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The effect of C-reactive protein reduction with a highly specific antisense oligonucleotide on atrial fibrillation
Conn Sugihara1, Nick Freemantle, Steven G Hughes
1Cardiology Research Department, Eastbourne Hospital, Kings Drive, Eastbourne, East Sussex, BN21 2UD, UK, connsugihara@gmail.com.
Insights
ISIS-CRPRx effectively lowered C-reactive protein (CRP) levels in patients with atrial fibrillation (AF). However, this reduction did not significantly decrease AF burden, suggesting CRP may not be a direct cause of AF in this population.
Area of Science:
- Cardiology
- Biochemistry
- Pharmacology
Background:
- C-reactive protein (CRP) is strongly correlated with atrial fibrillation (AF).
- The causal role of CRP in AF pathogenesis remains unclear.
- ISIS-CRPRx is an antisense oligonucleotide designed to reduce CRP production by inhibiting mRNA translation.
Purpose of the Study:
- To evaluate the effect of ISIS-CRPRx on atrial fibrillation (AF) burden.
- To determine if reducing CRP levels with ISIS-CRPRx impacts AF occurrence or severity.
Main Methods:
- A double-blind, phase II clinical trial was conducted.
- Participants included patients with paroxysmal AF and permanent pacemakers (PPMs).
- Beat-to-beat arrhythmia monitoring was performed using advanced Holters over 8 weeks, including crossover treatment periods of ISIS-CRPRx and placebo.
Main Results:
- ISIS-CRPRx achieved a significant 63.7% relative reduction in CRP levels compared to baseline (p=0.003).
- No significant difference in AF burden was observed between ISIS-CRPRx treatment and placebo (OR 1.6, p=0.37).
- ISIS-CRPRx was found to be safe and well-tolerated, with no serious adverse events reported.
Conclusions:
- Targeted reduction of CRP using ISIS-CRPRx did not reduce AF burden in patients with paroxysmal AF and PPMs.
- These findings suggest that in this patient group with relatively low baseline CRP, CRP reduction alone may not be sufficient to impact AF.
- Further investigation in AF patients with higher CRP levels may be warranted to explore the potential benefits of CRP-directed therapy.
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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