Atrial fibrillation and increased mortality: causation or association? Mexico City 2016 final version
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AF is associated with increased mortality, but it is unclear if this is directly caused by AF or associated conditions. Studies show AF patients have 1.5-2x higher risk of death than controls (1). While some evidence suggests AF directly increases mortality risk through stroke and heart failure worsening, randomized trials found rhythm control did not reduce mortality compared to rate control (2). It is likely AF directly increases mortality in some patients and is also a marker for worsening of linked conditions. Understanding the AF-mortality relationship could guide new treatments to lower premature death risk.
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Atrial fibrillation and increased mortality: causation or association? Mexico City 2016 final version
- 1. AF and increased mortality:AF and increased mortality: causation or association?causation or association? Antonio Raviele, MD, FESC, FHRSAntonio Raviele, MD, FESC, FHRS ALFA – Alliance to Fight Atrial fibrillation, Mestre – Venice, ItalyALFA – Alliance to Fight Atrial fibrillation, Mestre – Venice, Italy Curso de Actualizaciòn en Arritmias, Mexico City, Mexico - 16-18 November, 2016
- 2. Eur Heart J 2013; 34: 1061-1067
- 3. Andersson T et al. Eur Heart J 2013;34:1061-1067
- 4. Andersson T et al. Eur Heart J 2013;34:1061-1067
- 5. Andersson T et al. Eur Heart J 2013;34:1061-1067
- 6. All-cause mortality in AF patients vs controls Andersson T et al. Eur Heart J 2013;34:1061-1067 AF patients Controls ALFA – Alliance to Fight Atrial fibrillation, Mestre – Venice, ItalyALFA – Alliance to Fight Atrial fibrillation, Mestre – Venice, Italy
- 7. Unadjusted all-cause mortality risk All-cause mortality risk adjusted for concomitant diseases Age < 65 yrs Age 65-74 yrs Age 75-85 All patients - Women 3,57 2.15 2,55 1,72 1,94 1,44 - Men 2,80 1,76 2,03 1,36 1,72 1,24 Patients with primary diagnosis of AF - Women 2,20 1,63 1,76 1,46 1,43 1,28 - Men 1,91 1,45 1,44 1,17 1,25 1,10 Andersson T et al. Eur Heart J 2013;34:1061-1067
- 8. Andersson T et al. Eur Heart J 2013;34:1061-1067
- 9. Impact of Atrial Fibrillation on the Risk of Death Emelia J. Benjamin, Philip A. Wolf, Ralph B. D’Agostino, Halit Silbershatz, William B. Kannel, and Daniel Levy Circulation 1998; 98: 946-952
- 10. (Benjamin EJ et al. Circulation 1998; 98: 946-952)(Benjamin EJ et al. Circulation 1998; 98: 946-952) Impact of AF on the risk of death: the Framingham studyImpact of AF on the risk of death: the Framingham study N = 5209; follow-up: 40 yearsN = 5209; follow-up: 40 years 8080 6060 4040 00 00 22 44 66 88 1010 %ofsubjectsdeadinthefollow-up%ofsubjectsdeadinthefollow-up Follow-up (years)Follow-up (years) 7070 5050 2020 3030 1010 9977553311 Men without AFMen without AF Women without AFWomen without AF Women with AFWomen with AF Men with AFMen with AF HR = 1.5 HR = 1.9
- 11. General Population Specific clinical situations Relationship between AF & mortalityRelationship between AF & mortality - Heart failure - Myocardial infarction - Renal failure - Stroke - Hypertension - Diabetes mellitus - Post-cardiac surgery period
- 13. Wang TJ et al. Circulation 2003; 107: 2920-25
- 14. Risk of Death and Cardiovascular Events in Initially Healthy Women With New-Onset Atrial Fibrillation David Conen, MD, MPH; Claudia U. Chae, MD, MPH; Robert J. Glynn, ScD; Usha B. Tedrow, MD, MSc; Brendan M. Everett, MD, MPH; Julie E. Buring, ScD; Christine M. Albert, MD, MPH JAMA. 2011; 305: 2080-2087 Women’s Healthy Study
- 15. FU = 15.4 years Conen DT et al. JAMA. 2011; 305: 2080-2087
- 16. AFAF && ↑ MortalityMortality • Direct cause of death ? • Marker of an increased risk ?
