid-lowering therapy: a PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22) analysis". Journal of the American College of Cardiology. 52 (11): 914–20. doi:10.1016/j.jacc.2008.05.046. PMID 18772061. Unknown parameter |month= ignored (help)
  65. ↑ Liem AH, van Boven AJ, Veeger NJ; et al. (2002). "Effect of fluvastatin on ischaemia following acute myocardial infarction: a randomized trial". European Heart Journal. 23 (24): 1931–7. PMID 12473255. Unknown parameter |month= ignored (help)
  66. ↑ de Lemos JA, Blazing MA, Wiviott SD; et al. (2004). "Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial". JAMA : the Journal of the American Medical Association. 292 (11): 1307–16. doi:10.1001/jama.292.11.1307. PMID 15337732. Unknown parameter |month= ignored (help)
  67. ↑ Blazing MA, De Lemos JA, Dyke CK, Califf RM, Bilheimer D, Braunwald E (2001). "The A-to-Z Trial: Methods and rationale for a single trial investigating combined use of low-molecular-weight heparin with the glycoprotein IIb/IIIa inhibitor tirofiban and defining the efficacy of early aggressive simvastatin therapy". American Heart Journal. 142 (2): 211–7. doi:10.1067/mhj.2001.116959. PMID 11479456. Unknown parameter |month= ignored (help)
  68. ↑ Whitney EJ, Krasuski RA, Personius BE; et al. (2005). "A randomized trial of a strategy for increasing high-density lipoprotein cholesterol levels: effects on progression of coronary heart disease and clinical events". Annals of Internal Medicine. 142 (2): 95–104. PMID 15657157. Unknown parameter |month= ignored (help)
  69. ↑ Taylor AJ, Villines TC, Stanek EJ; et al. (2009). "Extended-release niacin or ezetimibe and carotid intima-media thickness". The New England Journal of Medicine. 361 (22): 2113–22. doi:10.1056/NEJMoa0907569. PMID 19915217. Unknown parameter |month= ignored (help)
  70. ↑ Amarenco P, Bogousslavsky J, Callahan A; et al. (2006). "High-dose atorvastatin after stroke or transient ischemic attack". The New England Journal of Medicine. 355 (6): 549–59. doi:10.1056/NEJMoa061894. PMID 16899775. Unknown parameter |month= ignored (help)
  71. ↑ Pitt B, Waters D, Brown WV; et al. (1999). "Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. Atorvastatin versus Revascularization Treatment Investigators". The New England Journal of Medicine. 341 (2): 70–6. doi:10.1056/NEJM199907083410202. PMID 10395630. Unknown parameter |month= ignored (help)
  72. ↑ Waters DD (2000). "Medical therapy versus revascularization: the atorvastatin versus revascularization treatment AVERT trial". The Canadian Journal of Cardiology. 16 Suppl A: 11A–3A. PMID 10653925. Unknown parameter |month= ignored (help)
  73. ↑ Kjekshus J, Apetrei E, Barrios V; et al. (2007). "Rosuvastatin in older patients with systolic heart failure". The New England Journal of Medicine. 357 (22): 2248–61. doi:10.1056/NEJMoa0706201. PMID 17984166. Unknown parameter |month= ignored (help)
  74. ↑ van der Harst P, Slart RH, Tio RA; et al. (2010). "Effects of rosuvastatin on coronary flow reserve and metabolic mismatch in patients with heart failure (from the CORONA Study)". The American Journal of Cardiology. 105 (4): 517–21. doi:10.1016/j.amjcard.2009.10.021. PMID 20152247. Unknown parameter |month= ignored (help)
  75. ↑ Lorgelly PK, Briggs AH, Wedel H; et al. (2010). "An economic evaluation of rosuvastatin treatment in systolic heart failure: evidence from the CORONA trial". European Journal of Heart Failure. 12 (1): 66–74. doi:10.1093/eurjhf/hfp172. PMC 2796144. PMID 20023047. Unknown parameter |month= ignored (help)
  76. ↑ McMurray JJ, Kjekshus J, Gullestad L; et al. (2009). "Effects of statin therapy according to plasma high-sensitivity C-reactive protein concentration in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA): a retrospective analysis". Circulation. 120 (22): 2188–96. doi:10.1161/CIRCULATIONAHA.109.849117. PMID 19917888. Unknown parameter |month= ignored (help)
  77. ↑ Tardif JC, Grégoire J, L'Allier PL; et al. (2007). "Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial". JAMA : the Journal of the American Medical Association. 297 (15): 1675–82. doi:10.1001/jama.297.15.jpc70004. PMID 17387133. Unknown parameter |month= ignored (help)
  78. ↑ Nissen SE, Tsunoda T, Tuzcu EM; et al. (2003). "Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial". JAMA : the Journal of the American Medical Association. 290 (17): 2292–300. doi:10.1001/jama.290.17.2292. PMID 14600188. Unknown parameter |month= ignored (help)
  79. ↑ Barter PJ, Caulfield M, Eriksson M; et al. (2007). "Effects of torcetrapib in patients at high risk for coronary events". The New England Journal of Medicine. 357 (21): 2109–22. doi:10.1056/NEJMoa0706628. PMID 17984165. Unknown parameter |month= ignored (help)
  80. ↑ Cannon CP, Dansky HM, Davidson M; et al. (2009). "Design of the DEFINE trial: determining the EFficacy and tolerability of CETP INhibition with AnacEtrapib". American Heart Journal. 158 (4): 513–519.e3. doi:10.1016/j.ahj.2009.07.028. PMID 19781408. Unknown parameter |month= ignored (help)
  81. ↑ Krishna R, Anderson MS, Bergman AJ; et al. (2007). "Effect of the cholesteryl ester transfer protein inhibitor, anacetrapib, on lipoproteins in patients with dyslipidaemia and on 24-h ambulatory blood pressure in healthy individuals: two double-blind, randomised placebo-controlled phase I studies". Lancet. 370 (9603): 1907–14. doi:10.1016/S0140-6736(07)61813-3. PMID 18068514. Unknown parameter |month= ignored (help)
  82. ↑ Lüscher TF, Taddei S, Kaski JC; et al. (2012). "Vascular effects and safety of dalcetrapib in patients with or at risk of coronary heart disease: the dal-VESSEL randomized clinical trial". European Heart Journal. 33 (7): 857–65. doi:10.1093/eurheartj/ehs019. PMC 3345558. PMID 22345126. Unknown parameter |month= ignored (help)
  83. ↑ Schwartz GG, Olsson AG, Abt M; et al. (2012). "Effects of dalcetrapib in patients with a recent acute coronary syndrome". The New England Journal of Medicine. 367 (22): 2089–99. doi:10.1056/NEJMoa1206797. PMID 23126252. Unknown parameter |month= ignored (help)

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