Dr sajeer Senior Resident Dept. of Cardiology, MCH, Calicut

Dr sajeer Senior Resident Dept. of Cardiology, MCH, Calicut
Statins for Secondary Prevention Journal review of evidence Dr sajeer Senior Resident Dept. of Cardiology, MCH, Calicut

Efficacy of statins in primary and secondary prevention of CV events - well established
Meta-analyses of RCTs : - demonstrated dramatic reductions in major CV events, cardiovascular morbidity, and all-cause mortality LDLC ↓ reduces initial coronary events - reduces recurrent coronary events - decreases stroke - Slows progression of atherosclerosis - induce regression of atherosclerosis - A 1% reduction in LDL-C reduces coronary events by 1% - High dose of statins→ reduces LDL-C levels and coronary events by 50%.

- Statins in Stable CAD - Intensive Statin therapy - Statins in Acute Coronary Syndromes - Statin therapy before PCI - Statins in Heart Failure

CAD & Statins Trials JUPITER Chest 2005;128:

Statin Trials: Chronology
The early statin trials demonstrated that statin therapy benefited both primary and secondary prevention patients with hypercholesterolemia. Subsequent trials extended this finding to patients with a broad range of cholesterol levels. The MIRACL trial was the first to show the benefit of statins in an acute coronary syndrome. More recent trials have demonstrated that intensive LDL-C reduction improves outcomes in patients with acute coronary syndromes and chronic coronary heart disease. Primary prevention Acute coronary syndromes Chronic Coronary heart disease

Statins Secondary prevention Trials
4S Scandinavian Simvastatin Survival Study CARE Cholesterol and Recurrent Events study LIPID Long-term Intervention with Pravastatin in Ischemic Disease study HPS Heart Protection Study

4S Scandinavian Simvastatin Survival Study
Patient Population: - 35–70 years of age - angina pectoris or - previous MI (≥6 months earlier) - serum cholesterol between mg/dL (mean LDL 188 mg/dL). Simvastatin 40 mg v/s placebo Study Design: - Enrolled : 4444 pts Mean Follow Up: yrs (median 5.4 yrs) Mean Patient Age: Female: 19% Objective : To investigate whether long-term simvastatin therapy reduces total mortality and coronary events in post-MI and or angina patients with total cholesterol between mg/dL. Primary Endpoints: - all-cause mortality Secondary Endpoints: - serum lipid levels, major coronary events Lancet 1994;344:1383–1389

Scandinavian Simvastatin Survival Study (4S)
30% RRR 11.5 12 8.2 8 Mortality (%) 4 The 4S trial was a landmark study that sought to evaluate the effect of statin therapy in secondary prevention. A total of 4,444 men and women with angina or prior MI and serum cholesterol levels of mmol/L ( mg/dL) were randomized to simvastatin (20-40 mg) or placebo for greater than 5 years. Treatment with simvastatin resulted in a 30% relative risk reduction in all-cause mortality (11.5 vs. 8.2%, p<0.001). P<0.001 Placebo Simvastatin Lancet 1994;344:1383–1389

Primary Endpoint: 4S trial
30% risk reduction % Surviving p = Years since randomization Lancet, Vol 344, November 19, 1994

(CARE) Cholesterol and Recurrent Events Study
Pravastatin 40 mg vs. placebo CARE - Study Design: 80 centers in the US and Canada 4159 men and women aged 21 to 75 yrs enrolled 3 to 20 months post-MI Total-C < LDL-C between 115 – 174 mg/dl Follow up - 5 yr Sacks, F. et al, N Engl J Med 1996; 335:1001-9

(CARE) Cholesterol and Recurrent Events Study
Sacks, F. et al, N Engl J Med 1996; 335:1001-9

Cholesterol and Recurrent Events (CARE) Study
24% RRR 15 13.2 10.2 10 Rate of MI or CHD death (%) 5 P=0.003 The CARE trial sought to evaluate the effect of statins in secondary prevention, particularly among those with average cholesterol levels. The mean total cholesterol level was <240 mg/dL and the LDL-C levels ranged between mg/dL. A total of 4,159 patients with a history of myocardial infarction were randomized to pravastatin (40 mg) or placebo for 5 years. Treatment with pravastatin resulted in a 24% relative risk reduction in the primary end point (myocardial infarction or coronary heart disease death). Placebo Pravastatin Sacks FM et al. NEJM 1996;335:1001–1009

Long-term Intervention with Pravastatin in Ischemic Disease study
LIPID Long-term Intervention with Pravastatin in Ischemic Disease study The LIPID study sought to evaluate the effect of statins in secondary prevention among those with a broad range of cholesterol levels. Patients with a history of known coronary artery disease were randomized to pravastatin (40 mg) or placebo over a mean of 6.1 years. Patients receiving pravastatin experienced a significant 24% relative risk reduction in coronary heart disease mortality, with no clinically significant adverse effects N Engl J Med 1998;339:

Heart Protection Study (HPS)- Simvastatin trial
20,536 patients with CAD, other occlusive arterial disease, or DM randomized to simvastatin (40 mg) or placebo for 5.5 years Event Rate Ratio (95% CI) Baseline LDL-C (mg/dL) Statin (n = 10,269) Placebo (n = 10,267) <100 282 (16.4%) 358 (21.0%) 100–129 668 (18.9%) 871 (24.7%) 130 1083 (21.6%) 1356 (26.9%) All patients 2033 (19.8%) 2585 (25.2%) Statin Better Statin Worse 0.76 (0.72–0.81) P<0.0001 The Heart Protection Study sought to evaluate the effect of simvastatin on all cause mortality in high risk patients regardless of LDL-C levels. Treatment with simvastatin resulted in a 12% relative risk reduction in all-cause mortality and a 24% relative risk reduction in the first occurrence of any major vascular event. The benefit of simvastatin even extended to individuals with a baseline LDL-C level <100 mg/dL. 0.4 0.6 0.8 1.0 1.2 1.4 HPS Collaborative Group. Lancet 2002;360:7-22

