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The effect of C-reactive protein reduction with a highly specific antisense oligonucleotide on atrial fibrillation assessed using beat-to-beat pacemaker Holter follow-up

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Journal of Interventional Cardiac Electrophysiology Aims and scope Submit manuscript

Abstract

Purpose

C-reactive protein (CRP) is known to be strongly associated with atrial fibrillation (AF). However, it is not clear if CRP is a causal factor for AF. ISIS-CRPRx is a novel antisense oligonucleotide that reduces CRP production by specifically inhibiting mRNA translation. The effect of ISIS-CRPRx on AF was evaluated.

Methods

A double-blind phase II trial of ISIS-CRPRx in patients with paroxysmal AF and DDDRP permanent pacemakers (PPMs) with advanced atrial and ventricular Holters allowing beat-to-beat arrhythmia follow-up.

Results

Twenty six patients were screened and seven patients dosed with ISIS-CRPRx. After 4 weeks of baseline assessment, patients were randomly assigned to two treatment periods of either placebo then ISIS-CRPRx or ISIS-CRPRx then placebo. All patients were followed up for 8 weeks after the active treatment period. There was a 63.7 % (95 % CI 38.4 to 78.6 %, p = 0.003) relative reduction in CRP on treatment with ISIS-CRPRx versus baseline. Sensitivity analyses demonstrated a consistent treatment effect. The primary end-point was change in AF burden assessed by PPM. There was no significant difference in AF burden on treatment with ISIS-CRPRx versus baseline (OR 1.6, 95 % CI −2.42 to 5.62, p = 0.37). ISIS CRPRx was safe and well tolerated and there were no serious adverse events.

Conclusions

Treatment with ISIS-CRPRx did not reduce AF burden in patients with paroxysmal AF and PPMs, despite a large relative reduction in CRP. In this population, highly specific CRP reduction had no clinically discernable effect upon paroxysmal AF. However, average levels of CRP at baseline were relatively low, so it remains possible that AF patients with higher levels of CRP may benefit from CRP-directed therapy.

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Acknowledgments

Data collection and analysis:

Janet Large*

Kerrie Nyland*

Diana O’Connell*

Leanne Beaver*

Sarah Bridgland BSc*

Jet Van Zalen MSc*

*Cardiology Research Department, Eastbourne Hospital, East Sussex Healthcare NHS Trust, UK.

Conflict of interest

Funding support from ISIS Pharmaceuticals Inc., Carlsbad, CA, USA

Steven G Hughes is an employee of ISIS Pharmaceuticals Inc., Carlsbad, CA, USA

Funding sources

ISIS Pharmaceuticals Inc., Carlsbad, CA, USA

Disclosures

None

Author information

Authors and Affiliations

  1. Cardiology Research Department, Eastbourne Hospital, Kings Drive, Eastbourne, East Sussex, BN21 2UD, UK

    Conn Sugihara, Steve Furniss & Neil Sulke

  2. Department of Primary Care and Population Health, University College London, London, UK

    Nick Freemantle

  3. ISIS Pharmaceuticals Inc., Carlsbad, CA, USA

    Steven G. Hughes

Authors
  1. Conn Sugihara
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  2. Nick Freemantle
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  3. Steven G. Hughes
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  4. Steve Furniss
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  5. Neil Sulke
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Corresponding author

Correspondence to Conn Sugihara.

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Sugihara, C., Freemantle, N., Hughes, S.G. et al. The effect of C-reactive protein reduction with a highly specific antisense oligonucleotide on atrial fibrillation assessed using beat-to-beat pacemaker Holter follow-up. J Interv Card Electrophysiol 43, 91–98 (2015). https://doi.org/10.1007/s10840-015-9986-3

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  • DOI: https://doi.org/10.1007/s10840-015-9986-3

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