title: High-Dose Atorvastatin Enhances the Decline in Inflammatory Markers in Patients With Acute Coronary Syndromes in the MIRACL Study A multicenter risk index for atrial fibrillation after cardiac surgery. Randomized Trial of Atorvastatin for Reduction of Postoperative Atrial Fibrillation in Patients Undergoing Cardiac Surgery: Results of the ARMYDA-3 (Atorvastatin for Reduction of MYocardial Dysrhythmia After cardiac surgery) Study Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. A statin in the treatment of heart failure? Controlled rosuvastatin multinational study in heart failure (CORONA): study design and baseline characteristics. Effect of C-reactive protein reduction on paroxysmal atrial fibrillation. Analysis of pravastatin to prevent recurrence of atrial fibrillation after electrical cardioversion. Effect of atorvastatin on the recurrence rates of atrial fibrillation after electrical cardioversion. Effects of atorvastatin on systemic inflammatory response after coronary bypass surgery
abstract: Background —Inflammation promotes acute coronary syndromes and ensuing clinical complications . Although statins reduce inflammatory markers in asymptomatic adults or in patients with stable angina , the effect of statins on the markedly heightened inflammation in patients with acute coronary syndromes is unknown . Methods and Results —We measured C-reactive protein ( CRP ) , serum amyloid A ( SAA ) , and interleukin 6 ( IL-6 ) in 2402 subjects enrolled the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering ( MIRACL ) study . Subjects with unstable angina or non – Q-wave myocardial infa rct ion were r and omized to atorvastatin 80 mg/d or placebo within 24 to 96 hours of hospital admission and treated for 16 weeks . The effect of treatment on inflammatory markers was assessed by ANCOVA after adjustment for presenting syndrome , country , and initial level of marker . All 3 markers were markedly elevated at r and omization and declined over the 16 weeks in both treatment groups . Compared with placebo , atorvastatin significantly reduced CRP , −83 % ( 95 % CI , −84 % , −81 % ) versus −74 % ( 95 % CI , −75 % , −71 % ) ( P < 0.0001 ) and SAA , −80 % ( 95 % CI , −82 % , −78 % ) versus −77 % ( −79 % , −75 % ) ( P = 0.0006 ) but not IL-6 , −55 % ( 95 % CI , −57 % , −53 % ) versus −53 % ( 95 % CI , −55 % , −51 % ) ( P = 0.3 ) . Reductions in CRP and SAA were observed in patients with unstable angina and non – Q-wave myocardial infa rct ion , with initial LDL cholesterol < 3.2 or ≥3.2 mmol/L ( 125 mg/dL ) , age ≥65 or < 65 years , and in men and women . By 16 weeks , CRP was 34 % lower with atorvastatin than with placebo . Conclusions —High-dose atorvastatin potentiated the decline in inflammation in patients with acute coronary syndromes . This supports the value of early statin therapy in these patients CONTEXT Atrial fibrillation is a common , but potentially preventable , complication following coronary artery bypass graft ( CABG ) surgery . OBJECTIVES To assess the nature and consequences of atrial fibrillation after CABG surgery and to develop a comprehensive risk index that can better identify patients at risk for atrial fibrillation . DESIGN , SETTING , AND PARTICIPANTS Prospect i ve observational study of 4657 patients undergoing CABG surgery between November 1996 and June 2000 at 70 centers located within 17 countries , selected using a systematic sampling technique . From a derivation cohort of 3093 patients , associations between predictor variables and postoperative atrial fibrillation were identified to develop a risk model , which was assessed in a validation cohort of 1564 patients . MAIN OUTCOME MEASURE New-onset atrial fibrillation after CABG surgery . RESULTS A total of 1503 patients ( 32.3 % ) developed atrial fibrillation after CABG surgery . Postoperative atrial fibrillation was associated with subsequent greater re source use as well as with cognitive changes , renal dysfunction , and infection . Among patients in the derivation cohort , risk factors associated with atrial fibrillation were advanced age ( odds ratio [ OR ] for 10-year increase , 1.75 ; 95 % confidence interval [ CI ] , 1.59 - 1.93 ) ; history of atrial fibrillation ( OR , 2.11 ; 95 % CI , 1.57 - 2.85 ) or chronic obstructive pulmonary disease ( OR , 1.43 ; 95 % CI , 1.09 - 1.87 ) ; valve surgery ( OR , 1.74 ; 95 % CI , 1.31 - 2.32 ) ; and postoperative withdrawal of a beta-blocker ( OR , 1.91 ; 95 % CI , 1.52 - 2.40 ) or an angiotensin-converting enzyme ( ACE ) inhibitor ( OR 1.69 ; 95 % CI , 1.38 - 2.08 ) . Conversely , reduced risk was associated with postoperative administration of beta-blockers ( OR , 0.32 ; 