Heart Protection Study (HPS)- Simvastatin trial
Significant benefits with simvastatin : - 13 percent reduction in all-cause mortality (12.9 v/s % ) - 18 percent reduction in deaths from heart disease (5.7 v/s 6.9 %) - 24 percent reduction in major cardiovascular events (19.8 v/s 25.2 %) - 25 percent reduction in the first event rate for stroke (4.3 v/s 5.7%)

Clinical trials of statins - secondary prevention

Treating to New Targets (TNT) study
Intensive lowering of LDL-C with high-dose atorvastatin therapy Patients with CAD + metabolic syndrome prospective, double blind, parallel-group trial done at 256 sites (14 countries between ) median follow-up: 4·9 yrs patients enrolled aged 35–75 yrs - with clinically evident coronary heart disease.

TNT: A comparison of two different intensities of lipid lowering
TNT: Treating to New Targets Assessment of intensive lipid lowering on clinical outcomes Design: 10,001 patients with stable CHD and LDL-C mg/dL Treatment: Randomized to Atorvastatin 10 mg or 80 mg Follow-up: 4.9 years Primary outcome: CHD death, MI, resuscitation after cardiac arrest, fatal/nonfatal stroke TNT: A comparison of two different intensities of lipid lowering TNT tested the hypothesis that intensive lipid lowering would be associated with better clinical outcomes than less intensive treatment in patients with stable CHD. TNT extends the results of PROVE IT-TIMI 22, which evaluated intensive lipid lowering in patients with ACS. LaRosa JC et al. N Engl J Med. 2005;352:

TNT: Treatment effects on primary outcome
Atorvastatin 10 mg (n = 5006) 0.15 At 5 year: 22% Risk reduction HR = 0.78 (0.69–0.89) P < 0.001 0.10 Major CV events (%) Atorvastatin 80 mg (n = 4995) TNT demonstrates benefit of intensive lipid lowering in stable CHD The higher dose showed significantly greater efficacy. Following the Heart Protection Study, the TNT study sought to determine whether high dose statin therapy provided additional cardiovascular benefit among individuals with chronic coronary heart disease. All patients entered an open-label eight week period with low dose atorvastatin (10 mg), those who experienced a statin related side effect or did not achieve an LDL-C level <130 mg/dL were excluded prior to randomization. High dose atorvastatin (80 mg) resulted in a significant 22% relative risk reduction in the primary composite endpoint (death from coronary heart disease, nonfatal MI, resuscitation after cardiac arrest, and fatal or nonfatal stroke) as compared to low dose atorvastatin (10 mg). Paralleling the reduction in the composite primary endpoint was a decrease in the LDL-C levels to 77 mg/dL and 101 mg/dl in the high and low dose atorvastatin arms, respectively. There were no differences in overall mortality. These results add to the body of data obtained in the PROVE IT-TIMI 22 and HPS trials, demonstrating a benefit with lower LDL-C levels in individuals with coronary heart disease. 0.05 0.00 1 2 3 4 5 6 Follow-up (years) CHD death, MI, resuscitation after cardiac arrest, fatal/nonfatal stroke LaRosa JC et al. N Engl J Med. 2005;352:

Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Trial
Evaluated the effect of intensive vs. moderate lipid lowering therapy in patients with a history of MI 8,888 patients with a history of acute MI randomized to atorvastatin (80 mg) or simvastatin (20 mg) for 5 years Primary endpoint : - occurrence of a major coronary event ( coronary death, confirmed nonfatal acute MI, or cardiac arrest with resuscitation)

Years Since Randomization
Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Trial Pedersen et al. JAMA 2005;294: Simvastatin (20 mg) Atorvastatin (80 mg) 12 8 Cumulative Hazard (%) 4 HR=0.89 ( 95% CI ) The Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) study evaluated the effect of intensive vs. moderate lipid lowering therapy in patients with a history of MI. Patients were randomized to receive atorvastatin (80 mg) or simvastatin (20 mg) over a mean period of 5 years. The primary endpoint was occurrence of a major coronary event, defined as coronary death, confirmed nonfatal acute MI, or cardiac arrest with resuscitation. There was no significant difference in the primary endpoint (HR 0.89, 95% CI, , p=0.07), despite an LDL-C difference of 23 mg/dL (81 mg/dL vs. 104 mg/dl in the atorvastatin vs. simvastatin treatment groups, respectively). There was, however, a significant reduction in nonfatal MI (6.0% vs. 7.2% respectively, p=0.02), major cardiovascular events, and any coronary event. There was no difference in mortality endpoints between the two groups. Importantly, the primary endpoint did not include stroke. When stroke was added to the primary end point, however, the relative risk reduction was similar to that seen in the TNT study. IDEAL trial — The Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) study was an open label trial with blinded endpoint analysis that randomly assigned 8888 patients with a past history of acute MI to receive intensive lipid lowering therapy with atorvastatin 80 mg daily or standard lipid lowering therapy with simvastatin 20 mg daily [66]. After 24 weeks, the dose of simvastatin could be increased to 40 mg daily if the total cholesterol concentration was greater than 190 mg/dL (5.0 mmol/L); at the end of the study 23 percent of patients were taking simvastatin 40 mg daily. The dose of atorvastatin could be decreased to 40 mg daily for adverse events; at the end of the study, 13 percent of patients were taking atorvastatin 40 mg daily. The primary endpoint of the trial was time to first occurrence of a major coronary event (coronary death, hospitalization for acute MI, or cardiac arrest). The following findings were seen with atorvastatin compared with simvastatin at a median follow-up of 4.8 years: A lower LDL-C concentration (81 versus 104 mg /dL [2.7 versus 2.1 mmol/L]). A statistically nonsignificant reduction in the primary endpoint (9.3 versus 10.4 percent, hazard ratio [HR] 0.89, 95% CI ). No effect on all-cause mortality (HR 0.98, CI ), cardiovascular mortality (HR 1.03, CI ) or noncardiovascular mortality (HR 0.92, CI ). A reduction in a number of secondary endpoints including nonfatal myocardial infarction (6 versus 7.2 percent, HR 0.83, CI ) and coronary revascularization (13.0 versus 16.6 percent, HR 0.77, CI ). A higher rate of adverse events leading to discontinuation of the study drug (9.6 versus 4.2 percent) including myalgia (2.2 versus 1.1 percent); elevated aminotransferase levels were also more common 1 2 3 4 5 Years Since Randomization Non significant reduction in the primary endpoint (9.3 versus 10.4 percent) A reduction in a number of secondary endpoints: - nonfatal myocardial infarction (6 versus 7.2 percent HR CI ) - coronary revascularization (13.0 versus 16.6 percent HR CI ) No effect on : all-cause mortality ( HR CI ) : cardiovascular mortality ( HR CI ) : non cardiovascular mortality (HR CI )