- 17. It is important to determine whether the excess mortality observed in patients with AF is directly due to AF or is just an association ConsiderationsConsiderations
- 18. AF is a largely diffuse clinical condition and the mortality due to this pathology is increasingly growing If AF directly causes excess mortality, then the use of therapies that specifically and successfully eliminate AF – rather than just prevent its symptoms – are preferable ConsiderationsConsiderations
- 19. Eur Heart J 2013; 34: 1027-1030
- 20. Leong DP et al. Eur Heart J 2013; 34: 1027-1030
- 21. Incident AF & Overall MortalityIncident AF & Overall Mortality HR = 1.5 – 2.0HR = 1.5 – 2.0 Andersson T et al. Eur Heart J 2013;34:1061-1067
- 22. Ferrie JE et al. Heart 2009 ;95 :1250-1257 In a 40-year prospective cohort study, smoking exhibited a similar hazard ratio of about 1.5
- 23. Leong DP et al. Eur Heart J 2013; 34: 1027-1030
- 24. Leong DP et al. Eur Heart J 2013; 34: 1027-1030
- 25. All these studies were observational and, despite adjustment for co-morbidities, they are subject to the potential for confounding factors that were not measured, such as myocardial fibrosis, digoxin use, obesity, obstructive sleep apnoea, control of hypertension, patient adherence to heart failure and other therapies, etc. ConsiderationConsideration
- 26. Leong DP et al. Eur Heart J 2013; 34: 1027-1030
- 27. J Am Heart Assoc 2013; doi: 10.1161/JAHA 113000126
- 28. Lubitz SA et al. J Am Heart Assoc 2013; doi: 10.1161/JAHA 113000126
- 29. Higher risk of death and stroke in patients with persistent vs. paroxysmal atrial fibrillation: results from the ROCKET-AF Trial Steinberg BA, Hellkamp AS, Lokhnygina Y, Patel MR, Breithardt G, Hankey GJ, Becker RC, Singer DE, Halperin JL, Hacke W, Nessel CC, Berkowitz SD, Mahaffey KW, Fox KA, Califf RM, Piccini JP; ROCKET-AF Steering Committee and investigators Eur Heart J. 2015; 36: 288-96
- 30. Steinberg BA et al. Eur Heart J. 2015; 36: 288-96
- 31. Leong DP et al. Eur Heart J 2013; 34: 1027-1030
- 32. Stroke / Thromboembolic events Worsening of Heart failure Plausible mechanisms of deathPlausible mechanisms of death in AF ptsin AF pts
- 33. Stroke appears to account for a very small proportion of the deaths in AF patients. In the AF-CHF study, reducing atrial fibrillation in heart failure patients did not mortality ConsiderationsConsiderations
- 34. Marijon E et al. Circulation 2013;128:2192-2201
- 35. Stroke appears to account for a very small proportion of the deaths in AF patients. In the AF-CHF study, reducing atrial fibrillation in heart failure patients did not decrease mortality ConsiderationsConsiderations
- 36. Roy D et al. N Engl J Med 2008; 358: 2667-2677 Death from cardiovascular cause (primary endpoint)
- 37. Leong DP et al. Eur Heart J 2013; 34: 1027-1030
- 38. Represent the strongest support to the causation hypothesis Randomized clinical trialsRandomized clinical trials
- 39. PIAF, Lancet 2000PIAF, Lancet 2000 AFFIRM, N Engl J Med 2002AFFIRM, N Engl J Med 2002 RACE, N Engl J Med 2002RACE, N Engl J Med 2002 STAF, JACC 2003STAF, JACC 2003 HOT- CAFE, Chest 2004HOT- CAFE, Chest 2004 AF-CHF, N Engl J Med 2008AF-CHF, N Engl J Med 2008 J-RHYTHM, Circ J 2009J-RHYTHM, Circ J 2009 AF Randomized TrialsAF Randomized Trials / Rhythm Control vs Rate Control/ Rhythm Control vs Rate Control
- 40. Trial Age, y Mean Follow-up Thrombo-embolic complications % Mortality % Modified from Falk, RH. Circulation (2005) 111: 3141 RateRate vsvs Rhythm TrialsRhythm Trials n PIAFPIAF 12m Rate control Rhythm control 125 127 61 60 10 56 100 100 NR NR 1.6 1.6 AFFIRMAFFIRM 42m Rate control Rhythm control 2027 2033 70 70 35 63 85 70 6 7.5 21 24 RACERACE 27m Rate control Rhythm control 256 266 68 68 10 39 96-99 86-99 5.5 7.9 17 13 STAFSTAF 22m Rate control Rhythm control 100 100 65 66 0 NR NR NR 0.6 3.1 5.0 2.5 Hot CafeHot Cafe 20m Rate control Rhythm control 101 104 61 60 NR 63.5 74 NR 1 2.9 1.0 2.9 AF-CHFAF-CHF 37m Rate control Rhythm control 694 682 67 66 30-41 73 92 88 4 3 33 32 JJ-RHYTHM-RHYTHM 19m Rate control Rhythm control 404 419 64.5 65 44 73 59 60 2.9 2.3 0.7 1.0 Sinus rhythm (%) Warfarin (%)
- 41. Circulation 2004; 109: 1509-13
