Correspondence

Valsartan and Recurrent Atrial Fibrillation

N Engl J Med 2009; 361:532-533July 30, 2009

Article

To the Editor:

Disertori et al. (April 16 issue)1 describe the effects of valsartan on the recurrence of atrial fibrillation. The disappointing results of the trial may be explained by two important limitations. First, no data were provided concerning how long patients were known to have had either atrial fibrillation or underlying heart disease. We would expect that the extent of remodeling would become more severe and even irreversible in patients with a longer history of atrial fibrillation or underlying heart disease. In patients with a shorter history, however, remodeling processes are less advanced, providing more opportunities for blockade of the renin–angiotensin–aldosterone system (RAAS) to be effective.2 Second, RAAS blockade was probably started too late in the trial — namely, when sinus rhythm was already obtained. Upstream therapy requires more time to influence remodeling processes, and it would have been better if valsartan had been started several weeks before instead of at least 2 days after obtaining sinus rhythm.3 Thus, the question still remains whether RAAS blockade is effective in maintaining sinus rhythm if it is started as soon as possible after presentation with atrial fibrillation.

Marcelle D. Smit, M.D.
Isabelle C. Van Gelder, M.D., Ph.D.
University Medical Center Groningen, 9700 RB Groningen, the Netherlands

3 References

1
The GISSI-AF Investigators. Valsartan for prevention of recurrent atrial fibrillation. N Engl J Med 2009;360:1606-1617[Erratum, N Engl J Med 2009;360:2379.]
Full Text | Web of Science | Medline

2
Cosio FG, Aliot E, Botto GL, et al. Delayed rhythm control of atrial fibrillation may be a cause of failure to prevent recurrences: reasons for change to active antiarrhythmic treatment at the time of the first detected episode. Europace 2008;10:21-27
CrossRef | Web of Science | Medline

3
Madrid AH, Bueno MG, Rebollo JM, et al. Use of irbesartan to maintain sinus rhythm in patients with long-lasting persistent atrial fibrillation: a prospective and randomized study. Circulation 2002;106:331-336
CrossRef | Web of Science | Medline

To the Editor:

Disertori et al. report that they found no significant reduction in the incidence of recurrent atrial fibrillation among patients receiving valsartan, as compared with those receiving placebo. The study is basically a secondary prevention trial. Previous studies have presented positive results for the use of angiotensin II receptor blockers (ARBs) for the secondary prevention of atrial fibrillation in a relatively small number of patients.1 In contrast, previous trials and meta-analyses involving more than 50,000 patients have suggested more pronounced effects of angiotensin-converting–enzyme (ACE) inhibitors or ARBs for the primary prevention of atrial fibrillation.2,3 In primary prevention trials, ACE inhibitors and ARBs might prevent the occurrence and progression of structural and electrical remodeling as the substrate for atrial fibrillation,4 but the remodeling process might be completed and irreversible in the secondary prevention setting. Thus, a large, randomized, prospective, placebo-controlled, multicenter trial to test an ARB for the primary prevention of atrial fibrillation would be mandatory before concluding that ARBs are not effective in preventing this condition. In such a trial, an evaluation of changes in cardiac-chamber dimensions would be useful in assessing the mechanism of prevention of atrial fibrillation.

Haruo Tomoda, M.D., Ph.D.
Tokyo Heart Institute, Tokyo 195-0061, Japan
tokyoheart@abelia.ocn.ne.jp

4 References

1
Madrid AH, Bueno MG, Rebollo JM, et al. Use of irbesartan to maintain sinus rhythm in patients with long-lasting persistent atrial fibrillation: a prospective and randomized study. Circulation 2002;106:331-336
CrossRef | Web of Science | Medline

2
Healey JS, Baranchuk A, Crystal E, et al. Prevention of atrial fibrillation with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: a meta-analysis. J Am Coll Cardiol 2005;45:1832-1839
CrossRef | Web of Science | Medline

3
Anand K, Mooss AN, Hee TT, Mohiuddin SM. Meta-analysis: inhibition of renin-angiotensin system prevents new-onset atrial fibrillation. Am Heart J 2006;152:217-222
CrossRef | Web of Science | Medline

4
Kumagai K, Nakashima H, Urata H, Gondo N, Arakawa K, Saku K. Effects of angiotensin II type 1 receptor antagonist on electrical and structural remodeling in atrial fibrillation. J Am Coll Cardiol 2003;41:2197-2204
CrossRef | Web of Science | Medline

Author/Editor Response

Smit and Van Gelder raise the question of the timing of the administration of valsartan in the evaluation of its effects. We reported the results of two additional analyses involving patients who were in sinus rhythm at 15 days (as prespecified in the protocol)1 and at 8 weeks (a post hoc analysis) after randomization. No trend in favor of valsartan was apparent. In the 8-week analysis, atrial fibrillation recurred at 1 year in 42.7% of patients in the valsartan group, as compared with 44.0% of those in the placebo group (hazard ratio, 0.96; 96% confidence interval, 0.80 to 1.14; P=0.62).

With respect to the duration of the history of atrial fibrillation, we do not have this information for the patients in our study. However, we performed a subgroup analysis as to whether the duration of the last episode of atrial fibrillation had an effect on the results. We did not observe any difference in the effect of valsartan between patients with episodes lasting more than 48 hours and those with shorter episodes.

As Tomoda correctly points out, the efficacy of RAAS blockade in the primary prevention of atrial fibrillation is still an open issue, with current evidence coming from post hoc analyses of large trials, databases, and overviews. Thus, a large, randomized clinical trial of such therapy in the primary prevention of atrial fibrillation may be appropriate. However, such a trial is likely to be difficult to carry out because of the broadening range of use of RAAS inhibitors in a variety of cardiovascular conditions.

Marcello Disertori, M.D.
Santa Chiara Hospital, 38100 Trento, Italy

Roberto Latini, M.D.
Mario Negri Institute for Pharmacological Research, 20156 Milan, Italy

Aldo P. Maggioni, M.D.
Italian Association of Hospital Cardiologists Research Center, 50121 Florence, Italy
maggioni@anmco.it

for the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico–Atrial Fibrillation (GISSI-AF) Investigators

1 References

1
Disertori M, Latini R, Maggioni AP, et al. Rationale and design of the GISSI-Atrial Fibrillation trial: a randomized, prospective, multicentre study on the use of valsartan, an angiotensin II AT1-receptor blocker, in the prevention of atrial fibrillation recurrence. J Cardiovasc Med (Hagerstown) 2006;7:29-38
CrossRef | Web of Science | Medline

Citing Articles (3)

Citing Articles

1
I. C. Van Gelder, L. M. Haegeli, A. Brandes, H. Heidbuchel, E. Aliot, J. Kautzner, L. Szumowski, L. Mont, J. Morgan, S. Willems, S. Themistoclakis, M. Gulizia, A. Elvan, M. D. Smit, P. Kirchhof. (2011) Rationale and current perspective for early rhythm control therapy in atrial fibrillation. Europace 13:11, 1517-1525
CrossRef
2
2011. Active Supraventricular Arrhythmias. , 93-180.
CrossRef
3
2011. Appendix. , 386-418.
CrossRef