The AVERT (Atorvastatin Versus Revascularization Treatment) trial
Compared the outcome of aggressive lipid-lowering with atorvastatin (80 mg/day) to that of angioplasty in 341 patients with 1 or 2 vessel CAD and LDL levels >115 mg/dl 18 month follow-up : - reduction in mean LDL levels was greater in the atorvastatin group - (140 to 77 mg/dL V/S 140 to 119 mg/dL in the angioplasty group) Atorvastatin group : Insignificant trend toward fewer composite endpoints (13 v/s 21 percent ) lower rate of CABG (1.2 v/s 5.1 percent) hospitalization for worsening angina (6.7 versus 14.1 percent) The AVERT (Atorvastatin Versus Revascularization Treatment) trial compared the outcome of aggressive lipid-lowering with atorvastatin (80 mg/day) to that of angioplasty in 341 patients with 1 or 2 vessel coronary artery disease and LDL levels >115 mg/dL (3.0 mmol/L) [112] . After an 18 month follow-up, the reduction in mean LDL levels was greater in the atorvastatin group (140 to 77 mg/dL versus 140 to 119 mg/dL in the angioplasty group). There was an insignificant trend toward fewer composite endpoints (death, myocardial infarction, stroke, resuscitated cardiac arrest, revascularization, and hospitalization for worsening angina) in the atorvastatin group (13 versus 21 percent for angioplasty); the atorvastatin group had a lower rate of bypass surgery (1.2 versus 5.1 percent) and hospitalization for worsening angina (6.7 versus 14.1 percent). The time to the first ischemic event was significantly longer in the atorvastatin group compared with the placebo group Time to the first ischemic event was significantly longer in the atorvastatin group compared with the placebo group

The AVERT (Atorvastatin Versus Revascularization Treatment) trial
Non significant trend toward fewer cardiac events (13 versus 21%). (Death, MI , stroke, resuscitated cardiac arrest, revascularization, and hospitalization for worsening angina)

PROVE IT: PRavastatin Or AtorVastatin Evaluation and Infection Therapy

PROVE IT: PRavastatin Or AtorVastatin Evaluation and Infection Therapy
Head-to-head comparison of Pravastatin and Atorvastatin First major trial to compare the effects of Pravastatin versus Atorvastatin in reducing the risk of MACE Designed to evaluate further the role of infection in cardiovascular disease The PROVE IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy) trial is a head-to-head trial, under the auspices of the TIMI trial group to compare two members of the statin class of lipid-lowering agents using a clinical event endpoint. This clinical trial will compare the effects of pravastatin against atorvastatin in reducing the risk of major cardiovascular events. Eugene Braunwald, MD, Distinguished Hersey Professor of Medicine and Faculty Dean for Academic Programs, Harvard Medical School, is the study Chairman and Christopher Cannon, MD, Associate Physician, Cardiovascular Division Brigham and Women’s Hospital and Assistant Professor of Medicine Harvard Medical School is the Principal Investigator.

PROVE IT study design Double-blind, randomised, 4,000 patients with ACS <10 days and total cholesterol <240 mg/dL Standard medical therapy Pravastatin 40 mg Atorvastatin 80 mg Gatifloxacin Placebo Gatifloxacin Placebo The PROVE IT trial is a placebo-controlled trial to investigate the effectiveness of early initiation of two statins, pravastatin and atorvastatin, with differential effects on lipid parameters and various pleiotrophic mechanisms. Both of these agents have been shown to be beneficial in ACS. Further rationale for the study is based on evidence supporting a role of infection with Chlamydia pneumoniae in the pathogenesis of atherosclerosis and acute coronary syndrome. This raises the possibility that therapy with antibiotics could further improve clinical outcome. Follow-up visit 30 days Minimum duration 18 months

PROVE IT-TIMI 22: RRR 16% Within 10 days of ACS or after PCI
N = 4162 with ACS 26.3% 30 P = 0.005 22.4% 40 mg Pravastatin 20 80 mg Atorvastatin Early, high-dose statin therapy is associated with early benefit Baseline LDL-C was 106 mg/dL in each group, and was reduced to 95 mg/dL and 62 mg/dL in the pravastatin and atorvastatin groups, respectively (P < 0.001). The primary outcome occurred in 26.3% and 22.4% of the pravastatin and atorvastatin groups, respectively (16% RRR in favor of atorvastatin, P = 0.005). Separation of the curves occurred as early as 30 days. Statistically significant benefit was evident at 4 months. Death or major CV event (%) 10 2 years follow-up Within 10 days of ACS or after PCI 3 6 9 12 15 18 21 24 27 30 Follow-up (months) Ray KK and Cannon CP Am J Cardiol. 2005;96(suppl):54F-60F. Adapted from Cannon CP et al. N Engl J Med. 2004;350:

