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August 2024
In today’s VETgirl online veterinary CE podcast, we review a paper entitled “Optimal rate control in dogs with atrial fibrillation—ORCA study—Multicenter prospective observational study: Prognostic impact and predictors of rate control” by Pedro et al that was published in the Journal of Veterinary Internal Medicine in 2023. Now, you likely remember being taught about the classic “sneakers in the dryer” arrhythmia – atrial fibrillation, or what we’ll call “a fib” from now on, and why it needs to be diagnosed and treated in our canine patients.
Atrial fibrillation (“a fib”) has detrimental effects on quality of life and survival in both dogs and humans. This is due to exhaustion of the myocardium by chronic tachycardia, known as tachycardia-mediated cardiomyopathy, as well loss of coordinated atrioventricular synchrony. Why VETgirl never tolerates a heart rate > 180 beats per minute in the dog, as it utilizes a lot of myocardial oxygen and results in secondary injury! Chronic sympathetic nervous stimulation associated with progressive structural cardiac disease serves as a driver for the tachycardia. There is no distinct evidence to support superiority of rhythm conversion versus heart rate control among the treatment strategies for a fib in humans to date. The majority of dogs with a fib have significant underlying structural heart disease (such as dilated cardiomyopathy or what we’ll call DCM from now on), thus rhythm conversion is less commonly pursued due to high risk of recurrence of a fib in this population. As a result, rate control is most commonly employed, but well-defined treatment targets or endpoints for what is considered adequate rate control remain unclear in the available literature. In other words, in dogs vs. in humans, we don’t just commonly reach for “ablation” techniques but rather treatment of the underlying cause and control of that tachycardia! We know from prior data that an in-clinic heart rate (HR) of < 160 bpm on electrocardiogram (ECG) was associated with improved outcome in dogs with a fib secondary to mitral valve disease but it is doubtful this is an appropriate treatment target because 1) in-clinic heart rates are known to be a poor representation of heart rate at home compared with mean heart rate obtained via 24-hour Holter monitoring, and 2) a prior retrospective study by the authors of the present paper documented an improved survival in dogs with a fib with mean HR < 125 bpm. So, the real question is: “how low can (should) we go?” when it comes to trying to adjust the HR in dogs with a fib?
So, Pedro and al wanted to evaluate this in their study entitled “Optimal rate control in dogs with atrial fibrillation—ORCA study—Multicenter prospective observational study: Prognostic impact and predictors of rate control.” This was a prospective multicenter study aimed to compare the survival of dogs with a fib that achieved rate control versus those that did not, with rate control specifically defined as a mean heart rate < 125 bpm on 24-hour Holter monitor. The primary endpoint was all-cause mortality. A secondary purpose was to determine which clinical variables, if any, including cardiac imaging and blood-derived biomarkers, predicted the ability to achieve rate control. Dogs were enrolled from 3 centers (two in the United Kingdom and 1 in the United States) over a two-year span. Dogs with recent onset a fib were included. Exclusion criteria for this study included dogs that had antiarrhythmic therapy prior to enrollment, significant concurrent systemic disease expected to impact survival, or history of potentially cardiotoxic chemotherapy (like getting doxorubicin). Dogs with additionally severe arrhythmias, such as severe ventricular arrhythmias or bradyarrhythmia, were also excluded.
In this study, upon enrollment, dogs underwent a physical exam, blood pressure, confirmatory electrocardiogram, routine hematology and chemistry database, thyroid testing if indicated, and assessment of N-terminal probrain natriuretic peptide (what we’ll call NT-proBNP from now on), cardiac troponin I, and C-reactive protein (CRP). Thoracic radiographs were performed as needed and standard echocardiogram was performed in all dogs to classify the dogs in one of four categories: 1) myxomatous mitral valve disease 2) dilated cardiomyopathy 3) congenital heart disease or 4) lone-a fib (no structural disease).
