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Rate control of atrial fibrillation in dogs with valvular heart disease or dilated cardiomyopathy

Clinical Scenario

Roland, a 9 year old MN Coonhound with a history of a loud left sided heart murmur, presents with a cough of 3 days duration, tachypnea and a rapid, irregular heart rate. Radiographs demonstrate pulmonary oedema and left sided cardiac enlargement. His ECG shows atrial fibrillation (AF) with a ventricular rate of 240 beats per minute (BPM). His congestive heart failure improves with frusemide and pimobendan within 24 hours but he remains in fast atrial fibrillation with a heart rate (HR) persistently >160 BPM. He is unlikely to have successful conversion to a sinus rhythm given his underlying heart disease; will diltiazem alone or diltiazem combined with digoxin be more likely to reduce his ventricular rate?

3-Part Question (PICO)

In [dogs with atrial fibrillation secondary to heart disease] does [diltiazem alone, or diltiazem in combination with digoxin] [improve ventricular rate control in the affected dogs]?

Search Strategy and Summary of Evidence

Search Strategy

MEDLINE(R) In-Process & Other Non-Indexed Citations and MEDLINE(R) 1946 to Present using the OVID interface

(Dog OR dogs OR canine OR canines OR canis OR canid OR canids OR canidae).mp. OR exp dogs/ OR exp Canidae/

AND

(atrial fibrillation OR afib OR a-fib OR atrial flutter OR atrial tachycardia OR supraventricular tachycardia OR AF).mp. OR exp Atrial Fibrillation/ OR exp Atrial Flutter/ OR exp Tachycardia, Supraventricular/

AND

(Digoxin OR digitalis OR lanoxin OR cardiac glycosides OR glycosides OR glycoside).mp. OR exp Digoxin/ OR exp Digitalis/ OR exp Cardiac Glycosides/ OR exp Glycosides/ OR exp Digitalis Glycosides/ OR (Diltiazem OR calcium channel blockers OR CCBs OR calcium channel blocker).mp. OR exp Diltiazem/ OR exp Calcium Channel Blockers/

CAB Abstracts 1910 to Present using the OVID interface

(Dog OR dogs OR canine OR canines OR canis OR canid OR canids OR canidae).mp. OR exp dogs/ OR exp Canidae/

AND

(atrial fibrillation OR afib OR a-fib OR atrial flutter OR atrial tachycardia OR supraventricular tachycardia OR AF).mp.

AND

(Digoxin OR digitalis OR lanoxin OR cardiac glycosides OR glycosides OR glycoside).mp. OR exp digoxin/ OR exp Digitalis/ OR exp glycosides OR (Diltiazem OR calcium channel blockers OR CCBs OR calcium channel blocker).mp.

Search Outcome

MEDLINE

  • 173 papers found in MEDLINE search
  • 165 papers excluded as they don't meet the PICO question
  • 4 papers excluded as they are in a foreign language
  • 2 papers excluded as they are review articles/in vitro research/conference proceedings
  • 2 total relevant papers from MEDLINE

CAB Abstracts

  • 45 papers found in CAB search
  • 38 papers excluded as they don't meet the PICO question
  • 2 papers excluded as they are in a foreign language
  • 5 papers excluded as they are review articles/in vitro research/conference proceedings
  • 2 total relevant papers from CAB

Total relevant papers

2 relevant papers from both MEDLINE and CAB Abstracts

Summary of Evidence

Gelzer et al. (2009) USA

Title:

Combination therapy with digoxin and diltiazem controls ventricular rate in chronic atrial fibrillation in dogs better than digoxin or diltiazem monotherapy: a randomized crossover study in 18 dogs

Patient group:

Eighteen medium and large breed dogs (>15kg) with advanced heart disease and rapid (>140 BPM) atrial fibrillation (AF) presenting to Cornell University Hospital for Animals for cardiac evaluation.

10 dogs were diagnosed with dilated cardiomyopathy, 7 dogs with degenerative valvular disease, 1 dog had valvular dysplasia.

15/18 dogs were in congestive heart failure (CHF) at enrollment.

Study Type:

Randomized crossover clinical trial

Outcomes:
  • 24-hour average heart rate (Holter)
  • Hourly average ventricular rate (Holter)
Key Results:
  • All three treatments (digoxin, diltiazem, and diltiazem-digoxin) significantly reduced average Holter heart rate (p<0.001).  However, diltiazem-digoxin combination therapy resulted in a significantly greater reduction in 24-hour average heart rate than did monotherapy of either agent (p<0.008).

    • Digoxin (DG) 24 BPM median reduction
    • Diltiazem (DT) 28 BPM median reduction
    • Diltiazem-digoxin (DGDT) 60 BPM median reduction
  • Proportion of dogs achieving target average rates:

    • DG: 5/11 dogs HR<160, 2/11 HR<140.
    • DT: 4/9 dogs HR<160, 3/9 dogs HR <140
    • DTDG: 18/18 dogs HR <160, 12/18 HR<140.
  • DGDT treatment resulted in dogs maintaining target heart rate range (<140bpm) for a greater proportion of the day (60%) than DG or DT monotherapy (ca. 12% each). 
  • No clinically consequential bradyarrhythmias were observed.  No signs of digitalis intoxication were observed (dosage target 0.005 mg/kg q12h, range 0.0035–0.0071 mg/kg).
Study Weaknesses:
  • No power calculation
  • Generalizability to dogs less than 15kgs in weight is unclear
  • Initial heart rates were obtained when most patients were in CHF
  • Short term trial; long term effect of these treatments on rate control not assessed in this study
  • Rate control is a surrogate marker and correlation to clinically relevant outcomes (mortality, repeat hospitalizations, quality of life) is unknown.
Attachment:
Evidence appraisalEvidence appraisal