A to Z: Early initiation of intensive regimen v/s delayed initiation of less-intensive regimen
Population: 4497 patients with ACS Treatments: Simvastatin 40 mg/d for 1 month, followed by 80 mg/d Placebo for 4 months, followed by simvastatin 20 mg/d Median follow-up: 2 years (721 days) Primary outcome: CV death, nonfatal MI, ACS readmission, stroke A to Z assessed two different lipid-lowering strategies The Aggrastat to Zocor (A to Z) trial randomized 4497 patients with ACS to one of two lipid-management strategies: Intensive: Simvastatin 40 mg for 1 month, followed by 80 mg thereafter. Less intensive: Placebo for 4 months, followed by simvastatin 20 mg thereafter. de Lemos JA et al. JAMA. 2004;292:

A to Z: Treatment effect on primary outcome at different time periods
N = 4497 with ACS within 2-5 days of events Primary composite outcome rate (%) Simvastatin 40/80 mg n = 2265 Placebo + simvastatin 20 mg n = 2232 Favors simvastatin 40/80 mg Favors placebo + simvastatin 20 mg Delayed treatment effect on clinical outcomes Post hoc analysis showed that no difference in the primary outcome occurred between the two arms over the first 4 months (placebo period) of the trial. From 4 months through study end, a treatment effect in favor of the more aggressive lipid-lowering therapy occurred (HR 0.75, 95% CI 0.66–0.95, P = 0.002). Overall study result 14.4 16.7 Randomization through month 4 Phase Z of the A to Z trial — Phase Z of the A to Z trial was a randomized trial that compared an aggressive statin strategy (simvastatin 40 mg daily for one month followed by 80 mg daily thereafter) with a delayed conservative strategy (placebo for four months followed by simvastatin 20 mg thereafter) in 4497 patients with acute coronary syndrome who had an initial total cholesterol level ≤ 250 mg/dL (6.48 mmol/L) [97] . The median follow-up was 721 days. 8.2 8.1 Months 4–24 6.8 9.3 0.5 1.0 1.5 Hazard ratio (95% CI) CV death, MI, recurrent ACS hospitalization, stroke de Lemos JA et al. JAMA. 2004;292:

Aggrastat to Zocor (A to Z) Trial
Placebo + Simvastatin 20 mg/day Simvastatin 40/80 mg/day Time from randomization (months) Cumulative event rate (%)* 5 10 15 20 4 8 12 16 24 HR=0.89, P=0.14 The A to Z trial sought to determine whether treatment with a low dose statin regimen would provide similar risk reduction in patients with an ACS as a high dose statin regimen (similar to that used in the PROVE IT-TIMI 22 and MIRACL trials). The high dose statin regimen consisted of treatment with simvastatin at 40 mg/day for one month, followed by an increase to 80 mg/day thereafter. The low dose statin regimen consisted of treatment with placebo for 4 months, followed by simvastatin at 20 mg/day thereafter. There was no statistical difference in the primary end point between the two treatment strategies; however, there was a trend towards a reduced event rate in the high dose statin regimen at the end of the 24 month follow-up. Unfortunately, the high dose statin regimen was associated with nine cases of statin-induced myopathy. Trend towards a reduced event rate in the high dose statin regimen at the end of 24 month follow-up - No statistical difference in the primary end point between the two treatment strategies de Lemos JA et al. JAMA 2004;292:

Relationship between LDL-C Levels and Event Rates in Secondary Prevention Statin Trials of Patients with Stable CHD 30 4S Statin Placebo 25 4S 20 LIPID Event (%) 15 LIPID CARE CARE 10 HPS HPS TNT (atorvastatin 10 mg/d) 5 TNT (atorvastatin 80 mg/d) Lowering of LDL-C levels with statin therapy leads to a reduction in cardiovascular morbidity and mortality, at multiple baseline risk levels. 70 90 110 130 150 170 190 210 LDL-C (mg/dL) CARE=Cholesterol and Recurrent Events Trial, HPS=Heart Protection Study, LIPID=Long-term Intervention with Pravastatin in Ischaemic Disease; 4S=Scandinavian Simvastatin Survival Study, TNT=Treating to New Targets LaRosa JC et al. NEJM 2005;352:

CHD event rates in secondary prevention trials (5 years in duration except the PROVE-IT study, which lasted 2 years) were directly proportional to low-density lipoprotein (LDL) cholesterol levels. The event rate is predicted to approach 0 at LDL of 30 mg/dL

RR in Primary End Point (%) LDL-C Reduction (mg/dL) Duration (years)
RR in MI or CHD Death (%) RR in Primary End Point (%) LDL-C Reduction (mg/dL) Duration (years) Population Trial 11 23 5 Stable CAD (N = 8888) IDEAL 21 22 24 Stable CAD (N =10,001) TNT 15 14 2 ACS (N = 4497) A to Z 16 33 ACS (N = 4162) PROVE IT- TIMI 22 Four trials of aggressive statin therapy have shown that an intensive strategy in patients with an acute coronary syndrome or stable coronary artery disease improves outcomes. In addition, the degree of LDL-C reduction seems to be related to the degree of clinical benefit. These trials support the idea that “lower is better”, whereby aggressive lowering of LDL-C is a primary means of reducing morbidity and mortality in patients with (or at risk for) cardiovascular disease. These trials also support the notion that increasing statin dose (intensity) reduce cardiovascular risk. It is important to note that the primary endpoints are not uniform across these trials. Specifically, the primary endpoints were: 1) PROVE IT-TIMI 22: A composite of death from any cause, myocardial infarction, documented unstable angina requiring rehospitalization, and revascularization 2) A to Z: A composite of cardiovascular death, nonfatal myocardial infarction, readmission for an acute coronary syndrome, and stroke 3) TNT: A composite of death from coronary heart disease, nonfatal MI, resuscitation after cardiac arrest, and fatal or nonfatal stroke 4) IDEAL: A composite of coronary death, confirmed nonfatal acute MI, and cardiac arrest with resuscitation Cannon CP et al. JAMA 2005;294:

