1、Study ResultsBackground:experimental dataRemodeling,which appears early after the onset of AF,plays an important role in the initiation and maintenance of AF:electrical:shortening of atrial effective refractory period(AERP)associated with loss of rate dependency of the AERP led to an increased atria
2、l vulnerability structural:rapid atrial rates are associated with enlargement of both atrial cavities,leading to structural remodeling In animal models,blockers of the RAAS have been shown to be able to modulate both types of remodelingCardiovasc Res 2002;54:456461J Am Coll Cardiol 2003;41:21972204C
3、irculation 2001;104:26082614Healey JS et al.JACC 2005;45:1832-39To evaluate whether in patients with previous AF episodes treated with the best recommended therapies the addition of valsartan can prevent AF recurrenceVisit 12Week Days-5 to-1Day 0Randomization324458624752Study Drug Treatmentplacebopl
4、aceboplacebo80 mg valsartan160 mg valsartan320 mg valsartanStudy Design All patients have been provided with a transtelephonic monitoring toolInclusion criteriaMale or female patients 40 years of age Sinus rhythmAt least two ECG documented episodes of symptomatic AF in the previous 6 months orAfter
5、a successful cardioversion for AF performed between 14 days and 48 hours before randomizationWritten informed consent to participate in the study prior to any study procedureInclusion AF criteriaInclusion criteriaValsartan(n.722)Placebo(n.720)P valueAt least 2 episodes of AF in the last 6 months 299
6、(42.5%)282(40.8%)0.45*CVE in the last 2 weeks 646(89.5%)630(87.5%)0.24*Chi-square testCVE=Cardioversion 1442 patients from 114 centers November 2004 -December 2007 Mean follow-up period 223152 days Median follow-up 283 daysValsartan(n.722)Placebo(n.720)P value*Heart failure and/or EF 70 years67.59.5
7、43.8%68.28.945.1%0.140.60*Females37.0%38.5%0.56*BMI(meanSD),kg/m228.04.527.74.20.19Heart rate(meanSD),bpm63.910.464.310.80.40Systolic blood pressure(meanSD),mmHg138.216.7139.016.90.40Diastolic blood pressure(meanSD),mmHg81.58.581.69.00.92Baseline characteristics T-test*Chi-square testDosage of study
8、 treatments2 weeks4 weeks8 weeks24 weeksSystolic pressure modifications by study treatmentsConcomitant treatmentsValsartanPlaceboTRATTAMENTOAB0.00.10.20.30.40.50.6timefirstFA0306090120150180210240270300330360Time to first recurrence of AF(n.1442)Valsartan:371/722(51.4%)Placebo:375/720(52.1%)Adjusted
9、*HR 0.9996%CI 0.85-1.15P value 0.84Pts at riskValsartanPlacebo*Adjusted for ACE-I,amiodarone use,cardioversion,PAD,CAD722586524491465445423398383368356343260720589520484454435407387377359344334254DaysRate of pts with 1 episode of AFValsartan:194/722(26.9%)Placebo:201/720(27.9%)OR 0.9599%CI*0.70-1.29
10、P value 0.66*The 99%CI was calculated by Logistic Regression modelSecondary endpointsValsartan(n.722)Placebo(n.720)PHR95%CI*Pts with hospitalization for any cause20.6%19.9%0.701.05 0.83-1.32Pts with hospitalization for CV reason15.8%16.9%0.590.93 0.72-1.20Pts with thromboembolic events-Ischemic stro
11、ke-TIA-Other sites1.4%0.6%0.4%0.4%0.28%-0.14%0.14%0.045.06 1.11-23.11*The 95%CI was calculated by Cox proportional hazards modelTime to first recurrence of AF:prespecified subgroup analysisValsartanEvents/Patients(%)PlaceboEvents/Patients(%)HR95%CI*Age 69 yearsAge 69 years183/368(49.7)188/354(53.1)1
12、86/353(52.7)189/367(51.5)0.941.040.76-1.150.85-1.27HF and/or LVDNo HF and/or LVD27/56(48.2)344/666(51.7)32/58(55.2)343/662(51.8)0.811.000.48-1.350.86-1.16ACE-INo ACE-I217/420(51.7)154/302(51.0)208/402(51.7)167/318(52.5)1.000.960.83-1.210.77-1.19AmiodaroneNo AmiodaroneOther antiarrhytmics109/253(43.1
13、)262/469(55.9)154/277(55.6)113/248(45.6)262/472(55.5)150/268(56.0)0.931.010.990.72-1.210.85-1.200.79-1.24BetablockersNo Betablockers110/223(49.3)261/499(52.3)110/213(51.6)265/507(52.3)0.961.000.74-1.250.84-1.18Lone AF42/78(53.9)55/94(58.5)0.970.65-1.45*The 95%CI was calculated by Cox proportional ha
14、zards model00.511.52Summary The 1-year rate of recurrence of AF in the GISSI-AF population was nearly 52%irrespective of the underlying CV disorder and the baseline characteristics of patients The neutral effect of valsartan(up to 320 mg/daily)was similar in all predefined subgroups of patients,with
15、 the exception of those with HF/LVD for whom a beneficial effect(not significant)was observedRobustness of GISSI-AF results The largest prospective RCT ever conducted testing RAAS blockers in patients with AF Adequately powered(correct assumptions in terms of 1-year rate of recurrence of AF):50%pred
16、icted vs 52%observed599 predicted events vs 746 observed events Differently from post-hoc or secondary analyses of other trials,the occurrence of AF was specifically evaluated through periodical ECG and transtelephonic monitoring The adherence to study treatments and procedures was maximized:Maximal
17、 dosage(320 mg)used and well tolerated by more than 80%of the patientsRate of permanent discontinuations less than 15%over 1 yearMore than 80%of the expected transtelephonic ECG have been actually transmitted No patients lost to follow-up All events centrally validated by an ad-hoc committeeRobustne
18、ss of GISSI-AF resultsInterpretation(1)Modulation of the RAAS appears inadequate for“secondary”prevention of AF:GISSI AF patients had a greater rate of AF recurrence(10%vs more than 50%)In patients with a documented history of AF the electrical remodeling was probably more relevant than structural r
19、emodelingThe blockers of the RAAS are more effective when the RAAS is highly activated.Patients enrolled in GISSI-AF,due to their relatively low-risk clinical conditions and to the optimization of background therapy,had likely a low level of RAAS activationThe trend towards a beneficial effect of valsartan in patients with HF/LVD confirms this hypothesis and the previous Val-HeFT post-hoc analysisInterpretation(2)Time to first recurrence of AF in patients with HF and/or LVD(n.114)Valsartan:27/56(48.2%)Placebo:32/58(55.2%)Adjusted*HR 0.8195%CI 0.48-1.35P value 0.41Days
