Nocturnal heartburn and related sleep disturbances are common among patients with gastroesophageal reflux disease (GERD). This study evaluated the efficacy of dexlansoprazole MR 30 mg in relieving nocturnal heartburn and GERD-related sleep disturbances, improving work productivity, and decreasing nocturnal symptom severity in patients with symptomatic GERD.
Patients (N=305) with frequent, moderate-to-very severe nocturnal heartburn and associated sleep disturbances were randomized 1:1 in a double-blind fashion to receive dexlansoprazole MR or placebo once daily for 4 weeks. The primary end point was the percentage of nights without heartburn. Secondary end points were the percentage of patients with relief of nocturnal heartburn and of GERD-related sleep disturbances over the last 7 days of treatment. At baseline and week 4/final visit, patients completed questionnaires that assessed sleep quality, work productivity, and the severity and impact of nocturnal GERD symptoms.
Dexlansoprazole MR 30 mg (n=152) was superior to placebo (n=153) in median percentage of nights without heartburn (73.1 vs. 35.7%, respectively; P<0.001). Dexlansoprazole MR was significantly better than placebo in percentage of patients with relief of nocturnal heartburn and GERD-related sleep disturbances (47.5 vs. 19.6%, 69.7 vs. 47.9%, respectively; P<0.001), and led to significantly greater improvements in sleep quality and work productivity and decreased nocturnal symptom severity. Adverse events were similar across treatment groups.
In patients with symptomatic GERD, dexlansoprazole MR 30 mg is significantly more efficacious than placebo in providing relief from nocturnal heartburn, in reducing GERD-related sleep disturbances and the consequent impairments in work productivity, and in improving sleep quality/quality of life.
Dexlansoprazole MR 30 mg daily was significantly better than placebo in improving symptoms of nocturnal heartburn in symptomatic GERD patients with frequent, moderate-to-very severe nocturnal heartburn leading to improved sleep quality, and decreased symptom severity and impact on morning activities. Dexlansoprazole MR 30 mg was also effective in increasing work productivity and reducing activity impairment. It should be noted that patients enrolled in this study had to be responsive to acid-suppression therapy. This inclusion criterion was used to limit the number of functional heartburn patients enrolled in the study.
During this study, the median percentage of nights without heartburn over 4 weeks for the intent-to-treat patients receiving dexlansoprazole MR 30 mg was 73.1%. In a previous dexlansoprazole MR phase 3 study, which assessed efficacy and safety among patients with non-erosive reflux disease, this value was 80.8%(vs. 51.7% for placebo; P<0.00001) (23), supporting the results of our study. Furthermore, the therapeutic gain, or the difference between active study drug and placebo, seen in this current nocturnal heartburn study was greater than that observed in a previous phase 3 symptomatic GERD trial (37 vs. 29%) (23).
Stratification of the primary end point by baseline mean nocturnal symptom severity reveals that patients with the most severe symptoms experience the greatest therapeutic gain. Although the median percentage of nights free of nocturnal heartburn declined with increasing baseline severity, the therapeutic gain increased. The therapeutic gain experienced by patients receiving dexlansoprazole MR with severe-to-very severe baseline nocturnal symptoms is more than twice that experienced by patients with mild-to-moderate or moderate-to-severe baseline nocturnal symptoms. Patients in the severe-to-very severe group who received placebo experienced a median of 0% heartburn-free nights, while the 34 patients in the dexlansoprazole MR group reported a median of 66%of their nights as heartburn free during the 4 weeks of the trial. This could be explained by the finding that patients with more severe non-erosive reflux disease (NERD; as determined by pH testing) are more responsive to PPI therapy than patients with less severe NERD (24). This is in contrast to the response of erosive esophagitis patients receiving anti-reflux treatment (25).
During the last 7 days of the study, 48 and 70% of patients receiving dexlansoprazole MR reported relief of nocturnal heartburn and GERD-related sleep disturbances, respectively, which were significantly greater than with placebo (P<0.001 for each comparison). A similar pattern was observed by Johnson et al.(26), where patients receiving esomeprazole, 20 or 40 mg, reported higher rates of relief from GERD-related sleep disturbances from nocturnal heartburn during the last 7 days of a 4-week study.
A significantly lower frequency of GERD-related sleep disturbances was observed in the dexlansoprazole MR group. Dexlansoprazole MR resulted in a significantly lower frequency of the different types of sleep disturbances attributed to nocturnal heartburn. Of note, the percentage of nights with sleep disturbances due to other causes did not differ significantly between treatment groups. Taken together, these results suggest that patients taking dexlansoprazole MR 30 mg can expect a reduction in or relief from nocturnal heartburn symptoms and therefore better sleep quality.
Recording daily symptoms via diaries is common in clinical trials where symptom relief is a primary outcome (27). However, the limitations of this approach, particularly with paper diaries, include non-adherence (skipping entries) and “hoarding” (the retrospective completion of entries), which can lead to recall errors (28,29). Objective analyses of paper diary use have shown high rates of both non-adherence and hoarding (29). Electronic diaries, such as those used during this study, do not allow for hoarding beyond 24 h before the scheduled entry. Compliance with diary entries was high: ≥90% in 87% of patients.
