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Keywords:

  • Heart failure;
  • 24 hours Holter antiarrhythmic;
  • Rate control

Abstract

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Footnotes
  9. Acknowledgments
  10. References
  11. Appendix

Background: Atrial fibrillation (AF) with excessively high ventricular rates (VR) occurs in dogs with advanced heart disease. Rate control improves clinical signs in these patients. Optimal drug therapy and target VR remain poorly defined.

Hypothesis: Digoxin-diltiazem combination therapy reduces VR more than either drug alone in dogs with high VR AF.

Animals: Eighteen client-owned dogs (>15 kg) with advanced heart disease, AF, and average VR on 24-hour Holter > 140 beats per minute (bpm).

Methods: After baseline Holter recording, dogs were randomized to digoxin or diltiazem monotherapy, or combination therapy. Repeat Holter evaluation was obtained after 2 weeks; dogs were then crossed over to the other arm (monotherapy or combination therapy) for 2 weeks and a third Holter was acquired. Twenty-four hour average VR, absolute and relative VR changes from baseline, and percent time spent within prespecified VR ranges (>140, 100–140, and <100 bpm) were compared. Correlations between serum drug concentrations and VR were examined.

Results: Digoxin (median, 164 bpm) and diltiazem (median, 158 bpm) decreased VR from baseline (median, 194 bpm) less than the digoxin-diltiazem combination (median, 126 bpm) (P < .008 for each comparison). With digoxin-diltiazem, VR remained <140 bpm for 85% of the recording period, but remained >140 bpm for 88% of the recording period with either monotherapy. Serum drug concentrations did not correlate with VR.

Conclusions and Clinical Importance: At the dosages used in this study, digoxin-diltiazem combination therapy provided a greater rate control than either drug alone in dogs with AF.

Abbreviations
ACE

angiotensin-converting enzyme

AF

atrial fibrillation

BL-HRHOLTER

24-hour average heart rate from Holter at baseline

CHF

congestive heart failure

CXR

thoracic radiograph

DG

digoxin

DGDT

combination therapy of digoxin and diltiazem

DT

diltiazem

HR

heart rate

HRHOLTER

24-hour average heart rate from Holter recordings

ΔHR

absolute change in heart rate from baseline

%ΔHR

percent change in heart rate from baseline

NYHA

New York Heart Association

VR

ventricular rate

2WK-HRHOLTER

24-hour average heart rate from Holter after 2 weeks of therapy

Atrial fibrillation (AF) with a rapid ventricular rate (VR) commonly occurs in dogs with advanced heart disease, and results in substantial morbidity, including worsening of congestive heart failure (CHF) and decreased survival times.1–3 Most dogs with AF and rapid VR fail electrocardioversion or do not maintain sinus rhythm, and improvement in clinical signs usually depends on rate control.4 Additionally, in humans with AF and CHF, VR control may provide clinical outcomes that are not different from those achieved with rhythm control after cardioversion.5

Clinicians have traditionally used digoxin for VR control in dogs with AF, but digoxin can inadequately control excessively rapid VR in dogs.1 Furthermore, digoxin inadequately controls VR in human patients with AF during exercise or CHF, because increased sympathetic tone overrides the vagal effects of digoxin resulting in “break-through.”6,7 Diltiazem also slows VR acutely in dogs with experimentally induced AF,8 but little is published on diltiazem in dogs with spontaneous AF. Additionally, some veterinary clinicians hesitate to use diltiazem because of potential negative inotropic effects. In humans, diltiazem typically fails to control VR adequately.7,9 Conversely, satisfactory VR control is often achieved in human patients with combinations of digoxin and either calcium channel blockers or β-blockers.7,10–12 Unfortunately, virtually no information is available about either diltiazem monotherapy or digoxin combination therapy in dogs with AF.a,1 Assessment of VR control in veterinary medicine also remains poorly defined. Several studies have demonstrated that continuous heart rate information collected for 24 hours by ambulatory electrocardiographic (Holter) monitoring provides more accurate VR information than short ECG “snapshots” obtained in a hospital setting,13,14 and thus is considered closer to ideal.15–17 Additionally, more complex analysis of VR control is possible with Holter monitoring.

Optimal or adequate VR control in dogs with AF remains similarly undefined. Limited dataa,4 measured by ECG or auscultation rather than 24-hour Holter suggest a target VR of <160 beats per minute (bpm) in dogs with AF secondary to CHF. No studies, however, have demonstrated that these target rates are either adequate or optimal in terms of improved management of CHF, enhanced quality of life, or prolonged survival. Recommendations for human patients suggest that target VR approximate the “situation-appropriate” sinus rates (ie, the VR of a patient with AF at rest or during a 6-minute walk test should be similar to what the sinus rate would be during that particular activity if the same patient were not in AF).18,19 Thus, more aggressive VR control in dogs with rapid VR might be appropriate.

