The Burden II Trial - what have we learnt?

In August 2003, Puglisi A et al first published the results of the Burden I trial in the European Heart Journal. This randomised study, presented some interesting findings with regards to atrial tachyarrhythmia burden in Brady-Tachy Syndrome. To accomplish this, the study compared overdrive pacing, the DDDR pacing mode and Closed Loop Stimulation (CLS).

Conclusions from the patient population of the study included:

• The CLS pacing mode was associated with a lower AT burden.

• CLS and DDD+ algorithms could provide an effective atrial overdrive with an Atrial Paced Percentage (APP) significantly higher than in DDDR.

Although the primary finding of the trial showed a reduction in Atrial Tachyarrhythmia burden associated with CLS there were some limitations however. Firstly, the study used different pacemaker models which meant the use of two different pacemaker models prevented further data reporting and comparisons concerning both the effect of pacing algorithms on the incidence of premature atrial contractions, and AT episode validation. Secondly, there was no crossover between the pacing algorithms and thirdly, one device algorithm leant towards permanent Ventricular pacing which could have possibly affected and limited the AT prevention efficacy of CLS. 1

Now, five years later, Puglisi A et al have released the findings of the Burden II trial which has tended to these limitations. This was accomplished by recruiting a greater patient population (Burden I = 149, Burden II = 451), incorporating a crossover at 4 and 7 months and also using the same pacemaker model for all patients which includes a CLS algorithm that does not require permanent Ventricular pacing (Protos DR CLS).

The following summarized information and results were the main findings from the Burden II trial. 2

Study Population

The population characteristics for the study were as follows:

451 Patients with Brady-Tachy-Syndrome

• Female gender 49%

• Age (yrs) 75 ± 7

• NYHA II/III 54/5%

• LVEF (%) 55 ± 8

• Left atrial size (mm) 42 ± 6

• Coronary artery disease 16%

• Documented AF 92%

• Documented AFlut 13%

• Sinus Bradycardia 93%

• AV block II/III 15/3%

• AA drug therapy 50%

Study design

Full crossover was performed between the three pacing algorithms at 4 and 7 months:

See Figure 1

The three pacing algorithms used in the Burden II trial were:

Atrial overdrive (DDDR+)

An algorithm designed to almost completely suppress spontaneous atrial beats by pacing slightly above sinus rhythm

Accelerometer-based rate modulation (DDDR)

A conventional rate modulation algorithm using an accelerometer for the detection of exercise-induced movements

Closed Loop Stimulation-based rate modulation (CLS)

Rate modulation based on information about the actual metabolic demand by measuring a contractility-related impedance signal coming from a normal right ventricle lead.

* Lower rate = 70 ppm, Upper rate = 130 ppm

Results - AT

See Figure 2

CLS was able to reduce the AT burden to only 0.04% of all atrial beats in the whole patient population.
CLS reduced the AT burden significantly by 66.7% vs. DDDR+ and by 50% vs. DDDR.

See Figure 3

177 (43%) patients had the lowest AT burden when CLS was activated in their device. Therefore the chance for patients to experience the lowest AT burden is the highest in the CLS mode.

See Figure 4

For episodes lasting longer than 1 minute and shorter than 1 hour, CLS has shown the lowest percentage of patients.
During episodes lasting longer than 1 hour and shorter than 24 hours, CLS only showed significance in comparison to DDDR+.
Episodes longer than 24 hours did not show significant differences.

• Figure 1 Figure 1
• Figure 2 Figure 2
• Figure 3 Figure 3
• Figure 4 Figure 4
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Results – APP

See Figure 5

Closed Loop Stimulation shows a higher atrial pacing percentage than the conventional accelerometer but lower than overdrive, which is due to the more physiological pacing behavior of CLS.
There was only a very poor correlation between the APP and the AT burden during all algorithms.

Results – VPP

See Figure 6

In patients with an AV Conduction Time <270 ms, CLS combined with an AV hysteresis of 300 ms reduced the VPP to 15%.
In a subgroup of patients with an AV Conduction Time <200 ms, the VPP was reduced to only 6% in the CLS group.

See Figure 7

In patients with Vp <40%, CLS demonstrates the lowest AT burden. However, the interaction of pacing mode, Vp and AT burden in patients with Vp >40% needs further investigation as each pacing therapy was active for only 3 months.

Results – PAC’s

See Figure 8

The CLS & DDDR groups demonstrated the lowest Short-
Coupling PAC occurrence per day; Short-Coupling PAC’s are considered the most important trigger for AT episodes, whereas Long-Coupling PAC’s have already proven to be substantially uncorrelated with AT burden 3

So, to answer the question, what have we learnt from Burden II?

• Figure 5 Figure 5
• Figure 6 Figure 6
• Figure 7 Figure 7
• Figure 8 Figure 8
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Conclusions

• PAC’s could be reduced significantly during the CLS & DDDR mode.

• With an AV hysteresis of 300 ms, CLS was able to reduce the VPP to 15% in general and to only 6% in patients with an AVCT <200 ms.

• CLS has demonstrated the lowest AT burden and a significant reduction of the mean AT burden in the complete patient population.

• In a sub-group of patients (Vp<40%) CLS was able to reduce the mean AT burden even more, however, a “real” correlation between VPP and AT burden could not be established.

• The majority of patients (43%) experienced the lowest AT burden during CLS mode.

• CLS showed the lowest number of patients, who had AT episodes lasting longer than 1 minute (27%) and shorter than 1 hour (14%)

Therefore, from the results of the Burden II trial we can also state the following:

• The two rate response (Accelerometer & CLS) algorithms performed significantly better than the simple atrial overdrive algorithm.

• By reducing premature atrial contractions, whilst delivering physiologic pacing therapy, CLS has a very positive effect on the AT burden.

• The more physiologic behavior of CLS as compared to DDDR has the biggest impact on reducing AT episodes and AT burden in patients with Brady-Tachy-Syndrome.

References:

1. A. Puglisi, et al.; Impact of Closed-Loop Stimulation, overdrive pacing and DDDR pacing mode on atrial tachyarrhythmia burden in Brady-Tachy Syndrome. European Heart Journal (2003) 24, 1952–1961

2. Puglisi A, et al.; Overdrive Versus Conventional or Closed-Loop Rate Modulation in the Prevention of Atrial Tachyarrhythmias in Brady-Tachy-Syndrome. PACE 2008; 31:1443-1455

3. Azzolini et al.; AT burden modeling by some EP parameters in IPG patients with BTS. Europace 2006; 8:474-481