In this study, the investigators aimed for a mean heart rate of < 125 bpm for all dogs in the study. If the patient’s heart rate was > 150 bpm on baseline ECG, antiarrhythmic therapy was initiated immediately. If the patient’s heart rate was < 150 bpm, a baseline Holter monitoring was performed first, and antiarrhythmic therapy was only initiated thereafter if the mean heart rate on the Holter monitor was > 125 bpm. Antiarrhythmic drugs/doses could be adjusted by the investigators as necessary with serial Holter monitoring every 1-3 weeks to assess for efficacy after each adjustment. When the target acceptable mean heart rate was achieved, this was considered the “final” Holter monitor assessment, after which no additional antiarrhythmic adjustments could be made. If additional adjustments were necessary, the patient was censored from the study. Investigators were also free to treat as needed and with appropriate therapies for patients with congestive heart failure (CHF). Echocardiography was repeated, and NT-proBNP, cardiac troponin I, and C-reactive protein were measured at each visit in which a Holter monitor was placed but this data was only analyzed for the final Holter monitor visit for each dog. Survival time was measured from the date of the final Holter monitor to death or last follow-up at time of termination of the study. Statistical significance for all variables was set at P < 0.05.
Ultimately, sixty dogs completed the study. The vast majority of dogs (80%) required immediate antiarrhythmic therapy based on a heart rate > 150 bpm on baseline ECG. Of the 20% that did not (12 dogs), 33% (4) of them ultimately did have antiarrhythmic therapy initiated after baseline Holter monitor documented a mean heart rate of > 125 bpm. Of the remaining 8 dogs in this group, 6 had a heart rate < 125 bpm and did not require antiarrhythmic therapy according to the study guidelines. Of the remaining 2, one dog’s owner refused to add any additional therapies and the other died prior to initiation of heart rate control therapy. The most common antiarrhythmic therapy for heart rate control was the combination of diltiazem and digoxin (in 58% of dogs).
So, what’d they find in this study? The results of the study are pretty telling, and provide the first powerful prospective evidence to confirm that the methods and parameters of assessing heart rate control in dogs with a fib we once viewed as acceptable were clearly suboptimal. Let’s dig in.
75% of the dogs in this study died during the study period, with a median survival of 160 days for the entire patient cohort. Heart rate control was achieved in only 55% of dogs. The median time to primary endpoint was 608 days in this group compared with 33 days in the 45% of dogs in which rate control was not achieved – wow! 33% of dogs in which rate control WAS achieved were still alive at the end of the study compared with only 7% of the non-rate-controlled group. Importantly, the time it took to achieve rate control was not associated with survival – so, dogs didn’t do worse if it took them a few more weeks to achieve heart rate control via medication adjustment versus their counterparts, provided the end-goal was ultimately still achieved.
In terms of the other cardiac variables assessed in this study, not surprisingly, the following parameters were associated with higher risk of death: presence of CHF, left sided cardiomegaly, higher mitral valve E velocity, higher NT-proBNP and cardiac troponin I concentrations, congenital heart disease, and faster minimum and mean heart rate on Holter monitor. Lower risk of death was associated with dilated cardiomyopathy, greater body weight, and mean HR < 125 bpm – the rate control study target. The latter was associated with a 74% risk reduction – impressive. This risk reduction was still 66% once the analysis was corrected for the effects of congenital heart disease and NT-proBNP as dictated by the statistical model. Two additional survival models were created, each of which is useful to view. One model indicated that for every increase of ten beats per minute in mean HR on Holter monitor, a 35.5% increase in risk of death was observed. WOAH. Did you hear that – that means for every increase in 10 beats per minute, there was a higher risk of DEATH observed! CONTROL THAT TACHYCARDIA!
In the other model, mean HR was divided into quartiles: 1) 70-107 bpm 2) 110-123 bpm 3) 127-138 bpm and 4) 144-225 bpm. Dogs in quartile 1 had the best outcome. For those of you who are not literally “on the run” while listening to this podcast, I would encourage you to look at figure 4, the Kaplan-Meier survival curve for the four quartiles, as a picture can tell a thousand words. In addition to the starkly better survival curve for quartile 1 (and conversely worse survival curve for quartile 4) in the figure, what strikes me is how much closer the curve for quartile 3 tracks to quartile 4 vs quartiles 1 or 2. Quartile 3 represents dogs with mean HR of 127-138 bpm – we would have historically considered that to still be very good rate control! It appears clear from this study that we need to reset our targets to improve patient outcome. And seriously focus on controlling that tachycardia.
