Atrial fibrillation and risks of cardiovascular disease, renal disease, and death: systematic review and meta-analysis
BMJ 2016; 354 doi: https://doi.org/10.1136/bmj.i4482 (Published 06 September 2016) Cite this as: BMJ 2016;354:i4482All rapid responses
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Dear Editors,
Let me start by saying that I think the above paper by Odutayo, et al. is an important one, and I suspect it will add impressively to the primary literature on this topic, filling a void that had not yet been sufficiently described, scientifically. In my estimation, the authors did a superb job of collecting and sifting through massive amounts of complicated data and synthesizing it in a manner relevant to the study question. In particular, I found myself impressed with the narrow selection criteria, and their stringent attempts to minimize the risk of bias and confounding. Given the volume of studies pooled in this analysis, this itself is a commendable feat.
Overall, the methodology employed here appears valid and sound, however I agree with Dr. Goh’s rapid response taking issue with the ability of the authors to discern precisely which patients were anticoagulated at baseline and which were not, however this is not my area of expertise, so I shall defer to those with more extensive knowledge. Aside from some concerns related to possible confounding variables, their was considerable heterogeneity in the sample, simply due to the way the original articles themselves were conducted, and, despite further attempts to improve the sensitivity and combinability of these data to increase internal validity and reduce inconsistency, this seemed to persist throughout the analysis. (e.g. I^2 = 76% and P < 0.001 in cardiovascular mortality, I^2 = 98% and P < 0.001 in major cardiovascular events.) And, given the wide range of 95% confidence intervals expressed in table 3, from the array of studies incorporated in the analysis, it may be prudent to interpret the results with caution. That said, I appreciated the authors' addition of absolute risks instead of just relative risk numbers, and those absolute risk values seem to indicate an important risk of non-stroke, cardiovascular, renal and all-cause mortality - this speaks to the comprehensiveness with which the authors seemed to have approached this analysis, for which I have great respect.
My overarching thought is that, while I agree with the concluding argument that further health outcomes research in this area ought to strongly consider non-stroke cardiovascular disease endpoints, I would like to see a stronger takeaway from this fascinating review perceived as a need for a better understanding of not just how to prevent a-fib induced, non-stroke-related all-cause mortality, renal disease and cardiovascular disease, but how best to implement preventive strategies that may serve to improve the underlying atrial fibrillation itself. Of course, there are innumerable researchers already trying to do this, and this sentiment is in no way intended to suggest that their work is or has been poor, merely that there seems to be a fixation on pharmacologic inhibition of atrial fibrillation induced diseases, as opposed to perhaps a more prevention-based, or lifestyle-modification strategy to improve the underlying atrial fibrillation itself.
For instance, Mozaffarian, et al. (2008) published a prospective observational study of greater than 5,000 adult participants, demonstrating that, while little exercise or physical activity and exceptionally vigorous physical exercise both worsened the incidence of atrial fibrillation in this cohort, the subjects whose conditioning was maintained with mild to moderate physical exertion had strong improvements in the state of their underlying atrial fibrillation. There seems to be a U-curve associated with the benefits of exercise, when it comes to persons with A-fib., but there are substantial benefits to be gained with moderate exercise, considering those data. And yet, too many providers seem disinclined to suggest patients' get moving to improve this condition. That suggestion alone might be enough in some instances to improve things, quantitatively, and perhaps avoid some of the devastating endpoints described by Odutayo and colleagues.
No less important, but often swept aside or forgotten, is sleep hygiene and quality. As with nutrition, exercise and psychological stress-management, sleep has a highly undervalued impact on the state of various medical conditions like atrial fibrillation. As discussed in the journal Circulation in 2003 and 2004, by Gami, et al. and Kanagala, et al., respectively, sleep deprivation due to obstructive sleep apnea seems to have a detrimental impact on the prevalence of atrial fibrillation - although small samples are of concern in these data. Just as with nutrition and exercise, there are various things that can be done to treat OSA; reducing overall visceral adiposity, being but one example.
Lastly, as has been vehemently discussed and debated in the responses to the many diet trials in the BMJ over the last year or so, body fatness and excess adiposity is itself a lifestyle disease, presumably with answers lying less in drug development and more in lifestyle modification and the adoption of healthful behavioral patterns. And again, atrial fibrillation and its recurrence has been strongly correlated with obesity and overweight, as described by Wanahita, et al. (2008).
I understand the above thought process is a secondary consideration, and that it does not directly address the results of this particular analysis, nor does it say anything about peoples' abilities or willingness to comply with a lifestyle medicine approach to the reduction of atrial fibrillation-associated disease outcomes. More than anything, I suppose it is a suggestion to patient advocates and consumers of these data to consider looking for lifestyle-related mediators, so as to potentially avoid some of the pitfalls described by the authors of this elegant paper, as well as to clinicians and future researchers, in their pursuit of answers, to look beneath the cardiovascular, renal disease and stroke endpoints, at direct causes of the electrophysiological changes and tissue functions that give rise to such dangerous arrhythmias.
Competing interests: No competing interests
Dear Editors
Like some of the peer reviewers of this study, I am intrigued by the consideration of the effects of the implementation of anti-coagulation upon the stroke rate and stroke-related mortality rate in patients with atrial fibrillation (AF); it appears (from the comments from the authors and reviewers) that they are unable to definitely detect any significant difference between those started on anticoagulation therapy, versus those not on it.