We sought to determine which treatment produces the greatest decrease in VR without adverse effects. We compared the effect of DG, DT, and a DGDT combination in decreasing VR in large-breed dogs with sustained, naturally occurring AF with rapid VR and severe cardiac disease, as assessed by 24-hour ambulatory ECG analysis.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Footnotes
  9. Acknowledgments
  10. References
  11. Appendix

Study Design and Patient Selection

In this prospective, randomized crossover, clinical trial, we examined the ability of 3 pharmacological protocols—DG or DT monotherapy, or DGDT—to control VR in large-breed dogs with severe cardiac disease exhibiting AF and high VR.

Candidate dogs, presented to Cornell University Hospital for Animals, underwent complete cardiac evaluation by a cardiologist, including physical examination, ECG (to confirm AF), echocardiogram, CXR, and a baseline Holter recording. To qualify for enrollment, the 24-hour average heart rate (HRHOLTER) recorded at baseline (before starting any antiarrhythmic drugs) had to exceed 140 bpm, and body weight had to be >15 kg. We chose these criteria because dogs with underlying heart disease and HRHOLTER≤ 140 bpm might not warrant VR control, and large-breed dogs are most commonly afflicted by AF secondary to severe heart disease. Qualifying patients were then randomly assigned to a specific drug treatment order, established by a random number generatorb before starting the trial. The study design and subject allocation are illustrated in Figure 1.

image

Figure 1.  Study design. Examination schedule and order of drug administration is shown. Numbers within circles represent the number of dogs in a particular phase of the study. PE, physical examination; ECG, electrocardiogram; echo, echocardiogram; CXR, thoracic radiograph; DG, digoxin phase; DT, diltiazem phase; DGDT, combination therapy (digoxin and diltiazem); 2 wk, 2 weeks; BL, baseline; AF, atrial fibrillation; [digoxin], serum digoxin concentration measurement; HR, heart rate; BW, body weight.

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CHF, when present, had to be controlled medically before the 1st treatment (phase 2 of 3) Holter recordings; in the dogs with CHF, the baseline Holters were acquired while CHF was still inadequately controlled. Dogs in CHF received standard medication for management of CHF as required (eg, diuretics, ACE inhibitors, and pimobendan), excluding DG. If patients were already receiving DG at presentation, DG therapy had to be discontinued for at least 1 week before acquiring the baseline Holter recording. Dogs were treated with DGc at approximately 0.005 mg/kg PO q12h, DTd at approximately 3 mg/kg PO q12h, or DGDT at these dosages. The dogs received each treatment for 2 weeks (to ensure drugs reached steady-state) before reexamination. During examination, a 1-minute ECG was acquired to document AF, serum samples were obtained for assessment of DG (6–8 hours post-pill) or DT (4–6 hours post-pill) concentrations, and a Holter recording was obtained. After removing the Holter recorder, each dog received the alternate scheduled treatment for 2 weeks, after which a 3rd examination was performed. Serum DG concentration was measured in-house by a fluorescent polarization immunoassay.e Serum DT concentration was measured by high-performance liquid chromatography at a commercial laboratory.f

Qualifying pet owners signed a consent form upon enrollment. The study protocol was approved by the Cornell University Institutional Animal Care and Use Committee.

Data Acquisition and Analysis

Holter monitoring was performed using 3-channel digital recorders, in an orthogonal lead arrangement.f A small area of hair was clipped for each electrode (2 per channel and 1 ground) and ECG electrodes were connected to the Holter recorder, which was fitted into a custom-made vest. Routine activities for the dogs were encouraged and an activity diary was kept by the owner.

We acquired Holter data at a sampling frequency of either 200 or 400 Hz, stored it on 350-MB removable PC flashcards, and transferred it to a hard drive for automated analysis by proprietary software.g We tabulated hourly VR averages and calculated the 24-hour average heart rate (HRHOLTER). To ensure the fidelity of automated data analysis, a trained technician blinded to the treatment (SAH) performed a thorough manual inspection and corrective editing of each Holter.

We evaluated the longitudinal dynamics of VR control over 24 hours by assessing the hourly average VR. The Holter recordings were not initiated at the same time of day for all dogs in the study. Thus, we examined all the hourly average VR both in real time (to examine the effects of daytime and nighttime activity on VR) and after normalizing to time of Holter application (to examine the effects of hospital visit on VR). We then examined the ability of each treatment to maintain VR within 3 arbitrarily defined VR ranges; (1) high VR (>140 bpm), (2) target range VR (100–140 bpm), and (3) slow VR (<100 bpm), and compared the percentage of time in each category for each treatment group.

