The first three Therapeutics Letters focused on complaints related to the upper gastrointestinal tract, a common presentation to the primary care physician.1-3 These Letters reviewed evidence about H2-blockers, eradication of Helicobacter pylori, and drugs used for gastroesophageal reflux. However, they also raised concerns about chronic acid suppression by daily dosing of omeprazole, the first proton pump inhibitor (PPI) on the Canadian market. By 1994 there was already concern that long-term proton pump inhibition could be problematic. Since then, the popularity of PPIs has increased to the point that they are amongst the most widely used drugs in the world. Seven Therapeutics Letters cover PPIs, reporting comparative effectiveness, benefits and harms, as well as evidence for deprescribing.4-10
This Letter examines PPI utilization trends in BC since the year 2000. As shown in Table 1, BC’s population grew by 20.4% during this period, while the number of PPI users increased by 257%. Defined daily dose (DDD) is the assumed average maintenance dose of a drug used for its main indication in adults. For PPIs, DDD is equivalent to 20mg/day of omeprazole. Annual per capita DDD of PPIs increased from 5.4 in 2000 to 22 in 2018. This represents a large per-capita increase in dose and inhibition of acid secretion in BC since 2000 (Table 1). According to the Canadian Institutes of Health Information (CIHI) approximately 9.5% of seniors in BC use PPIs chronically.11
CIHI defines “chronic drug use” as “at least 2 claims and 180 days’ supply for a given drug class.” It is unknown how many seniors in BC are taking PPIs for longer than 8 weeks.
BC citizens have spent $1.74 billion on drug and dispensing costs for PPIs over the last 18 years, an average of $96.7 million per year. These costs include BC Pharmacare, private drug insurance and out-of-pocket spending.12
|BC population||4.04 million||4.86 million||20%|
|Total PPI users||123,845||442,559||257%|
|Annual number of PPI prescriptions||442,000||2,391,000||440%|
|DDD of PPI per BC inhabitant||5.4||22.0||309%|
Is this a concern elsewhere?
PPIs are the second most commonly prescribed drug class among seniors in Canada: the use increased from 26.7% in 2011 to 29.1% in 2016; prolonged therapy is predominant: 73.5% of seniors using PPIs (even excluding those using oral corticosteroids or chronic NSAIDs) took them for 8 weeks or more.11 Growth in PPI consumption around the world over the last two decades has also generated global concern. Reports from Europe13 and Asia14 endeavouring to explain this trend raise questions about potentially inappropriate prescribing for non-approved indications. A Cochrane review reported that approximately 25% to 70% of people are prescribed a PPI inappropriately and that chronic PPI use without reassessment contributes to polypharmacy.15
What is the appropriate duration for PPIs?
Proton pump inhibitors (PPIs) treat several different conditions including dyspepsia, gastroesophageal reflux disease (GERD), and peptic ulcer disease (PUD). Randomized controlled trials (RCTs) for these conditions typically do not exceed 8-12 weeks of therapy. In seeking evidence on the comparative effectiveness of PPIs we reported that “studies were mostly short-term and excluded patients with any complications or co-morbidities so are mainly applicable to a relatively healthy population treated for short durations”.9
PPI product monographs in Canada recommend that initial treatment for GERD should be at least 4 weeks for PPIs to ensure healing, but also that after 4-8 weeks, therapy should be discontinued. Patients with recurring symptoms can be initiated on regular, intermittent or on-demand therapy. However, long-term PPI use should be reserved for people who need maintenance therapy: those taking oral corticosteroids or chronic NSAIDs and those with erosive esophagitis, Barrett’s esophagitis, or a pathological hypersecretory condition.
Our 2016 systematic review found evidence that at 4 to 8 weeks among patients with GERD 60% to 85% experienced relief of heartburn and endoscopic healing was seen in 66% to 82% patients with GERD or PUD.16
What do we know about PPIs and their long-term adverse events?
Estimates of the frequency of adverse events associated with long-term use of PPIs are derived from retrospective observational studies, rather than RCTs. They include fractures, hypomagnesemia, iron deficiency, vitamin B12 deficiency, enteric infection (including C. difficile), pneumonia, acid rebound, acute renal injury and neoplasia (gastric polyps, gastric cancer, carcinoids, and colon cancer).14
Despite considerable heterogeneity and inconsistency between observational studies, most studies support an association between long term PPI use and C. difficile infections in hospitalized patients17 as well as community and hospital acquired pneumonia18.
Causal associations are difficult to establish, yet many of the potential adverse effects of PPI therapy are underpinned by a reasonable explanatory biological hypothesis. The relationships of PPI dose or duration to harms remain unknown. High quality, prospective, well designed observational studies are needed to assess harm associated with dose and duration of therapy.