Certainly the following extract from the article generates great interests in readers like me:
"We observed that the association between atrial fibrillation and cardiovascular disease and death was generally consistent, irrespective of baseline history of ischaemic heart disease, baseline history of stroke, mean participant age, and baseline risk. There were, however, two notable exceptions. Firstly, relative risk estimates for general population studies were typically larger than estimates based on studies in specific settings. This could be related to the selection of the controls and the proportion of patients with atrial fibrillation receiving effective evidence based treatments. Secondly, the relative risk of all cause mortality was lower in studies with a higher proportion of participants receiving anticoagulation, but we did not observe a similar pattern for stroke. The absence of any association between the relative risk of stroke and the use of anticoagulation should be interpreted with caution because of the small number of studies included in this analysis. Furthermore, if warfarin is used, it is difficult to determine the effectiveness of anticoagulation without measurements of INR (international normalised ratio). Differences in the proportion of adults with a low INR would affect our stratified analyses for stroke."
I would like to point out that there will be few research articles that I am aware of in which there is close to 100% achievement of INR therapeutic target for AF of between 2.0 - 3.0. Transient deviation from this stipulated range is part of the expectation of warfarin therapy and at the end of the day the incidence of stroke in (warfarin) anticoagulated AF patients is an interaction of probability of therapeutic INR vs the probability of thromboembolic events resulting in clinical stroke over a period of time.
Even when the novel oral anticoagulation agents (NOACs - with their much lauded predictable pharmacokinetics) are compared head-to-head non-inferiority trials with standard warfarin therapy, there is no dramatic reduction of stroke in AF patients on NOACs as opposed to those on warfarin. Recurrent criticism involving the proportion of time patients on warfarin spent in subtherapeutic INR, does not match with real world experience; this should be placed in proper context.
Competing interests: Previously written on caution in unrestrained implementation of anticoagulation in patients with atrial fibrillation, based solely on scoring systems.
How to improve outcome in patients with concurrent heart failure and atrial fibrillation?
To the editors
We read with interest the publication by Odutayo et al (1) on the association between atrial fibrillation (AF) and cardiovascular disease, renal disease, and death. Among the outcomes examined, the highest absolute risk increase was for heart failure (HF). These results again beg the following questions: how much does AF truly contribute to HF associated mortality, and is it possible to characterize the underlying pathophysiology, so as to improve the outcome of AF/HF patients?
AF is particularly germane to HF with preserved left ventricular (LV) ejection fraction (HFpEF). Compared with patients with HF with reduced LV ejection fraction (HFrEF), not only AF occurs more often in patients with HFpEF (2), but also added risk of AF is more prominent (3). Loss of atrial kick associated diastolic filling contributes to different extents to the hemodynamic compromise between HFpEF and HFrEF. Patients with HFPEF also have a lower tolerability for uncontrolled ventricular rate, thus being more prone to deteriorate. Instead of being the marker for mirroring the disease stages of HFrEF, AF is likely a real culprit for the decompensated HFpEF.
Patients with AF and decompensated HF often manifest with a typical triad: tachypenic, tachycardiac, and hypotensive (sometimes with jugular venous dilation/low extremity edema). These classic “decompensated symptoms” are not always caused by increased LV filling pressure. Judging intravascular volume status based on these clinical signs are often misleading. Aggressive diuresis can result in intravascular volume depletion and trigger neurohormonal surge and heightens sympathetic tone. Hemodynamic compromise can be worsened by reflex tachycardia, which is resistant to rate/rhythm-control treatment.
Doppler echocardiography (DE) measures filling pressure of cardiac chambers, pulmonary vessels, and inferior vena cava, to guide volume therapy, assuming an increasingly greater role in evidence-based practice in the decompensated HF management (4, 5). Compared with traditional clinical/laboratory data, quantitative DE provides integrated anatomical, functional and hemodynamic information, improving our understanding on the pathophysiology underlying HF and AF. Identifying specific parametric imaging methods that quantify real-time cardiac hemodynamic change will help frontline physicians identify inappropriate cardiac preload and titrate volume therapy in a timely way. These efforts will prompt the development of multi-center prospective studies with standardized protocols to assess and validate new diagnostic/therapy strategies in improving outcome of AF/HF patients.
Reference
1. Odutayo A, Wong CX, Hsiao AJ, Hopewell S, Altman DG, Emdin CA. Atrial fibrillation and risks of cardiovascular disease, renal disease, and death: systematic review and meta-analysis. BMJ. 2016 Sep 6;354:i4482. doi: 10.1136/bmj.i4482.
2. Mountantonakis SE, Grau-Sepulveda MV, Bhatt DL, Hernandez AF, Peterson ED, Fonarow GC. Presence of atrial fibrillation is independently associated with adverse outcomes in patients hospitalized with heart failure: an analysis of get with the guidelines-heart failure. Circ Heart Fail. 5(2012), p191-p201.
3. Olsson LG, Swedberg K, Ducharme A, et al. Atrial fibrillation and risk of clinical events in chronic heart failure with and without left ventricular systolic dysfunction: results from the Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity (CHARM) program. J Am Coll Cardiol. 47(2006), p1997-p2004.
4. Ritzema JL, Richards AM, Crozier IG, et al. Serial Doppler echocardiography and tissue Doppler imaging in the detection of elevated directly measured left atrial pressure in ambulant subjects with chronic heart failure. JACC Cardiovasc Imaging 4(2011), p927–p934.
5. Lei J, Dhamoon AS, Wang J, Iannuzzi M, Liu K. Walking the tightrope: Using quantitative Doppler echocardiography to optimize ventricular filling pressures in patients hospitalized for acute heart failure. Eur Heart J Acute Cardiovasc Care. 5(2016), p130-p140.
Competing interests: No competing interests