The minimum hourly average VR of each Holter was evaluated to identify the presence of inappropriate bradycardia (heart rate < 40 bpm) induced by any of the treatment regimens. We also examined, but did not statistically analyze, pauses, maximum heart rates, and ventricular tachyarrhythmias (singles, couplets, and runs of ventricular tachycardia).

Statistical Analysis

Data were initially summarized by calculating descriptive statistics using commercial and community-based software.h,i All data were assessed for normality by the Shapiro-Wilk normality tests and subsequently analyzed by nonparametric tests. Confidence intervals for median values were calculated as described previously.20 The median, ranges, and 95% confidence intervals for median values are reported for HRHOLTER at baseline (BL-HRHOLTER) and after 2 weeks of treatment (2WK-HRHOLTER) with each of the 3 treatments. Because heart rate responses in dogs receiving a single drug first followed by combination therapy were not appreciably different from responses in dogs receiving combination therapy first followed by single drug, we concluded that no time/treatment interaction was present, and pooled the results for these groups. To determine whether any treatment provided better VR control than any other treatments, we compared the absolute change in heart rate from baseline (ΔHR = 2WK-HRHOLTER−BL-HRHOLTER) and the % change in heart rate from baseline (%ΔHR =ΔHR/BL-HRHOLTER× 100) between DGDT and DG or DGDT and DT with Wilcoxon's signed rank tests and between diltiazem and digoxin with a rank sum test.

We used Wilcoxon's signed rank tests to examine whether differences in VR control between monotherapy and combination therapy could be due to differences in either oral dose (mg/kg) or serum drug concentrations (ng/ml). The median and range for drug dosages and serum concentrations are reported. We used Spearman's rank correlation to examine whether VR control achieved by either drug was associated with serum drug concentration.

We used Bonferroni-corrected Wilcoxon's signed rank tests to compare the ability of each treatment to maintain VR within the prespecified VR ranges, except when comparing DG and DT groups, where we used Bonferroni-corrected rank sum tests.

In all analyses, to conserve the experiment-wise error rate (defined as the overall likelihood of committing a type-I error in a study by performing multiple independent statistical tests), a P value of <.008 was considered significant.

Results

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Footnotes
  9. Acknowledgments
  10. References
  11. Appendix

Patient Characteristics and Study Design

Twenty-four large-breed dogs were initially recruited; 4 dogs were excluded because BL-HRHOLTER was <140 bpm, 1 because body weight was <15 kg, and 1 dog died suddenly during the 1st phase of the study (after completing the baseline examination). The remaining 18 dogs all received DGDT, 11 dogs received DG, and 9 dogs received DT. Two dogs received all 3 treatments (Fig 1). These breeds were represented as Doberman Pinscher (4), German Shorthair Pointer (3), Great Dane and Greyhound (3), and 1 of each of the following: Newfoundland, Bull Mastiff, Rottweiler, St Bernard, German Shepherd mix breed, Shar Pei, and American Bulldog. Ten dogs were diagnosed with dilated cardiomyopathy, 7 dogs with degenerative valve disease, and 1 dog with AV valve dysplasia.

Fifteen dogs were in uncontrolled or poorly controlled CHF at presentation: 6/15 were not on any CHF medications at baseline examination, 2/15 were receiving furosemide alone, and 7/15 dogs were receiving combination diuretic and ACE inhibitor therapy. After acquiring the baseline Holter, all 15 dogs with CHF were stabilized and maintained on CHF therapy. All 15 dogs received furosemide and ACE inhibitors; additionally, 4 of these 15 received spironolactone, whereas 4 of them received pimobendan, and 6 of the 15 received both spironolactone and pimobendan. Three dogs had severe cardiac disease and AF, but no CHF at baseline.

Drug Efficacy Assessed by Holter Recordings

Each treatment significantly decreased 2WK-HRHOLTER from BL-HRHOLTER (DG P < .005, DT P < .005, DGDT P < .0001; Table 1, Fig 2). However, DGDT resulted in a greater reduction in heart rate (60 bpm) than obtained with either DG (24 bpm) or DT (28 bpm) alone (P < .008 for each comparison; Table 1). Additionally, DGDT produced a greater %ΔHR (30%) than either DG (14%) or DT alone (20%) (P < .008 for each comparison; Table 1). The %ΔHR did not differ between DG and DT (P= .54; Table 1). When comparing within-dog responses, DGDT decreased HRHOLTER by an additional 28 bpm over DG (median; range, 7–70 bpm) and by 22 bpm over DT (median; range, 2–49 bpm). All 18 dogs receiving DGDT achieved HRHOLTER < 160 bpm and 12/18 achieved HRHOLTER < 140 bpm. Conversely, only 4/9 dogs receiving DT and 5/11 dogs receiving DG achieved HRHOLTER <160 bpm; 3/9 and 2/11 in these groups, respectively, achieved HRHOLTER < 140 bpm.