95 % CI , 0.22 - 0.46 ) , ACE inhibitors ( OR , 0.62 ; 95 % CI , 0.48 - 0.79 ) , potassium supplementation ( OR , 0.53 ; 95 % CI , 0.42 - 0.68 ) , and nonsteroidal anti-inflammatory drugs ( OR , 0.49 ; 95 % CI , 0.40 - 0.60 ) . The result ing multivariable risk index had adequate discriminative power with an area under the receiver operating characteristic ( ROC ) curve of 0.77 in the validation sample . Forty-three percent ( 640/1503 ) of patients who had atrial fibrillation after CABG surgery experienced more than 1 episode of atrial fibrillation . Predictors of recurrent atrial fibrillation included older age , history of congestive heart failure , left ventricular hypertrophy , aortic atherosclerosis , bicaval venous cannulation , withdrawal of ACE inhibitor or beta-blocker therapy , and use of amiodarone or digoxin ( area under the ROC curve of 0.66 ) . Patients with recurrent atrial fibrillation had longer hospital stays and experienced greater infectious , renal , and neurological complications than those with a single episode . CONCLUSIONS We have developed and vali date d models predicting the occurrence of atrial fibrillation  after CABG surgery based on an analysis of a large multicenter international cohort . Our findings suggest that treatment with beta-blockers , ACE inhibitors , and /or nonsteroidal anti-inflammatory drugs may offer protection . Atrial fibrillation after CABG surgery is associated with important complications Background — Atrial fibrillation ( AF ) after cardiac surgery is associated with increased risk of complications , length of stay , and cost of care . Observational evidence suggests that patients who have undergone previous statin therapy have a lower incidence of postoperative AF . We tested this observation in a r and omized , controlled trial . Methods and Results — Two hundred patients undergoing elective cardiac surgery with cardiopulmonary bypass , without previous statin treatment or history of AF , were enrolled . Patients were r and omized to atorvastatin ( 40 mg/d , n=101 ) or placebo  ( n=99 ) starting 7 days before operation . The primary end point was incidence of postoperative AF ; secondary end points were length of stay , 30-day major adverse cardiac and cerebrovascular events , and postoperative C-reactive protein ( CRP ) variations . Atorvastatin significantly reduced the incidence of AF versus placebo ( 35 % versus 57 % , P=0.003 ) . Accordingly , length of stay was longer in the placebo versus atorvastatin arm ( 6.9±1.4 versus 6.3±1.2 days , P=0.001 ) . Peak CRP levels were lower in patients without AF ( P=0.01 ) , irrespective of r and omization assignment . Multivariable analysis showed that atorvastatin treatment conferred a 61 % reduction in risk of AF ( odds ratio 0.39 , 95 % confidence interval 0.18 to 0.85 , P=0.017 ) , whereas high postoperative CRP levels were associated with increased risk ( odds ratio 2.0 , 95 % confidence interval 1.2 to 7.0 , P=0.01 ) . The incidence of major adverse cardiac and cerebrovascular events at 30 days was similar in the 2 arms . Conclusions — Treatment with atorvastatin 40 mg/d , initiated 7 days before surgery , significantly reduces the incidence of postoperative AF after elective cardiac surgery with cardiopulmonary bypass and shortens hospital stay . These results may influence practice patterns with regard to adjuvant pharmacological therapy before cardiac surgery CONTEXT Patients experience the highest rate of death and recurrent ischemic events during the early period after an acute coronary syndrome , but it is not known whether early initiation of treatment with a statin can reduce the occurrence of these early events . OBJECTIVE To determine whether treatment with atorvastatin , 80 mg/d , initiated 24 to 96 hours after an acute coronary syndrome , reduces death and nonfatal ischemic events . DESIGN AND SETTING A r and omized , double-blind trial conducted from May 1997 to September 1999 , with follow-up through 16 weeks at 122 clinical centers in Europe , North America , South Africa , and Australasia . PATIENTS A total of 3086 adults aged 18 years or older with unstable angina or non-Q-wave acute myocardial infa rct ion . INTERVENTIONS Patients were stratified by center and r and omly assigned to receive treatment with atorvastatin ( 80 mg/d ) or matching placebo between 24 and 96 hours after hospital admission . MAIN OUTCOME MEASURES Primary end point event defined as death , nonfatal acute myocardial infa rct ion , cardiac arrest with resuscitation , or recurrent symptomatic myocardial ischemia with objective evidence and requiring emergency rehospitalization . RESULTS A primary end point event