Meta-Analysis of Intensive Statin Therapy Coronary Death or MI
Odds Reduction Event Rates No./Total (%) High Dose Std Dose -17% 147/2099 (7.0) 172/2063 (8.3) -15% 205/2265 (9.1) 235/2232 (10.5) -21% 334/4995 (6.7) 418/5006 (8.3) -12% 411/4439 (9.3) 463/4449 (10.4) -16% 1097/13798 (8.0) 1288/13750 (9.4) Odds Ratio (95% CI) PROVE IT-TIMI 22 A-to-Z TNT IDEAL Total OR, 0.84 95% CI, p= 1 High-dose better High-dose worse

Meta-Analysis of Intensive Statin Therapy All Endpoints
Odds Reduction Event Rates No./Total (%) High Dose Std Dose -16% 3972/13798 (28.8) 4445/13750 (32.3) 1097/13798 (8.0) 1288/13750 (9.4) -12% 462/13798 (3.3) 520/13750 (3.8) +3% 340/13798 (2.5) 331/13750 (2.4) -6% 808/13798 (5.9) 857/13750 (6.2) -18% 316/13798 (2.3) 381/13750 (2.8) Odds Ratio (95% CI) Coronary Death or Any Cardiovascular Event Coronary Death or MI Cardiovascular Death Non-Cardiovascular Death Total Mortality Stroke OR, 0.84 95% CI, p<0.0001 OR, 0.84 95% CI, p= OR, 0.88 95% CI, p=.054 OR, 1.03 95% CI, p=0.73 OR, 0.94 95% CI, P=0.20 OR 0.82 95% CI, p=0.012 0.5 1 2.5 High-dose statin better High-dose statin worse Cannon CP, et al. JACC 2006; 48:

SATURN trial - Compared two intensive statin therapy regimens
- Atorvastatin 80 mg daily v/s Rosuvastatin 40 mg daily patients with known CAD Compared with Atorvastatin patients treated with Rosuvastatin had - lower levels of LDL-C 62 md/dl v/s mg/dL - higher levels of HDL-C 50 mg/dl v/s mg/dL - No statistically-significant difference between the regimens in the primary endpoint of percent atheroma volume (↓ed with both regimens : 1.22 % V/S % respectively)

Early use of statins after an ACS
Secondary prevention trials : - primarily evaluated the role of statin therapy initiated 3 to 6 months or longer after acute MI Statins may decrease CVS events by a number of mechanisms ( important early after MI) - plaque stabilization - reversal of endothelial dysfunction - inhibition of monocyte recruitment - ↓ed thrombogenicity - reduction in inflammation led to the investigation of earlier initiation of statin therapy during ACS (MI or unstable angina)

Clinical evidence for the benefits of early statin initiation
Study Time to Statin Results initiation PTT1 6 h Pravastatin  coronary events  restenosis rates L-CAD2 6 d Pravastatin Improved outcomes  mean progression  coronary lesion regression RECIFE3 10 d Pravastatin Rapid improvement of endothelial function FLORIDA4 8 d Fluvastatin No significant benefit MIRACL5 24–96 h Atorvastatin  time to first event A number of small-scale studies have been carried out in recent times looking at the effects of early initiation of statin treatment after an ACS. PTT, L-CAD and RECIFE all studied the effects of pravastatin and, although all of these studies were of a small scale, in each case early initiation of pravastatin was demonstrated to be beneficial. FLORIDA was a double-blind, placebo-controlled trial of fluvastatin initiated at average 8 days after the onset of symptoms of AMI. The primary endpoint was the composite of clinical events (CV death, non-CV death, recurrent MI, recurrent ischaemia necessitating hospitalisation, CABG or PCTA) and myocardial ischaemia on 48-hour monitoring at 1 year. There was no significant benefit with fluvastatin therapy. Most recently the large MIRACL study has provided further evidence for the benefits of early statin initiation. References 1. Kayikcioglu M, Türkoglu C, Can L et al.The combined use of pravastatin and thrombolytic agents in acute myocardial infarction. Circulation 1999; 100: 1–303. 2. Arntz HR, Wunderlich W, Schnitzer L. The decisive importance of cholesterol lowering therapy for coronary lesions and clinical course immediately after an acute coronary event: short and long term results of a controlled study. Circulation 1998; 98 (Suppl. 1):1–45, 222. 3. Dupuis J, Tardif J-C, Cernacek P et al. Cholesterol reduction rapidly improves endothelial function after acute coronary syndromes. The RECIFE (REduction of Cholesterol in Ischaemia and Function of the Endothelium) trial. Circulation 1999; 99: 3227–3233. 4. Van Boven AJ, Liem AH. Fluvastatin On RIsk Diminishing after Acute MI. AHA 2000. 5. Schwartz GG, Oliver MF, Ezekowitz MD et al. Rationale and design of the myocardial ischemia reduction with aggressive cholesterol lowering (MIRACL) study that evaluates atorvastatin in unstable angina pectoris and in non-Q-wave acute myocardial infarction. Am J Cardiol 1998; 81: 578–581. 1 Pravastatin and Thrombolytic Therapy 2 Lipids in Coronary Artery Disease 3 Reduction of Cholesterol in Ischaemia and Function of the Endothelium 4 FLuvastatin On RIsk Diminishing after Acute myocardial infarction 5 Myocardial Ischaemia Reduction with Aggressive Cholesterol Lowering