Table 1.   Effects of 3 different treatments on VR of dogs with atrial fibrillation (AF).
Treatment (Number of Cases)HRHOLTER (bpm)%ΔHR Median (Range) 95% CI
Baseline Median (Range) 95% CI2-Week Median (Range) 95% CIΔHR Median (Range) 95% CI
  • Different from baseline (P < .001).

  • 95%CI, 95% confidence intervals for median values; HRHOLTER, 24 hours average heart rate determined by Holter monitoring; bpm, beats per minute; ΔHR, change in heart rate from baseline (bpm); %ΔHR, % change in heart rate from baseline. Note that all heart rate differences (ΔHR and %ΔHR) are reported as negative values because each treatment resulted in a reduction of the median heart rates as compared with baseline.

  • Median values within columns with different superscripts (a or b) are significantly different (P < .008).

Digoxin (11)195 (142–215) 172–199164 (119–194)a 144–180−24 (−79, 11)a −35, −12−14 (−40, 8)a −18, −8
Diltiazem (9)185 (142–234) 148–202158 (114–178)a 119–177−28 (−69, −4)a −52, −7−20 (−29, −2)a −27, −4
Digoxin-diltiazem (18)194 (142–234) 162–199126 (93–158)b 112–146−60 (−100, −29)b −69, −44−30 (−47, −16)b −36, −28
image

Figure 2.  Real-time (A) and normalized (B) hourly ventricular rate (VR) profiles of the 24-hour Holter recordings in dogs with atrial fibrillation. Median values of hourly average VR are shown, and the 4 curves represent baseline ♦ (BL, n = 18), digoxin ▪ (DG, n = 11), diltiazem ▴ (DT, n = 9), or digoxin and diltiazem • (DGDT, n = 18) therapy. (A) The unshaded area represents the period in the home environment for nearly all dogs. During the periods defined by the shaded portions, patients are in various environments (ie, hospital, travelling from/to hospital), and variable numbers of dogs are included during these periods (see Appendix 1 for details). (B) Shaded portions show a decrement (left) or increment (right) in VR, most likely associated with stress of the hospital visit. The unshaded area most likely represents VR in home environments during normal activity. All treatments reduced VR from baseline (P < .008), and DGDT reduced VR the most (P < .008). Additional descriptive statistics have been omitted from the figures for clarity, but are detailed in Appendix 1.

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Neither the DG dosage (0.005 mg/kg PO q12h; range, 0.0035–0.0071 mg/kg) nor the serum DG concentration (0.8 ng/mL; range, 0.27–1.57 ng/mL) during DG monotherapy differed from the digoxin dosage (0.005 mg/kg PO q12h; range, 0.0039–0.0058 mg/kg) or serum DG concentration (1.27 ng/mL; range, 0.49–2.9 ng/mL) in the same dogs during DGDT therapy (P= .7 and .11, respectively). Serum concentrations remained within the therapeutic range (0.5–2 ng/mL) in all but 1 dog, and none of the dogs in the study showed clinical signs of DG toxicity. Similarly, the DT dosage during DT monotherapy (3.21 mg/kg PO q12h; range, 2.67–3.50 mg/kg) did not differ from the DT dosage in the same dogs during DGDT therapy (3.29 mg/kg PO q12h; range, 2.4–5.65 mg/kg; P= .8). Technical problems (substance interference reported by the laboratory) restricted analysis of DT concentrations to 9/18 dogs. The DT concentration in these 9 dogs was 32 ng/mL (range, 10–134 ng/mL) while they received the DGDT therapy.