The efficacy of dexlansoprazole MR for the relief of nocturnal heartburn and relief from GERD-related sleep disturbances is further supported by the improvements seen in the patient-reported outcomes. Patients receiving dexlansoprazole MR reported significantly greater improvements from baseline in sleep quality compared with placebo, which manifested as greater decreases in PSQI scores. Decreases in overall and subscale N-GSSIQ scores also showed greater efficacy for dexlansoprazole MR 30 mg compared with placebo in decreasing symptom severity, next morning impact of nocturnal symptoms, and concern regarding nocturnal GERD among the patients, thus demonstrating improvements in HRQoL. Significant improvements in HRQoL due to treatment of heartburn, both daytime and nocturnal, have been documented previously (23,26,30,31).
Accompanying these improvements in sleep quality, decreased symptom severity, and reduced impact the following morning were decreases in impairments in work productivity, as demonstrated by decreases in the WPAI scores. Treatment with dexlansoprazole MR was more effective than placebo in decreasing impairment while working and improving overall work productivity and functionality during regular activities. Furthermore, this treatment was more effective in reducing the number of work hours missed due to GERD-related sleep disturbances. These results are not unexpected when one considers the connection between repeated lack of sleep during the night and daytime sleepiness (9), as well as reduced HRQoL and work productivity (11). The negative impact of nocturnal GERD on HRQoL and work productivity is well recognized (7,8,10).
A recent survey of over 600 GERD patients on various PPI therapies found that the majority of patients continued to experience heartburn, with 83% experiencing nocturnal symptoms and almost a quarter of these patients reporting severe or very severe nocturnal symptoms (32). Daily dosing of dexlansoprazole MR 30 mg may reduce the likelihood of persistent nocturnal symptoms due to its extended duration of plasma drug levels (33); however, additional studies are needed to determine if this property equates to improved clinical outcomes.
In the above-mentioned survey (32), only approximately one-half of the patients surveyed took their PPI within the recommended 1 h to 30 min before breakfast. Poor compliance with PPI therapy is likely the most common cause for PPI failure (25). In this study, patients were to take the study drug in the morning, without regard to food. Comparable acid suppression with dexlansoprazole MR dosing has been demonstrated regardless of the timing of food intake (fasting, before or after breakfast) (34) or the time of day (before breakfast, lunch, dinner, or evening snack) (35). Although additional studies are needed to assess the impact of various dosing timings of dexlansoprazole MR on GERD symptoms, it is not unreasonable to suggest that increased flexibility in administration, and therefore increased compliance, would lead to reduced symptoms, particularly at night.
Dexlansoprazole MR 30 mg was well tolerated by patients in this current trial. Rates of treatment-emergent AEs were low and similar between the dexlansoprazole MR and placebo groups, including the premature discontinuation due to AEs. Recent analyses of pooled safety data from the phase 3 pivotal trials demonstrated that the safety profile of dexlansoprazole MR 30 mg was comparable to that of lansoprazole 30 mg (36).
The economic implications of this study are readily apparent. The favorable effect of improvement for work productivity has significant implications to payers and employers. For the patients receiving dexlansoprazole MR compared with placebo, there was an apparent work productivity advantage—$38 for the fourth week ($227 vs. $189). If these savings were extrapolated over the 4-week study, the advantage would be $152/treated patient. This type of modeling allows for the development of a business plan for payers–employers to evaluate the cost benefits of effective therapy. By this type of analysis, the “investment” cost of therapy can be analyzed against the returns of improved work productivity.
This study has several limitations, the first being the lack of an active comparator, another PPI. Although direct comparisons of efficacy results from different trials cannot be made, a recent review comparing the efficacy of various PPIs (not including dexlansoprazole MR) in relieving or resolving nocturnal heartburn in a clinical trial setting found no outstanding differences in efficacy between comparable doses (37). Placebo has been the standard comparator used in other studies assessing the efficacy of a PPI for nocturnal heartburn and in all studies of GERD-related sleep disturbances (23,26,38).
A second limitation is the lack of pH monitoring to document the level of acid suppression or to distinguish symptomatic non-erosive reflux from functional heartburn. It is difficult to attribute any symptom to reflux without direct esophageal monitoring. The primary reason for no pH monitoring during this study was the potential sleep disruption caused by an intra-esophageal pH electrode. However, to mitigate lack of pH monitoring, inclusion criteria mandated previous response to acid-suppression therapy. We also did not utilize sleep labs for an objective assessment of sleep quality, which could be considered another limitation. Because a sleep lab is an artificial environment, it is likely that many patients would not have slept the same way there as they would at home. Changes in sleep quality are subjective, whether as reported in the daily diaries or in the PSQI and N-GSSIQ.
A third limitation is the assessment of response for productivity analysis limited to the fourth week of therapy. Questions remain as to what the effect is on a weekly basis beyond the early therapy effect on these particular measurements. Furthermore, an area of further research is to evaluate whether these favorable effects persist, wane, or continue to improve with extended therapy.
In summary, dexlansoprazole MR 30 mg was significantly more efficacious in providing relief from nocturnal heartburn and in reducing GERD-related sleep disturbances compared with placebo in symptomatic GERD patients with moderate-to-very severe nocturnal heartburn. This study also demonstrated significantly greater improvements in sleep quality, HRQoL, and work productivity for patients receiving dexlansoprazole MR compared with those receiving placebo.
Furthermore, there were notable economic implications with favorable advantages evident for patients treated with dexlansoprazole MR—allowing for estimates of a calculable rate of return on investment for effective therapy.