TY - JOUR
T1 - Failure of reflux inhibitors in clinical trials
T2 - Bad drugs or wrong patients?
AU - Kahrilas, Peter J.
AU - Boeckxstaens, Guy
PY - 2013
Y1 - 2013
N2 - Treatment modalities for gastro-oesophageal reflux disease (GORD) mirror the pathophysiology of the disease. Since acid plays a key role in GORD-associated mucosal lesions, proton pump inhibitors (PPIs) are the dominant GORD treatment, being the most potent inhibitors of acid secretion available. However, the clinical effectiveness of PPIs varies with the specific symptoms being treated; they are more effective for heartburn than for regurgitation than for extraoesophageal symptoms. An alternative therapeutic approach to GORD is to prevent the most fundamental cause of reflux symptoms, reflux itself, which most commonly occurs by transient lower oesophageal sphincter relaxation (TLOSR). Among potential pharmaceutical agents developed to target TLOSRs, the most advanced are GABAB (γ-aminobutyric acid) agonists, which experimentally reduce the occurrence of TLOSRs by about 40% in both animal and human studies. However, the effectiveness of GABAB agonists in clinical trials of patients with GORD with an incomplete response to PPI treatment has been modest. In part, this is probably attributable to the difficult problem of patient selection in these trials. Identifying patients by partial response to PPI treatment results in a heterogeneous population, including those with persistent weakly acidic reflux, patients with visceral hypersensitivity and those with functional heartburn, dyspepsia, or chest pain. From the clinical data available, the best treatment results and, hence, the patients most likely to benefit from reflux inhibitors, are those with persistent reflux, most commonly manifest as persistent regurgitation despite PPI treatment.
AB - Treatment modalities for gastro-oesophageal reflux disease (GORD) mirror the pathophysiology of the disease. Since acid plays a key role in GORD-associated mucosal lesions, proton pump inhibitors (PPIs) are the dominant GORD treatment, being the most potent inhibitors of acid secretion available. However, the clinical effectiveness of PPIs varies with the specific symptoms being treated; they are more effective for heartburn than for regurgitation than for extraoesophageal symptoms. An alternative therapeutic approach to GORD is to prevent the most fundamental cause of reflux symptoms, reflux itself, which most commonly occurs by transient lower oesophageal sphincter relaxation (TLOSR). Among potential pharmaceutical agents developed to target TLOSRs, the most advanced are GABAB (γ-aminobutyric acid) agonists, which experimentally reduce the occurrence of TLOSRs by about 40% in both animal and human studies. However, the effectiveness of GABAB agonists in clinical trials of patients with GORD with an incomplete response to PPI treatment has been modest. In part, this is probably attributable to the difficult problem of patient selection in these trials. Identifying patients by partial response to PPI treatment results in a heterogeneous population, including those with persistent weakly acidic reflux, patients with visceral hypersensitivity and those with functional heartburn, dyspepsia, or chest pain. From the clinical data available, the best treatment results and, hence, the patients most likely to benefit from reflux inhibitors, are those with persistent reflux, most commonly manifest as persistent regurgitation despite PPI treatment.
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U2 - 10.1136/postgradmedj-2011-301898rep
DO - 10.1136/postgradmedj-2011-301898rep
M3 - Review article
C2 - 23341641
AN - SCOPUS:84872975508
SN - 0032-5473
VL - 89
SP - 111
EP - 119
JO - Postgraduate Medical Journal
JF - Postgraduate Medical Journal
IS - 1048
ER -