- PPI utilization in British Columbia has risen much faster than population growth.
- For most indications, PPIs are only recommended for up to 8 weeks duration.
- In many clinical settings, we do not know whether the benefits of long-term PPI use outweigh the harms.
- Patients on long-term PPI therapy should be reassessed.
The draft of this Therapeutics Letter was submitted for review to 130 experts and primary care physicians in order to correct any inaccuracies and to ensure that the information is concise and relevant to clinicians.
- Therapeutics Initiative. Treatment of Non-Ulcer Dyspepsia in Adults: Common Questions about H2-blockers. Therapeutics Letter. 1994 (Oct); 1:1-2. https://ti.ubc.ca/letter1 [Accessed 15 Mar 2019]
- Therapeutics Initiative. Definitive Treatment of Peptic Ulcer Disease by Eradication of Helicobacter Pylori (H. pylori). Therapeutics Letter. 1994 (Nov); 2:1-2. https://ti.ubc.ca/letter2 [Accessed 15 Mar 2019]
- Therapeutics Initiative. Treatment of Gastroesophageal Reflux Disease (GERD). Therapeutics Letter. 1994 (Dec); 3:1-2. https://ti.ubc.ca/letter3 [Accessed 15 Mar 2019]
- Therapeutics Initiative. Review and Update. Therapeutics Letter. 1995 (Sep); 9:1-2. https://ti.ubc.ca/letter9 [Accessed 15 Mar 2019]
- Therapeutics Initiative. New Drugs. Therapeutics Letter. 1996 (Mar-Apr); 13:1-2. https://ti.ubc.ca/letter13 [Accessed 15 Mar 2019]
- Therapeutics Initiative. Review and Update. Therapeutics Letter. 1996 (Nov-Dec); 16:1-2. https://ti.ubc.ca/letter16 [Accessed 15 Mar 2019]
- Therapeutics Initiative. New Drugs IV. Therapeutics Letter. 1998 (Sep-Oct); 26:1-2. https://ti.ubc.ca/letter26 [Accessed 15 Mar 2019]
- Therapeutics Initiative. Do Single Stereoisomer Drugs Provide Value? Therapeutics Letter. 2002 (Jun-Sep); 45:1-2. https://ti.ubc.ca/letter45 [Accessed 15 Mar 2019]
- Therapeutics Initiative. Comparative Effectiveness of Proton Pump Inhibitors. Therapeutics Letter. 2016 (Mar-Apr); 99:1-2. https://ti.ubc.ca/letter99 [Accessed 15 Mar 2019]
- Therapeutics Initiative. Deprescribing Proton Pump Inhibitors. Therapeutics Letter. 2018 (Mar-Apr); 111:1-2. https://ti.ubc.ca/letter111 [Accessed 15 Mar 2019]
- Canadian Institute for Health Information. Drug Use Among Seniors in Canada, 2016. Ottawa, ON: CIHI; 2018. https://www.cihi.ca/sites/default/files/document/drug-use-among-seniors-2016-en-web.pdf [Accessed 15 Mar 2019]
- Therapeutics Initiative. Analysis of BC PharmaNet data. March 2019.
- Lanas A. We Are Using Too Many PPIs, and We Need to Stop: A European Perspective. Am J Gastroenterol. 2016; 111(8):1085-6. DOI: 10.1038/ajg.2016.166
- Kinoshita Y, Ishimura N, Ishihara S. Advantages and Disadvantages of Long-term Proton Pump Inhibitor Use. J Neurogastroenterol Motil. 2018;24(2):182-96. DOI: 10.5056/jnm18001
- Boghossian TA, Rashid FJ, Thompson W, et al. Deprescribing versus Continuation of Chronic Proton Pump Inhibitor Use in Adults. Cochrane Database of Systematic Reviews 2017, Issue 3. Art. No.: CD011969. DOI: 10.1002/14651858.CD011969.pub2
- Therapeutics Initiative. A Systematic Review of the Comparative Effectiveness of Proton Pump Inhibitors for the Treatment of Adult Patients with Gastroesophageal Reflux Disease or Peptic Ulcer Disease. 2016. https://ti.ubc.ca/derp-ppi [Accessed 15 Mar 2019]
- McDonald EG, Milligan J, Frenette C, Lee TC. Continuous Proton Pump Inhibitor Therapy and the Associated Risk of Recurrent Clostridium difficile Infection. JAMA Intern Med. 2015;175(5):784–791. DOI: 10.1001/jamainternmed.2015.42
- Lambert A, Lam J, Paik J, et al. Risk of community-acquired pneumonia with outpatient proton-pump inhibitor therapy: A systematic review and meta-analysis. PLoS ONE. 2015; 10(6):e0128004. DOI: 10.1371/journal.pone.0128004