Before we get further along, let’s not ignore that the data reported DCM as associated with a lower – that’s right, lower – risk of death with a fib. Traditionally, we associate DCM with a worse prognosis with CHF than mitral valve disease in dogs. This study doesn’t refute that, but it suggests that DCM dogs fare better with a fib, at least, than dogs with mitral valve disease. The authors did not postulate a possible explanation for this. Perhaps there were fewer dogs with DCM in the CHF group in the study, indicating they had less advanced disease. Or perhaps it could be related to left atrial size, as the most severe mitral valve disease patients have larger left atria than those with DCM. Or perhaps it is just a spurious finding due to relatively small sample size.
Overall, survival time for dogs in the lone-a fib group (4 dogs, 6.7%) could not be analyzed as none of the dogs in this group died during the study period. Interestingly, in dogs with congenital heart disease, which comprised 18% of the study population, achieving heart rate control was not associated with improved survival.
The authors also aimed to determine what clinical parameters might be associated with the likelihood of achieving heart rate control. Left atrial size was closely associated with the ability to achieve heart rate control in the study – namely, the larger the left atrium, the less likely it was to be able to achieve HR control. Other parameters that were associated with a lower likelihood of achieving heart rate control included larger left ventricle, higher mitral valve E wave velocity, higher cardiac troponin I and CRP, lower blood pressure, and lower body weight (Remember, bigger dogs are more likely to get DCM). In the multivariable analysis, left atrial size, C-reactive protein, and lower blood pressure remained predictive. A left atrial:aortic root ratio > 2.4 appeared to provide the best balance of sensitivity and specificity and could potentially be used as a cutoff marker. Intuitively, the larger the left atrium, the greater substrate exists to develop and maintain atrial fibrillation. What is not clear, is why this would provide a greater challenge at pharmacologic rate control, as drugs such as diltiazem and digoxin slow conduction through the atrioventricular (AV) node, the properties of which should not theoretically be impacted by atrial size. It’s been suggested that left atrial size might modulate autonomic nervous system function, but at this point we simply are not sure.
Interestingly, in this study, the type of structural disease present (in other words, mitral valve disease, DCM, or congenital disease) did not affect the ability to achieve HR control. What this statement suggests when viewed together with the fact that achieving heart rate control did not improve survival in the congenital group, is that for dogs with congenital heart disease, the negative impact of a fib is proportionally smaller than the negative impact of the type of congenital disease, itself, when compared with acquired heart disease.
So, remember… “how low can, or should, we go” with rate control in a fib? The present study does not provide us with a complete answer simply because survival time improved with each successive quartile of HR reduction. However, it seems unlikely that trend would continue indefinitely. Mean heart rate for normal dogs in sinus rhythm is generally between 70-100 bpm. At some point, a significant pharmacologic-induced bradycardia would presumably be detrimental to dogs with chronic structural heart disease and inherently impaired cardiac output (as that heart rate is keeping them alive!). But where does that occur? Mean heart rate < 100 bpm? < 75 bpm? Fodder for the next study perhaps. We just don’t know!
C-reactive protein, a marker for generalized inflammation, was associated with reduced ability to achieve heart rate control, the latter of which was negatively associated with survival of course, but CRP did not have a direct negative effect on overall survival, interestingly. Further investigation of C-reactive protein in cardiac disease in dogs may yield additional information and should be explored.
In VETgirl’s opinion, this was a really strong study, as it was well-designed and prospective (which are really hard to do in veterinary medicine!), in addition to being multi-institutional (involving other hospitals). Although limited by the lack of standardization, randomization or blinding with regards to drug protocols, this study was still well-designed and thorough in its data accumulation and analysis, yielding some very interesting and useful results. Most importantly, what do we take away from this VETgirl podcast? Every effort should be made to achieve Holter monitor-derived mean heart rates less than 125 bpm in dogs with atrial fibrillation in order to extend survival. Control that heart rate and become tachycardiac when your patient is tachycardia! How do we apply this to our patient population? What this will require of us as veterinarians is more vigilant serial Holter monitoring and antiarrhythmic drug titration than historically has been performed, which subsequently will also require more thorough client education as to the purpose and benefits of these measures when juxtaposed with the additional costs.
Reference:
1. Pedro B, Mavropoulou A, Oyama MA et al. Optimal rate control in dogs with atrial fibrillation—ORCA study—Multicenter prospective observational study: Prognostic impact and predictors of rate control. J Vet Intern Med. 2023;37:887–899.
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