HSC Section 6 Nov2016 Green Book

Reichel et al Double-blind, placebo-controlled trial with . . .

the only RSI subscore with a statistically significant differ- ence in improvement between the two study groups after both six weeks and three months. This finding, in our opinion, clearly demonstrates that PPI therapy has achieved an earlier and stronger reduction of distal reflux episodes potentially causing heartburn compared to placebo. This result also reflects the well-known fact that esophagitis caused by reflux shows an earlier resonse to PPI treatment than reflux-induced laryngitis. 3,17 Several issues should be addressed. As we did not ran- domize our otolaryngologic evaluations performed by only one examiner, the term double-blind can only be used to describe the medication randomization. Another critical as- pect of our trial may be the fact that we did not perform 24-hour pH monitoring to diagnose LPR objectively before patient inclusion. According to reports of other authors, patient tolerance is poor for this procedure. 7 As such, we decided to assess LPR-related symptoms and signs alone with the use of RSI and RFS. Moreover, Vaezi et al, in the above-mentioned study, found that only a small proportion of their patients undergoing pH monitoring had documented pharyngeal acid exposure despite typical LPR symptoms and laryngoscopic signs. 9 From this finding they concluded that sensitivity of pH monitoring for detection of proximal esophageal or hypopharyngeal reflux episodes might not be more than 50%. 9 Another argument against performing pH monitoring before inclusion was the fact that more and more authors doubt that 24-hour pH monitoring, although sup- posed to be the gold-standard test for LPR, is the preferable initial step in the work-up of most patients with LPR. 9,18,20 A third limitation of our study might be the short follow-up of 12 weeks. The significance of our study results probably would have been higher after a treatment period of six months. However, only Vaezi et al performed a trial with a follow-up of more than three months. 9 Another critical aspect might be the dose of esomeprazole used (20 mg). It can be hypothesized that the differences in RSI and RFS improvement between the study groups would have been even more significant with a dose of 40 mg twice daily. This is the dose generally recommended for treating LPR. 2 How- ever, we chose a dose of 20 mg esomeprazole twice daily as many institutions and general practitioners in Germany pre- fer to start with the lower dose. Nevertheless, we suppose our results clearly demonstrate a therapeutic effect of PPI treatment for LPR-related symptoms and signs. This esti- mation is confirmed by the subjective opinion of our study patients concerning the drug effect, with only 42% of pla- cebo recipients and more than 78% of the esomeprazole group being free of symptoms ( P 0.006).

tically significant better improvement was noted for PPI- treated patients. In our opinion, it is not surprising that in this study laryngeal signs of LPR showed no stronger im- provement in PPI recipients compared to control within two months, as the physical findings of LPR improve more slowly than the symptoms. 17 In our study we could also find no statistically significant difference in the laryngeal ap- pearance (reflected by the total RFS) between the esome- prazole and placebo group after a short treatment period of six weeks ( Table 2 ). Another critical point for the men- tioned study is the fact that patients were not instructed on when to take the medication. This could have seriously affected the results of this study. In a randomized, double- blind, placebo-controlled trial, Wo et al evaluated the effi- cacy of single-dose pantoprazole 40 mg for 12 weeks in newly diagnosed LPR. 8 The response was similar between the pantoprazole and placebo group. As 60% of the study subjects had additional abnormal distal esophageal reflux and the single-dose PPI was not sufficient to reach a pH- documented measurable suppression of hypopharyngeal acid reflux, the results of this study are not adequately comparable to those of our study with a double-dose PPI design. Noordzij et al performed another prospective, pla- cebo-controlled, randomized, and double-blind study to de- termine the efficacy of 40 mg omeprazole twice daily for two months in the treatment of LPR. 13 The authors could demonstrate a significant improvement of a composite la- ryngeal symptom score in the omeprazole group but not the placebo group. Again, the endoscopic laryngeal signs did not change significantly over the course of the study for either treatment group. As mentioned above, the two-month follow-up period may not have been sufficient to detect changes in laryngeal appearance. Another study investigat- ing the therapeutic benefit of lansoprazole 30 mg twice daily for treating LPR, by El-Serag et al, provided evidence that lansoprazole therapy for three months achieved significantly better symptomatic response than placebo. 18 Due to a se- lected referral study population with a high likelihood of GERD, the authors suggested not to generalize their results to patients with LPR in a primary care setting. The analysis of the respective RFS subscores in our study revealed a highly significant reduction of posterior commissure hypertrophy in the esomeprazole but not in the placebo group after a treatment period of 12 weeks ( P 0.01). This laryngeal sign is supposed to be one of the mucosal alterations most related to LPR. 19 The fact that the most significant difference in laryngeal appearance between the two study groups after 12 weeks could be detected in this special area in our opinion strongly indicates the effi- cacy of a PPI treatment in patients with symptoms and signs associated with LPR. The improvement of posterior com- missure hypertrophy was not significantly better in the es- omeprazole group compared to control at the first follow- up. This result underlines the importance of a PPI treatment for at least three months in patients with suspected LPR. Another striking result was that we found heartburn to be

CONCLUSION Especially during the first weeks of PPI therapy, a signifi- cant placebo effect appears to exist in the treatment of LPR-related symptoms. However, compared to placebo,

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