VR Control over Time

Figure 2 displays the median hourly average VR both in real time (Fig 2A) and normalized to the time of Holter application (Fig 2B) for each treatment group over the 24-hour period. To preserve figure clarity, specific descriptive statistics for these data are presented in Appendix 1. The unshaded portion in Figure 2A (6:00 pm to 12 noon the following day) is highlighted because nearly all dogs in all treatment phases had Holter data during this period and all dogs were in their home environment and at least 1 hour of Holter recording had been acquired by this time. Thus, this period most likely represents the VR control that might be anticipated in a home environment. All 4 groups showed similar profiles, which were vertically separated. An initial steep decrement in VR was apparent in the normalized data, with an increment in the terminal hours in the baseline and DG groups (Fig 2B, shaded regions). We initiated >70% of Holter recordings after 14 hours; thus, the unshaded period represents the period from early evening to the following noon for most dogs. In agreement with the median HRHOLTER reported in Table 1, the normalized hourly baseline VR was consistently >180 bpm and showed relatively little hour-to-hour variation after the initial decrease. Normalized DG and DT monotherapy profiles indicated more erratic variation in VR over the 24-hour period, whereas DGDT therapy had a relatively smooth profile after the initial decrease (Fig 2B).

Figure 3 displays the percentage of time VR remained in each category with each treatment over the 24 hours of recording. Within each VR range, DGDT therapy differed significantly from baseline (P= .0002, .003, and .003). Additionally, dogs receiving DGDT therapy spent significantly less time at VR > 140 bpm than dogs receiving either DG or DT monotherapy (P= .005 and .008).

image

Figure 3.  Box-and-whisker diagram demonstrating the ability of each treatment to maintain ventricular rate (VR) in specific ranges. Data are displayed as median percentage of time that the VR spends in each range (black line); box limits represent the interquartile range, and whiskers represent the maximum and minimum values. Note that in the VR range <100 bpm, the baseline and digoxin groups have median and interquartile values of 0%. BL, baseline (n = 18); DG, digoxin (n = 11); DT, diltiazem (n = 9); DGDT, digoxin-diltiazem (n = 18) therapy. Horizontal bars inline image connect groups that are significantly different (P < .008).

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The median minimum hourly VR at baseline was 90 bpm (range, 54–150 bpm) and all treatment groups experienced decreased median minimum hourly average VR (DG: 68 bpm, 52–90 bpm; DT: 67 bpm, 53–95 bpm; DGDT: 53 bpm, 40–104 bpm). The minimum hourly VR were all recorded between midnight and 6:00 am (“24” and “6,” respectively, in Fig 2A), and were considered appropriate for sleep-associated bradycardia.

Relationship of DG or DT Concentrations with VR Control

During both DG monotherapy and DGDT therapy, we could find no correlation between serum DG concentration and HRHOLTER. (P= .9 and .67).

Similarly, during DGDT therapy, we could find no correlation between serum DT concentration and HRHOLTER. (P= .76). In the DT monotherapy group, the DT concentrations were not available because of technical errors at the commercial laboratory and thus could not be correlated to HRHOLTER.

Adverse Effects

No dogs developed signs of DG toxicity and no clinically relevant adverse effects associated with DT (eg, weakness, collapse, syncope, and hypotension) were documented. One dog (a Doberman Pinscher) exhibited occasional pauses of up to 4.4 seconds followed by ventricular escape beats while sleeping during baseline recording. These pauses were prolonged with DT monotherapy (longest pause of 5.7 seconds); however, the remaining VR of this dog was comparable to all dogs in the study and no clinical signs of weakness or syncope were reported. No adverse effects were noted in dogs receiving DGDT combination therapy. Most dogs in this study had clinically inconsequential ventricular arrhythmias but no dogs in the study required antiarrhythmic medication for the ventricular arrhythmias.

Discussion

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Footnotes
  9. Acknowledgments
  10. References
  11. Appendix

Our study demonstrates that in dogs with underlying heart disease and AF with rapid VR, DGDT for 2 weeks results in greater VR reduction than that achieved with either DT or DG alone. Although both drugs given individually produced significant reductions in VR as compared with pretreatment, substantial additional VR reduction was achieved in our patients with combination therapy.

DGDT therapy decreased VR most effectively (Table 1), and maintained VR < 140 bpm for approximately 60% of the time, whereas both monotherapies achieved this level of VR control only 12% of the time. In no patient was VR higher with DGDT therapy than with monotherapy. In humans, this improvement is attributed to an enhanced control of heart rate during exercise.7,9–12 The sustained VR control during periods of regular activity in the home environment (Fig 2A) and the relatively flat normalized hourly VR profile compared with monotherapy (Fig 2B) suggest that VR control during daily activity in dogs may be improved with combination therapy. Calcium channel blockers in canine AF likely complement the vagomimetic effects of DG, consistent with studies in human patients in sinus rhythm.21 Although Bonagura and Ware1 reported favorable effects of co-administration of DG with propranolol in dogs with AF, our study provides evidence that DT might provide a suitable substitute for propranolol.

