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Study Results

Study Results. Background: experimental data. Remodeling , which appears early after the onset of AF, plays an important role in the initiation and maintenance of AF:

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Study Results

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  1. Study Results

  2. Background: experimental data Remodeling, 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 atrial 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 remodeling Cardiovasc Res 2002; 54:456–461 J Am Coll Cardiol 2003; 41:2197–2204 Circulation 2001; 104:2608–2614

  3. Healey JS et al. JACC 2005; 45:1832-39

  4. To evaluate whether in patients with previous AF episodes treated with the best recommended therapies the addition of valsartan can prevent AF recurrence

  5. Study Design 320 mg valsartan 160 mg valsartan 80 mg valsartan placebo placebo placebo 1 6 Visit 7 3 2 4 5 52 24 Week 4 8 Day 0 Randomization Days -5 to -1 2 All patients have been provided with a transtelephonic monitoring tool Study Drug Treatment

  6. Inclusion criteria • Male or female patients 40 years of age • Sinus rhythm • At least two ECG documented episodes of symptomatic AF in the previous 6 months or • After a successful cardioversion for AF performed between 14 days and 48 hours before randomization • Written informed consent to participate in the study prior to any study procedure

  7. Inclusion criteria At least one of the following underlying cardiovascular diseases/comorbidities: • heart failure/documented history of LV dysfunction (defined as an EF <40%) • history of hypertension 6 months with/without LVH • type II diabetes mellitus • documented history of stroke or peripheral vascular disease • documented history of coronary artery disease • lone atrial fibrillation with documented LA dilation (LA diameter 45 mm for men and  40 mm for women)

  8. StudyEnd-points • Co-primaryEnd-points • Time to first recurrence of AF • Rate of patients with more than one AF episode • SecondaryEnd-points • Total number of AF episodes • Number of hospitalizations for CV reasons • Number of all-cause hospitalizations • Incidence of thromboembolic events • Safety profile

  9. Inclusion AF criteria • 1442 patients from 114 centers • November 2004 - December 2007 • Mean follow-up period 223±152 days • Median follow-up 283 days * Chi-square test CVE = Cardioversion

  10. Inclusion clinical criteria * Chi-square test

  11. Baseline characteristics ° T-test * Chi-square test

  12. Systolicpressuremodificationsbystudytreatments Dosageofstudytreatments 2 weeks 8 weeks 4 weeks 24 weeks

  13. Concomitant treatments Valsartan Placebo

  14. Time to first recurrence of AF (n. 1442) Valsartan: 371/722 (51.4%) Placebo: 375/720 (52.1%) Adjusted* HR 0.99 96%CI 0.85-1.15 P value 0.84 Days Pts at risk Valsartan Placebo 722 586 524 491 465 445 423 398 383 368 356 343 260 720 589 520 484 454 435 407 387 377 359 344 334 254 * Adjusted for ACE-I, amiodarone use, cardioversion, PAD, CAD

  15. Rate of pts with >1 episode of AF Valsartan: 194/722 (26.9%) Placebo: 201/720 (27.9%) OR 0.95 99%CI* 0.70-1.29 P value 0.66 * The 99%CI was calculated by Logistic Regression model

  16. Secondary endpoints * The 95%CI was calculated by Cox proportional hazards model

  17. Time to first recurrence of AF: prespecified subgroup analysis 0 0.5 1 1.5 2 * The 95%CI was calculated by Cox proportional hazards model

  18. Summary • 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 the exception of those with HF/LVD for whom a beneficial effect (not significant) was observed

  19. Robustness 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% predicted vs 52% observed • 599 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

  20. Robustness of GISSI-AF results • The adherence to study treatments and procedures was maximized: • Maximal dosage (320 mg) used and well tolerated by more than 80% of the patients • Rate of permanent discontinuations less than 15% over 1 year • More 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 committee

  21. Interpretation (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 remodeling

  22. Interpretation (2) • The 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 activation • The trend towards a beneficial effect of valsartan in patients with HF/LVD confirms this hypothesis and the previous Val-HeFT post-hoc analysis

  23. 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 0.81 95%CI 0.48-1.35 P value 0.41 Days

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