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GISSI-HF trial: ancillary results - effects of rosuvastatin on atrial fibrillation occurrence

Clinical Trial Update I

Atrial Fibrillation

Presenter | see Discussant report

Aldo Pietro Maggioni, FESC (Italy)

Presentation webcast

Presentation slides

List of Authors:

Aldo P. Maggioni, Gianna Fabbri, Donata Lucci, Roberto Marchioli, Maria Grazia Franzosi, Roberto Latini, Gian Luigi Nicolosi, Maurizio Porcu, Franco Cosmi, Severo Stefanelli, Gianni Tognoni, Luigi Tavazzi on behalf of the GISSI-HF Investigators


Aims: This ancillary analysis of the GISSI-HF database aims at assessing the effect of rosuvastatin on the occurrence of atrial fibrillation (AF) in patients with chronic heart failure (HF) who were not in AF at study entry.

Methods and Results: GISSI-HF was a double-blind, placebo-controlled trial testing n-3 PUFA and rosuvastatin versus corresponding placebos in patients with chronic HF. AF occurrence was defined as presence of AF in the electrocardiogram performed at each visit during the trial or AF as a cause of worsening HF or hospital admission or as an event during hospitalization. Among the 3690 patients (80.7%) without AF on their baseline electrocardiogram, 15.0% developed AF during a median follow-up period of 3.7 years, 258 randomized to rosuvastatin (13.9%) versus 294 allocated to placebo (16.0%). While the difference was not significant at unadjusted (p=0.097) and multivariable analysis adjusting for clinical variables (p=0.067), it became significant after adjustment for clinical variables and laboratory examinations (p=0.039), clinical variables, laboratory examinations and background therapies (p=0.038).

Conclusion: This study shows that there is some evidence of a beneficial effect of rosuvastatin in terms of reduction of AF occurrence in patients with HF. Larger populations are needed to provide a definite answer to the question.

Discussant | see Presenter abstract

Harry Crijns, FESC (Netherlands)

Presentation webcast

Presentation slides



Rosuvastatin and the insufferable odd couple heart failure and atrial fibrillation

Atrial fibrillation (AF) frequently complicates heart failure (HF) and vice versa and - when found together – for clinicians they form an insufferable odd couple. Once AF appears HF can worsen and stroke rate increases. Therefore prediction and prevention of AF may be desirable goals.
Prevention of AF in HF patients using conventional antiarrhythmic drugs is associated with increased mortality. In these high risk patients, primary prevention of AF using non-antiarrhythmic drugs such as ACE-inhibitors, angiotensin-receptor blockers and statins might be useful. The so-called upstream effects of these drugs prevent the atria from remodelling. This is important in HF patients since HF leads to stretch and fibrosis of the atria and atrial fibrillation. These notions are supported by experimental studies in which atrial fibrosis and atrial fibrillation were ameliorated by statin therapy.
A recent meta-analysis incorporating 3 different primary prevention studies did not show a significant effect of statins with respect to incident AF. The ancillary study of GISSI-HF presented at the Clinical trial update at ESC can be added to this analysis. GISSI-HF found that rosuvastatin compared to placebo reduces – although non-significantly - the incidence of AF from 16 to roughly 14% in patients with HF. After adjustment there was however a statistically significant difference in favour of rosuvastatin but the anti-arrhythmic effect is not large and the question remains whether suppressing AF in HF patients is beneficial or only kills the messenger.
Strictly speaking, GISSI-HF was not a primary prevention trial since ~15% had had AF before and many more patients may have had asymptomatic AF, since detection of AF before inclusion was not very robustly performed.
The GISSI-HF investigators took time to new onset of AF as an endpoint. Time to new onset AF is from technical viewpoint a very robust parameter. However, clinically the burden of AF or progression to persistent forms of AF is of more importance than one single event and in my mind - should be a focus of treatment of HF pts.

The Kaplan-Meier survival curve shows step-ups at each visit since most of the incident AF was only detected at those time points suggesting that these patients were asymptomatic with their AF. This observation indicates that AF may not have had a large impact on the course of HF.
Why did rosuvastatin not work as well as expected?
The most important reason is that once AF emerges in the setting of HF the atria are already very fibrotic and strongly remodeled. Under those circumstances, a statin or other anti-fibrosis drug cannot be very effective anymore. This probably also holds for the patients included in GISSI-HF. Many GISSI-HF patients will have had HF for a long time providing the substrate for AF to develop. Unfortunately, as in all HF trials, the duration of HF is not mentioned in GISSI-HF. If available however, an interesting analysis might be to examine whether in patients with a short previous duration of HF rosuvastatin is more effective than placebo in preventing new onset AF and ameliorating the burden of AF.

In summary, rosuvastatin is not extremely effective in preventing incident AF in patients with class II-IV CHF from any cause. There are still a few unanswered questions concerning the effects of statins in HF patients. First, it is important to know whether statins can reduce the progression and burden of AF. This is a question which might still be answerable from the GISSI-HF database. Secondly, can upstream statin therapy prevent AF in HF when started very early, i.e. before significant atrial fibrosis has occurred? Finally, and most importantly, the question is whether all the efforts made to uncouple AF from HF will eventually improve morbidity or mortality in these patients.




Effects of rosuvastatin on atrial fibrillation occurrence: ancillary results of the GISSI-HF trial

Notes to editor

This congress report accompanies a presentation given at the ESC Congress 2009. Written by the author himself/herself, this report does not necessarily reflect the opinion of the European Society of Cardiology.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.