Although we improved VR control with DGDT therapy, all treatments showed a VR decrement in the hours immediately after Holter application (Fig 2B). This most likely represents a decrease from the high level of stress experienced during the hospital visit, and highlights potential concerns of measuring treatment efficacy in a hospital environment. Thus, excluding this period from analysis might provide a more physiologically representative assessment of VR control. We highlighted the period spent in the home environment in Figure 2A (6:00 pm to 12 noon), although our analysis was based on 24-hour averages, because 24-hour averages are more easily obtained with routine clinical Holter analysis, and would be more relevant to clinicians. Additionally, the hourly profiles demonstrate that differences between treatments, assessed by HRHOLTER, were not because of marked transient changes in VR in the DGDT group that might have skewed the HRHOLTER data enough to produce a difference; rather, these effects persisted over the entire recording period.

Although the dogs in this study received standard DG dosages (0.005 mg/kg q12h), and maintained serum concentrations within the therapeutic range (0.9 ng/mL), DG therapy decreased heart rate significantly, but only modestly. All our patients receiving DG monotherapy had CHF, and their VR remained >140 bpm for almost 90% of time with DG therapy. Less than 50% of dogs achieved the traditionally accepted satisfactory (in-hospital ECG-derived) VR control (140–160 bpm) with DG therapy alone.4 This is consistent with findings in human patients with AF and CHF in whom markedly increased sympathetic tone overrides the vagomimetic effects of DG.7,22 A lack of correlation between serum DG concentration and HRHOLTER argues against the hypothesis that higher serum concentrations might have improved VR control, consistent with findings in humans, where even toxic concentrations fail to achieve appropriate VR control.6,10

DT monotherapy decreased the VR comparable to DG monotherapy. This parallels observations in humans with AF in whom moderate-dose DT monotherapy inadequately controlled rate,7,9 but attenuated exercise-induced VR “break-through” events better than DG.7,10 Similar to DG monotherapy, DT monotherapy resulted in VR > 140 bpm for almost 90% of the time, and both monotherapies differed from DGDT therapy. The wide VR range for the DT group shown in Figure 3 was because of 3 dogs in this group that did not have CHF. When these were excluded from analysis, the range resembled the group receiving DG (data not shown).

Whether higher doses of DT would safely improve VR control remains to be determined. Based on preliminary observations of the extended-release DT used in this study, we selected and achieved a well-tolerated target dosage of 3 mg/kg. We found no correlation between DT serum concentrations and HRHOLTER with DGDT therapy. In normal anesthetized Beagle dogs with experimentally induced AF, acute oral administration of DT at 5 mg/kg (but not 2.5 mg/kg) decreased VR to pre-AF values.8 However, because pharmacokinetics and pharmacodynamics of various DT preparations differ, direct dose comparisons are inappropriate. Nevertheless, “high-dose” DT therapy was superior to “low-dose” (360 versus 240 mg/day) as assessed by ECGs at rest and during exercise in human patients with AF.9

Similar to previous reports in dogs,8 DT concentrations measured in our study would be considered subtherapeutic by human standards (50–200 ng/mL), possibly due to extensive first-pass clearance of oral DT in dogs.23 Interestingly, the dog with the greatest VR control with DGDT therapy also had the highest DT dose and serum concentration, whereas the dog with the least VR control had the second-lowest DT concentration, but a near-median oral dose. Most importantly, however, with DGDT therapy, the DT serum concentrations we measured exerted a significant effect on HRHOLTER. These serum concentrations, therefore, represent effective therapeutic concentrations for dogs with severe cardiac disease, when used with DG. Although DT dose titration might have resulted in even greater VR control, the study design limited our ability to manipulate the DT dose.

The optimal target heart rate for dogs with high-rate AF secondary to severe heart disease and its assessment are poorly defined. Ideally, the lowest VR achievable without hemodynamic compromise is desired. Recent guidelines in humans recommend a target VR similar to a “situation-appropriate” sinus rate: 60–80 bpm at rest and 90–115 bpm during mild exercise18,19 in NYHA I and II patients. Surprisingly, target rates in NYHA III or IV human patients are poorly defined, but are generally tailored to performance on 6-minute walk tests, and approximate VR of similar patients in sinus rhythm. Our study shows that HRHOLTER < 140 bpm is easily achieved in this population of dogs without increased morbidity. Indeed, the median HRHOLTER on DGDT therapy was 126 bpm (and 128 bpm for the CHF dogs), and only 6/18 dogs (5/15 CHF dogs) had HRHOLTER > 140 bpm. Thus, our target VR may have actually been conservative, and more aggressive VR control might be warranted in these patients. However, this ultimately needs to be demonstrated by improvements in both hemodynamic variables (eg, cardiac output, atrial pressures, and oxygen delivery) and clinical variables (eg, decreased morbidity and mortality), which our study did not address.