- 42. AFFIRM Circulation 2004; 109: 1509-13AFFIRM Circulation 2004; 109: 1509-13
- 43. These data suggest that any beneficial antiarrhythmic effects of AADs are offset by their adverse effects, and that if an effective method for maintaining SR with fewer adverse effects were available, it might be beneficial in reducing the increased mortality of AF patients ConsiderationsConsiderations
- 44. Leong DP et al. Eur Heart J 2013; 34: 1027-1030
- 45. Consistent evidence indicates that AF is associated with increased mortality, but the extent to which this is a direct effect of AF itself or is related to the numerous serious associated conditions remains a puzzle. Conclusions (1)Conclusions (1)
- 46. It is likely that AF itself directly increases the risk of death in some patients; and it is also a marker of worsening of heart failure, hypertension, valvular disease, and other associated conditions. Conclusions (2)Conclusions (2)
- 47. Improving our understanding of how AF is associated with mortality may offer the potential for new treatments that reduce the risk of premature death. Conclusions (3)Conclusions (3)
Notas del editor
- Mister Chairmen, Ladies and Gentlemen, first of all let me thank the Directors of this Curso de Actualizacion en arritmias, Pedro Iturralde Torres y Jorge Rafael Gomez and the new president of the Sociedad Mexicana de Electrofisiologia y Electroestimulacion Cardiaca Manlio Marquez Murillo for their kind invitation to participate in this very interesting meeting in a so prestigious venue, the Instituto Nacional de Cardiologia de Mexico, thank you very much my dear frienda Pedro, Jorge y Manlio. The topic of my presentation today is AF and increased mortality: causation or association? Undoubtely this is a controversial issue.
- In a recent paper published in the EHJ in 2013
- the data of the Swedish National Patient Registry and the Cause of Death Registry were utilized to evaluate the long-term risk of all-cause mortality in women and men hospitalized with incident atrial fibrillation compared with matched controls
- In total, two hundred 72 thousand AF patients and 5 hundred 44 thousand controls were examined, average age 72 years, 44% women. Patients and controls did not significantly differ except for the presence of concomitant diseases that was higher in patients, 69% vs 27%.
- In one hundred 19 thousand patients, AF was the primary diagnosis for hospitalization. These patients were younger, average age 69 years, and had fewer concomitant diseases, 53%, than the entire (intàia) AF population.
- During the 14 years of follow-up, the all-cause mortality was higher in AF patients than in controls, especially in the first year.
- more in women and younger patients than in men and older patients. This was true for both unadjusted and adjusted risk for concomitant diseases, as well as for all patients and for those with primary diagnosis of AF.
- Based on these data the authors concluded that AF is an indipendent risk factor for all-cause mortality in patients with incident atrial fibrillation.
- These results are neither new nor surprising. Similar data had been already observed in the Framingham study and reported by Benjamin and coworkers in Circulation in 1998.
- increased risk of death in both women and men with AF compared to controls with an HR of 1.9 and 1.5, respectively.
- The relationship between AF and mortality has been reported not only in the general population but also in different specific clinical situations, such as heart failure, myocardial infarction, renal failure, stroke, hypertension, diabetes mellitus, and post-cardiac surgery period.
- For example, in the Framingham study,
- the occurrence of incident AF in patients with heart failure, increased the risk of all-cause mortality by 2.7 fold in women and by 1.6 fold in men.
- Also apparently healthy subjects seem to have reduced survival with the development of AF. Indeed, in the Women’s Healthy Study,
- all-cause mortality was significantly higher, during the 15 years of follow-up, in subjects with incident AF compared to those without, even after adjustment for multiple variables, with an HR ranging from 1.70 to 2.14.