Timing of statin therapy initiation after ACS in recent clinical studies
Atorvastatin Pravastatin MIRACL PTT Simvastatin Fluvastatin 4S WOSCOPS FLORIDA L-CAD CARE ACS RECIFE LIPID The Pravastatin and Thrombolytic Therapy (PTT) trial had the earliest time for initiation of treatment. Patients suffering an acute myocardial infarction were randomised within the first 6 hours of experiencing chest pain to receive either pravastatin (40 mg/day) within 1 hour of thrombolytic therapy (TT), irrespective of serum lipid level, or TT alone. Reference 1. Kayikcioglu M, Türkoglu C, Can L et al.The combined use of pravastatin and thrombolytic agents in acute myocardial infarction. Circulation 1999; 100: 1– 303. Primary prevention Secondary prevention 6 12 18 24 2 4 6 8 10 12 3 6 Hours Days Months

Patients with event (%)
Pravastatin and Thrombolytic Therapy trial (PTT): Early therapy improves event-free survival Patients with event (%) 30 Pravastatin (n=72) Control (n=78) 20 † ‡ 10 The Pravastatin and Thrombolytic Therapy (PTT) trial looked at patients suffering an acute myocardial infarction, within the first 6 hours of experiencing chest pain. Patients were randomised to receive either pravastatin (40 mg/day; n=72) within the first hour after initiation of thrombolytic therapy (irrespective of serum lipid levels) or thrombolytic therapy alone (n=78). In both groups, tissue plasminogen activator and streptokinase administration rates were similar, as were baseline characteristics. The results revealed a lower incidence of in-hospital death. Furthermore, non-fatal MI and recurrent angina were reduced in the pravastatin group (the difference between the groups was statistically significant in the case of non-fatal MI) during the 6-month period following the initial event. Reference 1. Kayikcioglu M, Türkoglu C, Can L et al.The combined use of pravastatin and thrombolytic agents in acute myocardial infarction. Circulation 1999; 100: I–303. Non-fatal MI ** Recurrent angina ** In-hospital death *Within 6 hours of MI; **6 months follow-up †p=0.01, ‡p=0.03

Atorvastatin Pravastatin MIRACL Simvastatin PTT Fluvastatin 4S WOSCOPS FLORIDA L-CAD CARE ACS RECIFE LIPID The Lipids in Coronary Artery Disease (L-CAD) Study investigated the impact of early initiation of lipid-lowering therapy on coronary stenoses and clinical outcome in patients with elevated low-density lipoprotein cholesterol (LDL-C) levels. Patients were randomised, on average 6 days after an acute MI and/or PTCA secondary to unstable angina, to pravastatin (combined where necessary with cholestyramine and/or nicotinic acid) to achieve LDL-C levels 130 mg/dL (3.4 mmol/L). In control groups antilipidaemic therapy was decided by family physicians. Reference 1. Arntz H-R. Evidence for the benefit of early intervention with pravastatin for secondary prevention of cardiovascular events. Atherosclerosis. 1999; 147 (Suppl. 1): S17–S21. Primary prevention Secondary prevention 6 12 18 24 2 4 6 8 10 12 3 6 Hours Days Months

L-CAD study design 126 men and women post acute MI and/or PTCA for UA
Baseline cholesterol 130–250 mg/dL Pravastatin 20–40 mg (+cholestyramine and nicotinic acid) to achieve an LDL <130 mg/dL Usual care Patients were randomised, on average, 6 days after an acute myocardial infarction (MI) and /or PTCA secondary to unstable angina (UA) to receive either pravastatin (combined, when necessary, with cholestyramine and/or nicotinic acid) to achieve a low-density lipoprotein cholesterol (LDL-C) level of 130 mg/dL (3.4 mmol/L). In the control group, antilipidaemic therapy was decided by the family physician. Patients were followed for up to 2 years. The combined clinical endpoint was total mortality, cardiovascular death, non-fatal MI, need for coronary intervention, stroke and new onset of peripheral vascular disease. Reference 1. Arntz HR et al. Am J Cardiol, in press. Clinical – 2 years, Angiography – 6 months and 2 years major CV clinical events L-CAD = Lipids in Coronary Artery Disease

L-CAD: Survival without major cardiovascular events
1.0 0.8 Pravastatin-based intensified (n=70) 0.6 Conventional (n=56) 0.4 In the L-CAD study, intensive therapy involving pravastatin treatment (combined, where necessary, with cholestyramine and/or nicotinic acid) was given to patients 6 days after acute MI or PTCA to achieve LDL-C levels <130 mg/dL (3.4 mmol/L). In the control group, antilipidaemic therapy was decided by family physicians. Significantly fewer cardiovascular events were recorded in the group receiving pravastatin than in patients randomised to conventional treatment. At the end of the 2-year follow-up period, major clinical events (death, MI, cerebral infarction, new peripheral vascular disease or need for coronary intervention) had occurred in 43% of patients in the conventional therapy group compared with only 17% of patients in the intensive therapy group (p<0.03). Reference 1. Arntz HR et al. Am J Cardiol, in press. 0.2 Log rank = Breslow = 2 4 6 8 10 12 14 16 18 20 22 24 Time (months)

(REduction of Cholesterol in Ischemia and Function of the Endothelium Atorvastatin Pravastatin MIRACL Simvastatin PTT Fluvastatin 4S WOSCOPS FLORIDA L-CAD CARE ACS RECIFE LIPID The RECIFE trial – REduction of Cholesterol in Ischemia and Function of the Endothelium – studied the effects of pravastatin on endothelium-dependent flow-mediated dilatation of the brachial artery as an indicator of likely benefit in risk reduction. Patients with acute MI or unstable angina and total cholesterol levels at admission 200 mg/dL (5.2 mmol/L) or LDL 130 mg/dL (3.4 mmol/L) were randomised to receive pravastatin (40 mg/day) or placebo for 6 weeks. The mean delay between admission and randomisation into the study was 10.4  0.69 days. Reference 1. Dupuis J, Tardif J-C, Cernacek P et al. Cholesterol reduction rapidly improves endothelial function after acute coronary syndromes. The RECIFE (REduction of Cholesterol in Ischemia and Function of the Endothelium) trial. Circulation 1999; 99: –3233. Primary prevention Secondary prevention 6 12 18 24 2 4 6 8 10 12 3 6 Hours Days Months