Limitations

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Footnotes
  9. Acknowledgments
  10. References
  11. Appendix

The study involved only 18 dogs in a somewhat complex crossover design. Only 2 dogs received all treatments, but all remaining dogs received DG or DT and DGDT therapy in a randomized order. Thus, as some of our data illustrate, some variables had large variation. Although this strengthens the differences we observed, some differences might have been missed because of relatively low power. Nevertheless, our data provide clinically important and relevant findings on VR control in AF.

The study results are applicable only to large-breed dogs with high-rate AF, which constitute a clinically relevant population. Because we have no reason to suspect differences in pharmacodynamics of DT or DG, in dogs of different sizes, we would expect similar outcomes in all dogs that have high-rate AF secondary to severe heart disease.

Baseline Holter recordings were acquired in most dogs while CHF was present, which might contribute to excessively high VR in those dogs. It is likely that stabilization of uncontrolled CHF (with diuretics, ACE-inhibitors, and pimobendan) may have contributed to the effect on VR observed at the first-treatment Holter. However, randomly assigning dogs to each treatment arm would control for this factor. Indeed, as Figure 1 illustrates, similar numbers of dogs received each of the treatment options as their first treatment, suggesting that any effect of CHF medication on VR would be equally distributed.

Drug doses were predetermined, rather than being optimized on a per-patient basis, to simplify study design. The doses selected represented clinically relevant doses, and we feel that the comparisons are valid. It is possible that greater VR reductions could have been achieved with dosages more specifically tailored to each patient. Nevertheless, the VR reductions with combination therapy demonstrated that our a priori standardized approach results in responses that have been considered “clinically appropriate” as suggested previously.4

The lack of correlations between serum concentrations and HRHOLTER should be viewed cautiously, because they are based on small sample populations and relatively stringent statistical criteria (P < .008). Larger pharmacodynamic studies are required to substantiate our initial observations.

Conclusions

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Footnotes
  9. Acknowledgments
  10. References
  11. Appendix

We have shown that the combination of DG and DT produces a greater reduction in VR in dogs with high-rate AF secondary to severe heart disease than either DG or DT administered individually. Combination therapy consistently (but not universally) decreased VR to <140 bpm as determined by 24-hour average heart rate. Although a decrease in VR is easily measured, it remains a surrogate end-point. The definitive endpoint of effective VR control should be an improvement in clinical signs, quality of life, and mortality. Future clinical studies that investigate how VR control prolongs survival and improves clinical signs in dogs with spontaneous AF are warranted.

Footnotes

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Footnotes
  9. Acknowledgments
  10. References
  11. Appendix

a Hamlin R. Clinical use of Diltiazem for dogs with atrial fibrillation. Proc Am Coll Vet Intern Med 1988:759

b Random Number Generator for Excel (add-in for Microsoft Excel 2007), Microsoft Office 2003, Microsoft Corporations, Bellevue, WA

c Lanoxin; Glaxo Smithkline, Research Triangle Park, NC

d Dilt-XR 240 mg (diltiazem hydrochloride extended release), Apotex Inc, Toronto, ON, distributed by Apotex Corp, Weston, FL

e Abbott Laboratories, North Chicago, IL

f Medtox Laboratories Inc, St Paul, MN

g Spacelabs Burdick Inc, Deerfield, WI

h Statistix 8.0, Tallahassee, FL

Acknowledgments

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Footnotes
  9. Acknowledgments
  10. References
  11. Appendix

The authors thank Hollis N. Erb for invaluable statistical consultation and for offering comments on the manuscript. This study was supported in part by grants from the Doberman Pinscher Foundation and Cornell University.

References

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Footnotes
  9. Acknowledgments
  10. References
  11. Appendix
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    Koh KK, Song JH, Kwon KS, et al. Comparative study of efficacy and safety of low-dose diltiazem or betaxolol in combination with digoxin to control ventricular rate in chronic atrial fibrillation: Randomized crossover study. Int J Cardiol 1995;52:167174.
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    Saxonhouse SJ, Curtis AB. Risk and benefits of rate control versus maintenance of sinus rhythm. Am J Cardiol 2003;91:27D32D.
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Appendix

