Proton pump inhibitors in acid-related diseases. Issues in diagnosis, treatment and outcome
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Acid-related disease (ARD) is a term used to describe a range of conditions in which acid is involved in the generation of symptoms and/or complications. Two of the most common ARDs are gastro-esophageal reflux disease (GERD) and peptic ulcer disease (PUD).
PPIs are today regarded as the gold standard in the treatment of both symptoms and mucosal injury in patients with GERD as well as for prevention and acute treatment of PUD. Since the PPIs were introduced in the late 1980-ies there has been a sharp increase in the usage in the Western world. Although this increase coincides with the GERD epidemic it has also led to concerns related to PPI over-utilization, with high costs and associated long-term side-effects. In contrast, there is an apparent underutilization of PPIs as gastroprotective therapy in patients at elevated risk of PUD when taking certain medication. Observational studies have also suggested that the clinical efficacy of PPI therapy may be reduced because of poor adherence. Despite PPIs being among the most widely used prescription drugs there are scarce data on the natural utilization patterns of PPIs. Furthermore the implementation of various cost-containment programs, imposing restrictions on PPI prescriptions, has rarely been evaluated in a systematic manner.
A much debated issue is whether the diagnosis and initial treatment of GERD, after excluding patients with an indication for prompt esophagogastroduodenoscopy (EGD) (alarm symptoms or age above 50 years), should be based on symptoms or if EGD shall be performed upfront. A number of patient reported questionnaires have been developed in order to facilitate the symptom-based diagnosis of GERD.
In the first study a validation of a questionnaire (GerdQ) as a diagnostic tool for GERD was performed. A GerdQ cutoff score ≥9 gave the best balance between sensitivity, 66% (95% CI 58-74%) and specificity, 64% (95% CI 41-83%), for GERD. It was concluded that GerdQ is a useful complementary tool for the diagnosis of GERD.
In the second study the GerdQ questionnaire was integrated into an algorithm for the symptom-based diagnosis and initial treatment of patients with symptoms suggestive of GERD and compared against an endoscopy-based approach. In this randomized controlled trial patients with symptoms of GERD, but without alarm features, the symptom-based approach (response rate 87%) was non-inferior, but not superior (p=0.14) to the endoscopy-based approach (response rate 80%). The net cost-savings in the 8 weeks within-trial analysis was 146€ in favor of the symptom-based approach. To conclude we found that patients with a high likelihood of GERD (high GerdQ scores) profited from a symptom-based approach while patients with low likelihood of GERD (low GerdQ scores) favored further investigation with EGD/pHmetry.
In sum the first two papers show that when facilitated by GerdQ the responsibility for diagnosis and initial treatment of patients with GERD, without indication for EGD, could confidently be transferred to primary care. This will hopefully lead to a reduced number of costly and unnecessary referrals.
In the third paper we used the Norwegian Prescription Database (NorPD) to retrieve all individual level prescriptions dispensed on a PPI from 1 January 2004 to 1 January 2008. Dispensations (or the absence of dispensations) were used as a proxy for starting, shifting or discontinuing PPI therapy.
The study found that although GERD is considered a chronic disease a considerable alteration in the pool of patients treated with PPI was demonstrated. High proportions of patients discontinued PPI therapy long-term (23% and 39% per year in two different periods) likely reflecting the relapsing-remitting nature of GERD or, but less likely, a lasting remission. The switch between different PPIs was low (5% and 7% in two different periods) likely reflecting the natural switching patterns due to treatment failure or intolerance. A new restrictive prescription policy program defining generic alternatives as preferred treatment was successfully introduced among new PPI users with the proportion of patients receiving esomeprazole dropping from 57% before to 20% after the introduction of the new policy. A mandatory shift in ongoing esomeprazole users was harder to implement with 64% not shifting from esomeprazole to generic PPI during the first year after implementation. Amongst the 36% who shifted from esomeprazole to generic PPI, one out of four subsequently shifted back to esomeprazole.
In the fourth paper we assessed the association between PPI adherence and the risk of upper GI complications (ulcer, bleeding and perforation) among NSAID users. This case-control study, being the largest of its kind, linked nationwide Swedish data from the Prescribed Drug Registry with the National Patient Registry. A total of 3.649 cases of upper GI complications were identified. Patients with poor adherence (<20% PPI coverage) had approximately twice the risk of peptic ulcer (OR=1.88; 95% CI 1.22-2.88) compared with fully adherent patients (≥80% PPI coverage). As NSAIDs are among the most frequently prescribed prescription drugs, and upper GI complications carry a high mortality risk, efforts to increase adherence with PPIs should be an integrated part of clinical practice.
In sum this thesis addresses relevant questions of importance for the diagnosis and treatment of acid-related diseases. We have validated a questionnaire (GerdQ) as a diagnostic tool for GERD and also demonstrated that a symptom-based management algorithm is equally efficacious, but less costly, compared to an endoscopy based approach. The thesis has also provided intriguing new data on the natural utilization patterns for PPIs. Lastly it has been demonstrated that NSAID users with poor adherence to PPI have twice the risk of developing a serious upper GI event compared to full adherers.