Flow-mediated dilatation (%)*
The RECIFE study: Pravastatin rapidly improves endothelial function after ACS Flow-mediated dilatation (%)* 8 7 Pravastatin 40 mg/day p<0.05 6 Placebo The RECIFE trial (REduction of Cholesterol in Ischemia and Function of the Endothelium) conducted at the Montreal Heart Institute in Canada randomised 60 patients with an acute coronary syndrome (on average 10 days after an event) to either pravastatin 40 mg/day or placebo. After 6 weeks, there was no significant change in endothelium-dependent flow-mediated dilatation of the brachial artery in placebo-treated patients. However, those receiving pravastatin had a significant improvement relative to placebo. There were no differences in dilatation with nitroglycerin, which is independent of endothelial function. Hence, with pravastatin treatment endothelial function improves rapidly within 6 weeks following an acute coronary syndrome. Reference 1. Dupuis J, Tardif J-C, Cernacek P et al. Cholesterol reduction rapidly improves endothelial function after acute coronary syndromes. The RECIFE (REduction of Cholesterol in Ischaemia and Function of the Endothelium) trial. Circulation ; 99: 3227–3233. 5 4 6 Time (weeks) *60 patients admitted for acute MI or unstable angina, enrolled before hospital discharge

Atorvastatin Pravastatin MIRACL Simvastatin PTT Fluvastatin 4S WOSCOPS FLORIDA L-CAD CARE ACS RECIFE LIPID The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study has provided further support for the benefit of early statin initiation following an acute coronary syndrome. Reference 1. Schwartz GG, Oliver MF, Ezekowitz MD et al. Rationale and design of the myocardial ischemia reduction with aggressive cholesterol lowering (MIRACL) study that evaluates atorvastatin in unstable angina pectoris and in non-Q-wave acute myocardial infarction. Am J Cardiol 1998; 81: 578–581. Primary prevention Secondary prevention 6 12 18 24 2 4 6 8 10 12 3 6 Hours Days Months

Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL)
Effects of Atorvastatin on Early Recurrent Ischemic Events in ACS: A Randomized Controlled Trial The Hypothesis Rapid and early cholesterol reduction Diminished incidence of recurrent ischemic events Early plaque stabilisation Objective: “To prove that early, rapid, and intensive cholesterol lowering therapy will reduce early recurrent ischemic events in patients with unstable angina or non-Q-wave MI”

MIRACL study design Prospective, randomised, multicentre, double-blind
Exclusion criteria Serum cholesterol >270 mg/dL Concurrent or previous interventional therapy (6 months) or surgery (3 months) Concurrent lipid-lowering therapy Any agent likely to induce rhabdomyolysis when taken with statins 3,086 patients Inclusion criteria UA or non-Q-wave MI in previous 1–4 days MIRACL included both unstable angina and non-Q-wave MI patients. A dose of 80 mg atorvastatin was chosen to ensure maximum lipid-lowering activity. Exclusion criteria were total cholesterol > 7 mmol/L (270 mg/dL), planned coronary revascularisation, recent Q-wave MI (< 1 month), CABG (< 3 months), or PTCA (<6 months), LBBB or paced ventricular rhythm, concurrent lipid-lowering therapy, treatment with agents increasing the risk of myopathy, (including those interfering with cytochrome P450), serum ALT >2 x ULN, or severe systemic disease. Reference 1. Schwartz GG, Oliver MF, Ezekowitz MD et al. Rationale and design of the myocardial ischemia reduction with aggressive cholesterol lowering (MIRACL) study that evaluates atorvastatin in unstable angina pectoris and in non-Q-wave acute myocardial infarction. Am J Cardiol 1998; 81: 578–581. 80 mg atorvastatin, commenced within 24–96 h of event Placebo, commenced within 24–96 h of event Follow up at 2, 6 and 16 weeks for endpoints

MIRACL study outcome measures
Primary Time from randomisation to first occurrence of any of the following: Death (any cause) Non-fatal MI Resuscitated cardiac arrest Worsening angina pectoris with new objective evidence of myocardial ischemia, requiring urgent rehospitalisation Secondary Time to occurrence and incidence of each of the primary outcome components, plus: Stroke Myocardial revascularisation (CABG or PTCA) Worsening congestive heart failure Worsening angina without new objective evidence of ischemia The outcome measures studied covered multiple endpoints. Interestingly, the primary outcome variable was defined as time from randomisation to first occurrence of a composite endpoint, and not the rate of occurrence of the event, as has been the case in a number of previous studies. However, incidence of each event was measured as a secondary outcome variable. Reference 1. Schwartz GG, Oliver MF, Ezekowitz MD et al. Rationale and design of the myocardial ischemia reduction with aggressive cholesterol lowering (MIRACL) study that evaluates atorvastatin in unstable angina pectoris and in non-Q-wave acute myocardial infarction. Am J Cardiol 1998; 81: 578–581.

Primary efficacy measure
Cumulative incidence (%) 17.4% Placebo 15 14.8% Atorvastatin 10 Time to first occurrence of composite endpoint of: Death (any cause) Non-fatal MI Resuscitated cardiac arrest Worsening angina with new objective evidence and urgent rehospitalisation Risk reduction = 16% p=0.048 5 The graph shows the time to the first occurrence of death (any cause), non-fatal MI, resuscitated cardiac arrest, and worsening angina with new objective evidence of ischaemia requiring hospitalisation. Due to an interim analysis being performed, the p-value required to achieve significance was adjusted to p= There was a significant 16% reduction in the atorvastatin-treated patients (p=0.048; relative risk 0.84 [95% confidence interval ]). Reference 1. Olsson AG, Schwartz GG, for the MIRACL investigators and study committee. Myocardial ischaemia reduction with aggressive cholesterol lowering: MIRACL rationale and results. AHA 2000, Late breaking clinical trials presentation. 95% CI = 0.701–0.999 4 8 12 16 Time since randomisation (weeks)