Jung et al. (2016) USA

Title:

Atrial fibrillation as a prognostic indicator in medium to large-sized dogs with myxomatous mitral valvular degeneration and congestive heart failure

Patient group:

Medium and large breed dogs (>15 kg) with CHF secondary to myxomatous mitral valvular degeneration (MMVD) recorded in the electronic medical records of the University of California (Davis) William R Pritchard Vet Med Teaching hospital from Jan 1, 2005-Dec 31, 2010. 33/64 dogs in this cohort were diagnosed with sustained rapid atrial fibrillation (AF, HR>160) at or after time of CHF diagnosis.

Study Type:

Study design was described as a retrospective by the authors but contained elements of cross-sectional (prevalence and risk factors for development of atrial fibrillation) and retrospective cohort design (survival analysis of effects of atrial fibrillation and pharmacologic rate control).  Therefore cohort questions have been used to appraise this study

Outcomes:
  • Death attributable to cardiac disease (including euthanasia) as measured by median survival time (MST).
  • Average heart rate measured with non-ambulatory ECG (dichotomized as >160 BPM, < 160 BPM)
Key Results:
  • Median heart rate lower with diltiazem-digoxin combination (144 BPM) than with diltiazem alone (180 BPM)
  • Median survival time with diltiazem-digoxin (130 days) was improved compared with diltiazem alone (35 days; p=0.024)
  • AF patients with adequate rate control of less than160 BPM had improved survival -  (less than 160 BPM-- 171 days; greater than160 BPM--61 days; p=0.002)
  • AF was associated with decreased median survival time (AF--142 days, non-AF--234 days; p=0.002)

 

Study Weaknesses:
  • No power calculation.
  • Observational study in which interventions were not randomly assigned poses high risk for unmeasured confounding.  Additionally, it is unclear if records abstractor(s) were blinded to any study hypotheses.
  • No statistical significance testing on differences in heart rate under different drug therapies.
  • Use of non-ambulatory ECG recorded in-clinic (rather than Holter monitoring) to assess heart rates may be a less reliable method of assessing rate control..
  • Generalizability to dogs less than 15kgs in weight is unknown
  • Use of cardiac-related death as both inclusion criteria and endpoint for cohort could bias survival analysis. Use of only dogs who reached primary endpoint for survival analysis assumes independent/non-informative censoring.
  • Study period straddled introduction of pimobendan (50% of patients did not receive pimobendan). 
  • Ethical approval is not commented upon nor is funding source stated.

 

Attachment:
Evidence appraisalEvidence appraisal

Comments

The diltiazem formulation used in the Gelzer study was an extended release formulation which may not currently be available and may be too large for some dogs.

Gelzer’s paper (2009) was directly related to our PICO question and was a well conducted and well reported crossover study in dogs with either valvular heart disease or dilated cardiomyopathy.  The paper by Jung and colleagues (2016) did not include our PICO question as a primary study aim but reported heart rates and survival data obtained under the two treatment regimens from observational data in a population of dogs with atrial fibrillation from mitral valvular disease.  Jung reported lower heart rates with diltiazem-digoxin versus diltiazem monotherapy but did not provide statistical comparison between the two treatment groups.  Jung did provide lower quality evidence that AF survival was prolonged by rate control (<160bpm) and by administration of diltiazem-digoxin (versus diltiazem alone) in a retrospective cohort, although the use of the endpoint as cohort inclusion criterion could have biased this result. 

Bottom line

In dogs >15 kg with heart disease and fast atrial fibrillation (>160 BPM), use of diltiazem in combination with digoxin may lead to improved rate control as compared to use of diltiazem alone. However, prospective randomized trials are needed to confirm this effect and to assess for the frequency of serious adverse side effects.

Disclaimer

The BETs on this website are a summary of the evidence found on a topic and are not clinical guidelines. It is the responsibility of the individual veterinary surgeon to ensure appropriate decisions are made based on the specific circumstances of patients under their care, taking into account other factors such as local licensing regulations. Read small print

References

Gelzer, A. R. M., Kraus, M. S., Rishniw, M., Moïse, N. S., Pariaut, R., Jesty, S. A., & Hemsley, S. A. (2009). Combination therapy with digoxin and diltiazem controls ventricular rate in chronic atrial fibrillation in dogs better than digoxin or diltiazem monotherapy: a randomized crossover study in 18 dogs. Journal of veterinary internal medicine, 23: 499-508.

Jung, S. W., Sun, W., Griffiths, L. G., & Kittleson, M. D. (2016). Atrial Fibrillation as a Prognostic Indicator in Medium to Large-Sized Dogs with Myxomatous Mitral Valvular Degeneration and Congestive Heart Failure. Journal of Veterinary Internal Medicine, 30: 51-57.

About this BET

First author:
Constance White
Second author:
Zoe Belshaw
Institution:

Fremont Veterinary Clinic

University of Nottingham

Search last performed:
2018-11-27 19:25:01
Original publication date:
2018-12-17 19:25:01
Last updated:
2018-12-13 19:25:01
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