- But, if it is indisputable (indispiùtbol) the relationship between AF and increased mortality, a question arises spontaneous, is the AF the direct cause of death or is it only a marker of an increased risk?
- It is important to determine whether the excess mortality observed in patients with AF is directly due to AF or is just an association
- Indeed, AF is a largely diffuse clinical condition and the mortality due to this pathology is increasingly growing. Moreover, if AF directly causes excess mortality, then the use of therapies that specifically and successfully eliminate AF – rather than just prevent its symptoms – are preferable
- In order to answer the question causation or association critically,
- we can use the criteria proposed by Hill to assess a causality (kozàlity). They include strength of association, consistency (konsìstensi) of association, biological gradient, biological plausibility (plozibìlity) and experimental evidence. Let me start with strength of association
- As mentioned before, the adjusted hazard ratio for all-cause mortality observed by Andersson and coworkers in Sweden amongst patients with incident AF is 1.5–2, This represents a moderately strong association
- To put this relative risk into a correct context, we can remenber in a 40-year prospective cohort study, smoking exhibited a similar hazard ratio of ∼1.5 for all-cause mortality
- Regarding consistency of association
- studies evaluating the association between AF and death have been consistent in reporting an independent relationship between AF and mortality with relative risks ranging from 1.1 to 2.8,
- However we have to outline that, despite adjustment for co-morbidities, all these studies are observational and subject to the potential for confounding factors that were not measured, such as myocardial fibrosis, digoxin use, obesity, obstructive nocturnal apnea, control of hypertension, patient compliance to the therapy of heart failure, etc.
- Coming to the biological gradient
- there is some evidence to suggest a relationship between the burden of AF and mortality. For example, in this paper published in the Journal of American Heart Association in 2013
- patients with recurrent and especially with sustained AF had a higher mortality compared to patients without recurrent AF, the HR being 2.04 and 2.36, respectively.
- Similarly, in this subanalysis of the ROCKET-AF trial
- All-cause death was consistently higher in patients with persistent AF compared to those with paroxysmal AF, annual incidence 4.78% vs 3.52%, even after adjustments for multiple variables
- And now biological plausibility
- The plausible (plòozbol) mechanisms by which AF might cause death include stroke and worsening of heart failure.
- However, stroke appears to account for a very small proportion of the deaths in AF patients.
- For example, in the RE-LY study, the most common causes of death were sudden cardiac death (22%), progressive heart failure (15%) and cancer (14%), whereas stroke accounted for only 7% of all deaths.
- Moreover, in the AF-CHF study, reducing AF in heart failure patients did not prevent worsening heart failure or heart failure deaths
- As you can see in this slide, no difference in mortality was observed, in the AF-CHF study, between patients assigned to rhythm control and those assigned to rate control.
- Finally, experimental evidence.
- According to the general opinion, randomized clinical trials, represent the strongest support to the causation hypothesis
- As you know, several randomized controlled trials have been conducted in the last years to compare rate control and rhythm control strategies in patients with AF
- These trials have demonstrated that rate control is not inferior to rhythm control in terms of mortality
- However, a substudy of the AFFIRM trial that has investigated the relationships between sinus rhythm, treatment and survival
- has shown that the presence of sinus rhythm is associated with a lower risk of death (about 50% reduction) whereas the use of AAD is associated with a higher risk of death (about 50% increase),
- suggesting that any beneficial antiarrhythmic effects of AADs are offset by their adverse effects, and that If an effective method for maintaining SR with fewer adverse effects were available, it might be beneficial in reducing the increased mortality of AF patients.
- At the end of this presentation, taking into account all the Hill criteria for establishing causality between AF and excess mortality, we can say that the strength of association is moderate, the consistency of association strong, the biological gradient moderate, the biological plausibility moderate, and the experimental evidence against.
- In conclusion, mister chairmen, Ladies and Gentlemen, consistent evidence indicates that AF is associated with increased mortality, but the extent to which this is a direct effect of AF itself or is related to the numerous serious associated conditions remains a puzzle
- It is likely that AF itself directly increases the risk of death in some patients; and it is also a marker of worsening of heart failure, hypertension, valvular disease, and other associated conditions.
- Improving our understanding of how AF is associated with mortality may offer the potential for new treatments that reduce the risk of premature death.
- If we refer to Guidelines, the two Expert Consensus documents on AF ablation published in 2012, the HRS/ECAS/EHRA Expert Consensus Statement,