occurred in 228 patients ( 14.8 % ) in the atorvastatin group and 269 patients ( 17.4 % ) in the placebo group ( relative risk [ RR ] , 0.84 ; 95 % confidence interval [ CI ] , 0.70 - 1.00 ; P = .048 ) . There were no significant differences in risk of death , nonfatal myocardial infa rct ion , or cardiac arrest between the atorvastatin group and the placebo group , although the atorvastatin group had a lower risk of symptomatic ischemia with objective evidence and requiring emergency rehospitalization ( 6.2 % vs 8.4 % ; RR , 0.74 ; 95 % CI , 0.57 - 0.95 ; P = .02 ) . Likewise , there were no significant differences between the atorvastatin group and the placebo group in the incidence of secondary outcomes of coronary revascularization procedures , worsening heart failure , or worsening angina , although there were fewer strokes in the atorvastatin group than in the placebo group ( 12 vs 24 events ; P = .045 ) . In the atorvastatin group , mean low-density lipoprotein cholesterol level declined from 124 mg/dL ( 3.2 mmol/L ) to 72 mg/dL ( 1.9 mmol/L ) . Abnormal liver transaminases ( > 3 times upper limit of normal ) were more common in the atorvastatin group than in the placebo group ( 2.5 % vs 0.6 % ; P<.001 ) . CONCLUSION For patients with acute coronary syndrome , lipid-lowering therapy with atorvastatin , 80 mg/d , reduces recurrent ischemic events in the first 16 weeks , mostly recurrent symptomatic ischemia requiring rehospitalization BACKGROUND Previous prospect i ve outcome studies of statins have not provided any guidance on benefit-risk in patients with heart failure . AIM The primary objective is to determine whether rosuvastatin ( 10 mg ) reduces the combined endpoint of cardiovascular mortality , non-fatal myocardial infa rct ion or non-fatal stroke ( time to first event ) . The first secondary endpoint is all-cause mortality . METHODS CORONA is a r and omized , double-blind , placebo-controlled trial . Briefly , men and women , aged > or = 60 years with chronic symptomatic systolic heart failure of ischemic aetiology and ejection fraction < or = 0.40 ( NYHA class III and IV ) or < or = 0.35 ( NYHA class II ) were eligible if they were not using or in need of cholesterol lowering drugs .  RESULTS Mean age was 73 years ( n=5016 ; 24 % women ) , with 37 % in NYHA II and 62 % in NYHA III , ejection fraction 0.31 , total cholesterol 5.2 mmol/L. Sixty percent have a history of myocardial infa rct ion , 63 % hypertension , and 30 % diabetes . Patients are well treated for heart failure with 90 % on loop or thiazide diuretics , 42 % aldosterone antagonists , 91 % ACE inhibitor or AT-I blocker , 75 % beta-blockers , and 32 % digitalis . CONCLUSION CORONA is important for three main reasons : ( 1 ) A positive result is very important because of the high risk of the population studied , the increasing prevalence of elderly patients with chronic symptomatic systolic heart failure in our society , and the health economic issues involved . ( 2 ) If negative , new mechanistic questions about heart failure have to be raised . ( 3 ) If neutral we can avoid unnecessary polypharmacy BACKGROUND C-reactive protein ( CRP ) lowering is associated with a reduction in recurrent and permanent atrial fibrillation . This study sought to determine whether CRP lowering also results in a reduction of paroxysmal atrial fibrillation ( PAF ) during daily life . METHODS AND RESULTS We enrolled 80 patients with proven PAF , CRP between 0.8 and 13 mg/L , and at least 1 episode of PAF on ambulatory electrocardiographic monitoring . Forty patients were r and omized to placebo ( placebo group ) and 40 to atorvastatin ( treatment group ) .  Plasma  CRP levels and ambulatory monitoring were repeated after 4 to 6 months of therapy . The 2 groups were comparable with respect to baseline characteristics , number of episodes of PAF , and baseline plasma CRP levels . The treatment group had lower median CRP levels at study end and experienced a significant reduction in the number of episodes of PAF compared with the placebo group . Paroxysmal atrial fibrillation was completely resolved in 26 ( 65 % ) of 40 patients in the treatment group versus 4 ( 10 % ) of 40 in the placebo group . The treatment group exhibited a highly significant reduction in PAF ( P < .001 ) . By logistic regression , treatment with atorvastatin was an independent predictor of PAF resolution . CONCLUSIONS C-reactive protein lowering with atorvastatin appears to be effective in eliminating PAF during daily life in a significant proportion of patients To test the hypothesis that a statin could reduce the recurrence rate of atrial fibrillation after electrical cardioversion ( EC ) , we performed an open , controlled multicenter study . Patients ( n = 114 ) who had atrial fibrillation > 48 hours and who were scheduled for EC were r and omized to receive 40 mg of pravastatin once daily for 3 weeks before and 6 weeks after EC or no drug in addition to st and ard therapy . Pravastatin did not reduce the recurrence rate of atrial fibrillation after EC To study the effect of atorvastatin on recurrence of atrial fibrillation ( AF ) after electrical cardioversion ( EC ) , 48 patients with AF lasting 48 hours who were scheduled for EC were r and omized to the atorvastatin ( group I ) and control ( group II ) groups . Six patients in group I ( 25 % ) and 2 patients in group II ( 8.3 % ) had spontaneous conversion before EC ( p > 0.05 ) . The end point was the recurrence of AF during 3 months of follow-up . Eighteen patients in group I ( 12.5 % ) and 11 patients in group II ( 45.8 % ) had recurrence ( p = 0.01 , log-rank test ) . With the Cox proportional model , the predictors of recurrence included a body mass index of 25 to 30 kg/m2 ( relative risk [ RR ] 0.07 , 95 % confidence interval [ CI ] 0.008 to 0.59 ) , body mass index > or = 30 kg/m2 ( RR 0.24 , 95 % CI 0.08 to 0.72 ) , AF duration of > or = 3 months ( RR 0.28 , 95 % CI 0.09 to 0.83 ) , diabetes mellitus ( RR 0.34 , 95 % CI 0.12 to 0.98 ) , and left atrial diameter of > or = 45 mm ( RR 0.23 , 95 % CI 0.07 to 0.74 ) . Atorvastatin was associated with a significantly reduced risk of developing AF ( unadjusted RR 0.23 , 95 % CI 0.064 to 0.82 , p = 0.024 ) . This association remained significant after adjustment for these predictors ( adjusted RR 0.19 , 95 % CI 0.052 to 0.72 , p = 0.01 ) . High-sensitivity C-reactive protein levels at baseline were not different between the 2 groups ( p = 0.92 ) . Although the high-sensitivity C-reactive protein levels decreased significantly 48 hours after EC compared with the baseline levels in group I ( 2.82 + /- 1.46 vs 2.56 + /- 1.3 mg/dl , p = 0.02 ) , no significant change occurred in group II ( 2.87 + /- 0.8 vs 2.84 + /- 0.8 mg/dl , p = 0.09 ) . In conclusion , atorvastatin decreased the recurrence rate of AF after EC Objectives : Systemic inflammatory response occurs frequently after coronary artery bypass surgery , and it is strongly correlated with the risk of postoperative morbidity and mortality . Recent studies demonstrate that treatment with statin is associated with a significant and marked decrease in inflammation-associated variables such as the C-reactive protein , cytokines , and adhesion molecules . Therefore , we investigated the effects of preoperative atorvastatin treatment on systemic inflammatory response and perioperative morbidity after cardiopulmonary bypass . Design : Double-blinded , placebo-controlled , r and omized study . Setting : University hospital . Patients : Forty patients were r and omized to treatment with atorvastatin ( 20 mg/day , group A , n = 20 ) or placebo ( group B , n = 20 ) 3 wks before surgery . Interventions : Three-week treatment by atorvastatin 20 mg/day . Measurement and Main Results : Postoperative serum levels of both interleukin-6 and interleukin-8 increased significantly over baseline , but the peak levels observed 4 hrs postoperatively were significantly lower in the atorvastatin group . In the same fashion , CD11b expression on neutrophils was significantly lower in the statin group at 4 and 24 hrs postoperatively . Finally , neutrophil-endothelial adhesion was significantly reduced in the statin patients compared with controls . The operation time , blood loss , need for inotropic support , intubation time , and length of intensive care unit or hospital stay did not differ significantly between the two groups . The systemic inflammatory response syndrome score on postoperative days 1 and 2 was comparable in both groups . Conclusions : Pretreatment with atorvastatin significantly reduces cytokine release and neutrophil adhesion to the venous endothelium in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass
target: Use of statins was significantly associated with a decreased risk of incidence or recurrence of AF in patients in sinus rhythm with a history of previous AF or undergoing cardiac surgery or after acute coronary syndrome
background: OBJECTIVES To improve the evaluation of the possible antiarrhythmic effect of statins , we performed a meta- analysis of r and omized trials with statins on the end point of incidence or recurrence of atrial fibrillation ( AF ) .
  BACKGROUND The use of statins had been suggested to protect against AF in some clinical observational and experimental studies but has remained inadequately explored .