Atorvastatin Pravastatin MIRACL Simvastatin PTT Fluvastatin 4S WOSCOPS FLORIDA L-CAD CARE ACS RECIFE LIPID The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study has provided further support for the benefit of early statin initiation following an acute coronary syndrome. Reference 1. Schwartz GG, Oliver MF, Ezekowitz MD et al. Rationale and design of the myocardial ischemia reduction with aggressive cholesterol lowering (MIRACL) study that evaluates atorvastatin in unstable angina pectoris and in non-Q-wave acute myocardial infarction. Am J Cardiol 1998; 81: 578–581. Primary prevention Secondary prevention 6 12 18 24 2 4 6 8 10 12 3 6 Hours Days Months

Limiting Under treatment of lipids in ACS With Rosuvastatin
Comparison of Lipid-Modifying Efficacy of Rosuvastatin Versus Atorvastatin in Patients With ACS (LUNAR Study) Limiting Under treatment of lipids in ACS With Rosuvastatin Am J Cardiol 2012;109:1239 –1246

Compared the efficacy of RSV20 and RSV40 with ATV80
in patients with ACS Prospective, multicenter, randomized, open-label, 3-arm, parallel-group trial. Inclusion Criteria: ACS patients with in 48 hrs of ischemia - STEMI pts with intervention with in 12 hrs of symptoms (TLT or PCI) - NSTEMI/UA with conservative management - LDL-C >70 mg/dl, fasting TG < 500 mg/dl with in 72 hrs of symptom onset

Baseline characteristics of randomized patients

* p <0.05; † p < 0.01; ‡ p < 0.001 versus atorvastatin 80 mg/day.

Mean percent change from baseline by weeks 2, 6, and 12 in low-density lipoprotein cholesterol (LDL-C)

Mean percent change from baseline by weeks 2, 6, and 12 in (high-density lipoprotein cholesterol (HDL-C)..

Conclusion: LUNAR study
RSV 40 more effectively decreased LDL-C , increased HDL-C and improved other blood lipid parameters when compared to RSV20 And ATV80 in patients with ACS

ARMYDA-RECAPTURE (p = 0.04) (p = 0.02) 25 23 20 15 13
Trial design: This study evaluated the efficacy of an atorvastatin reloading strategy in patients on chronic statin therapy undergoing PCI for stable angina or NSTEMI. Results (p = 0.04) (p = 0.02) 30-day MACE: 3.4% vs. 9.1%, p = 0.04 CK-MB elevation: 13% vs. 23%, p = 0.02 Troponin-I elevation: 36% vs. 47%, p = 0.03 Peak CRP: 2.1 ± 6.7 vs. 3.0 ± 9.5, p = 0.12 25 23 20 Conclusions 15 13 An 80 mg loading dose of atorvastatin followed by a 40 mg preprocedural dose may reduce the incidence of post-procedure MACE in patients on background statin therapy These data support a strategy of routine atorvastatin reloading prior to PCI in patients on background statin therapy % Patients 9.1 10 5 3.4 MACE CK-MB Atorvastatin (n = 177) Placebo (n = 175)

Effects of Withdrawal of Statin After AMI
Kaplan–Meier analysis of effect of statin treatment patterns on 1-year all-cause mortality among survivors of a first acute myocardial infarction (AMI). Non-users =defined as patients not receiving statins before or after AMI; users those receiving statins before and continuing after AMI; starters those who did not receive statins before their AMI but who started after it; and, stoppers were defined as those who stopped statin therapy after their AMI. starters = did not receive before AMI but started after; users = before and continuing after AMI Non-users =not receiving before or after AMI; stoppers = stopped statin after AMI. Daskalopoulou S, et al. European Heart Journal (2008) 29, 2083–2091

Controlled Rosuvastatin in Multinational Trial in HF
CORONA Trial: Controlled Rosuvastatin in Multinational Trial in HF elderly patients (age >60) - with ischemic cardiomyopathy - NYHA class II to IV HF - median follow-up of 32.8 months - randomly assigned to Rosuvastatin 10 mg or placebo Primary composite outcome: CVS death, nonfatal MI, or nonfatal stroke Secondary outcomes: Death from any cause, any coronary event, death CVS causes, number of hospitalizations.

Controlled Rosuvastatin in Multinational Trial in HF
CORONA Trial: Controlled Rosuvastatin in Multinational Trial in HF N Engl J Med 2007;357:2252 No significant risk reduction in primary outcome - death from CVS causes nonfatal MI nonfatal stroke

- No effect on CVS outcome, NYHA class or quality of life.
Fewer hospitalizations for CVS causes ( Rosuvastatin (2193) v/s placebo (n 2564) (P < .001)

Meta-analysis of Statin Use in HF
- Meta-analysis of 13 HF trials estimated survival benefit of statin use in patients with HF of ischemic and nonischemic etiologies Statin use in HF associated with 26% RRR in mortality (HR ; 95% CI, 0.68 to 0.8) 8 trials - statin use associated with an improved survival among patients who had HF Effect is noted independent of etiology for HF (for ischemic etiology HR 0.73; 95% CI 0.65 to 0.82) ( for nonischemic etiology HR 0.73; 95% CI 0.61 to 0.87)

Meta-analysis of mortality among patients with heart failure
HF patients using statins (n = 30,107) HF patients not using statins (n =101,323) J Am Coll Cardiol 2008;51:422

Adjusted mortality among patients with ischemic HF (n = 62,273) using
statins, compared with those not using statins (B) Mortality among patients with HF of nonischemic HF (n 5 31,551) using statins compared with those not using statins. J Am Coll Cardiol 2008;51:423

Thank you

Dr sajeer Senior Resident Dept. of Cardiology, MCH, Calicut

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Dr sajeer Senior Resident Dept. of Cardiology, MCH, Calicut

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