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Footnotes
  9. Acknowledgments
  10. References
  11. Appendix
Table A1.   Descriptive statistics for hourly average ventricular rates illustrated in Figure 2.
TreatmentClock TimeHolter Time
Time (h)Sample (n)Min25thMedian75thMaxTime (h)Sample (n)Min25thMedian75thMax
Baseline10AM0018165205214228248
11AM1228228228118150199207224238
12PM2165195224218142186204217238
1PM3161215215318121185204217237
2PM4150173192207218418137175203217232
3PM10150205210214228518132175188209231
4PM16168199210225239618125170177198236
5PM18121187206222248717111169180196236
6PM18137185201220238817110169184198236
7PM18132177206218237917138170180196237
8PM181251662032142321017128174182195236
9PM171431731882082311117113175186207237
10PM171281691911992361217118172186198236
11PM171111681771982361317135171187195234
12AM171101711781942361416134170192199238
1AM171381691821962371516135171188200234
2AM171281751842032361616130163188196239
3AM171131751861922371716147166188202234
4AM171181691841952361816142165191196231
5AM161351731811932341916125161184195231
6AM161341731871982382016139158191203230
7AM161351691912022342116143166184197224
8AM161301641861982392216141162185199224
9AM161421661911992342315132164187204232
10AM161271651831992312412144177191210228
11AM16125158187198231254138186206212222
12PM15140152187197230       
1PM14141168188197224       
2PM13144168195201224       
3PM11132176191203232       
4PM8144193206211228       
5PM3138213222       
Digoxin10AM0011138182203224238
11AM0111133150205213231
12PM1199199199199199211128149180198204
1PM2192197201206210311129145174192201
2PM3199204208223238411126148162191198
3PM5138146178204218511122142179186208
4PM10136164185203228611100140163178210
5PM11128151187209229711119132154179195
6PM1112914917919623181195122168180207
7PM1113214816019220891193131154169188
8PM111221441681902061011115136156169186
9PM111201431651871981111114136154170192
10PM111001361521741831211113138153175205
11PM111161351571772101311111137157183201
12AM11951241531841951411108143158174186
1AM11931311571682071511111146164168201
2AM111141381571741901611125146157167181
3AM111131351541651801711118143154170214
4AM111111381591771921811116143154170190
5AM111081381571752051911110145153169190
6AM111111451581672012011103142157180191
7AM111251451671711902111108141164172183
8AM111181471541842012211107147159175183
9AM111161431541681872311106145159170204
10AM111101371551712142410122147159180193
11AM11103145153166183252166174181
12PM11108142162180193       
1PM10107139157172185       
2PM9106144159181182       
3PM8122137154169183       
4PM6146152159175204       
5PM2166173179       
Diltiazem10AM118918918909150157189196213
11AM318719319919128133187192219
12PM715015719220021329116126174188210
1PM712813117419721939112134150173205
2PM811613115416921049104144152167175
3PM911213715217319659120131160182223
4PM910414416018519769107138165173217
5PM912013216518322379123143169187214
6PM911613816917821789118135167177202
7PM912313016717721499107139163165200
8PM9107135165171197109100109158162180
9PM912114316016219111996118164168228
10PM9100118151168187129102112147155189
11PM996115155166228139107114143144167
12AM9102110144155189149109130141151176
1AM9107118141147162159115128140144178
2AM9109130140151172169107136150153188
3AM9114128144153165179106133144148181
4AM910711913614617618999124137154182
5AM910612714414818819998108134145188
6AM99913514515419120989140148161191
7AM910412014115018821989120147173183
8AM910114016116518322990111159163177
9AM98912014716518223970129155165180
10AM989111150168186248116137147157216
11AM870120141160178251142142142
12PM5111123142183216       
1PM392142163       
2PM2116140163       
3PM1150150150       
4PM0       
5PM0       
Digoxin-Diltiazem10AM1124124124018116140162179224
11AM211712813911887120143153202
12PM2118130142218111122134146172
1PM3118138143318108125136156172
2PM711111715115918641890111128142170
3PM1110911813716722451863112130140166
4PM178712014416620261863108126141164
5PM1710312513914916571879104125139157
6PM1810312513014817281868105116140151
7PM189812114415417291862106121130149
8PM188012213014617010186196113120146
9PM189210712213716611186192108120146
10PM187910111312816412188398116120154
11PM18639111713815713187496114127167
12AM186289114121148141868103110119166
1AM18619211012414915186799110129170
2AM186196109120146161870105113140172
3AM1874100114120146171893108117131164
4AM186896111118154181890102114129180
5AM1867102107122167191883104117142194
6AM1870105115124166201884109121142157
7AM1893110123141170211887109118140181
8AM1896114125140172221890118124145171
9AM18821061171441642316101117128140165
10AM17841021161421802414104120129147183
11AM1787108124147194252129129129
12PM1687100115145171       
1PM1594116122139153       
2PM14101117126146174       
3PM10104121138140165       
4PM9128129129160183       
5PM0