{"id":754,"date":"2015-06-25T11:00:16","date_gmt":"2015-06-25T11:00:16","guid":{"rendered":"http:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/?p=754"},"modified":"2017-08-21T11:46:48","modified_gmt":"2017-08-21T11:46:48","slug":"primary-care-corner-with-geoffrey-modest-md-ppis-associated-with-mis","status":"publish","type":"post","link":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/2015\/06\/25\/primary-care-corner-with-geoffrey-modest-md-ppis-associated-with-mis\/","title":{"rendered":"Primary Care Corner with Geoffrey Modest MD: PPIs associated with MIs???"},"content":{"rendered":"

By: Dr. Geoffrey Modest<\/strong><\/p>\n

There was a recent article published online and hitting the press\u00a0regarding a possible association between the use of\u00a0proton-pump inhibitors (PPIs)\u00a0and subsequent MIs\u00a0(see\u00a0DOI:10.1371\/journal.pone.0124653<\/strong>\u200b). The article was unusual in that it used a new technique for medical research: data-mining. \u00a0The bottom line is that if there were a real association between PPI use and MIs, this would have profound medical implications, since over 113 million PPI\u00a0scripts\u00a0are filled annually around the world\u00a0with\u00a0over $13 billion in sales, and in the US in 2009 21 million people filled at least one PPI script (the 3rd highest seller in the US).<\/p>\n

Details:<\/p>\n

–they looked at over 16 million clinical documents on 2.9 million people to assess PPI use and cardiovascular risk. There were 2 large data sources for the data mining (Stanford, and Practice Fusion, Inc) and one prospective source for\u00a0a survival analysis.\u00a0For the data-mining, they electronically evaluated clinic notes to search for patients with a GERD diagnosis, use of meds, and subsequent notes with diagnoses of cardiovascular disease<\/p>\n

–overall, 32,363 patients were identified (mean age 55, 44% male, 50% white\/27% unknown, 6% on clopidogrel). They identified a\u00a0similar number of propensity score-matched controls. Mean followup 2.1 years<\/p>\n

Results:<\/p>\n

–overall, patients with GERD and on PPIs had an adjusted odds ratio of\u00a01.16 (1.09-1.24) for association with MI.\u00a0H2 blockers were not associated with increased cardiovasc risk<\/p>\n

–survival analysis in the\u00a0prospective cohort followed\u00a05.2 years\u00a0found a 2-fold increased association with cardiovascular mortality [HR=2.00 (1.07-3.78, p=0.031)]. No association was found for H2-blockers<\/p>\n

–the PPI association was independent of the concommitant use of clopidogrel (used in only 5.9%\u00a0of the population)<\/p>\n

Although this data-mining is potentially a powerful tool to look at possible\u00a0real associations, it is much less persuasive than the\u00a0usual organized epidemiologic studies in terms of the types and\u00a0quality of the data collected. \u00a0I bring up this article for several reasons.<\/p>\n

    \n
  1. As I have highlighted in many of my older blogs (prior to the BMJ posts), I am very concerned about the over-use of PPIs. It used to be said that treatment for GERD (the most common indication for PPIs)\u00a0could be either step-up (start with calcium, then go to H2 blocker, then to PPI as needed for symptom control)\u00a0or step-down therapy (hit hard with PPI, then wean down to H2 blocker or calcium as tolerated). Not so surprisingly, it is rare that we in primary care actually do the step-down (after all,\u00a0the patient is doing well on the PPI, there are lots of other issues to address in the confines of a quick primary care visit, so dealing with stepping down therapy just isn’t the priority). But\u00a0PPIs\u00a0are very powerful drugs, and there are known and potential problems associated with their use. The documented adverse effects include those associated with infections (since neutralizing the gastric acid eliminates one of the barriers to infection), malabsorption (since stomach acidity is important for some nutrient absorption), and potentially other issues. In terms of infections, there are pretty good data that prolonged PPI use is associated with increased risk of C. difficile infections, other enteric infections (salmonella, campylobacter), and\u00a0community-acquired pneumonia (though\u00a0data here\u00a0are a bit mixed). Malabsorption has been found for iron, vitamin B12, magnesium and calcium, and the possible association of PPIs\u00a0with hip, spine and wrist fractures (and an FDA warning about this). And one of the other concerns is the profound hypergastinemia, with potential risk of colon cancer (not found so far) and\u00a0atrophic gastritis (which may be more common in those who are H Pylori positive, and could\u00a0potentially lead to gastric cancer). And potential drug interactions (eg with clopidogrel) or other unusual adverse effects (acute interstitial nephritis)<\/li>\n
  2. There are many plausible explanations of an association between PPI use and MI, including:<\/li>\n<\/ol>\n

    –PPIs inhibit the activity of dimethylarginine dimethylaminohydrolase (DDAH), which is responsible for 80% of the clearance of asymmetric dimethylarginine (ADMA), which is an endogenous molecule which inhibits the activity of nitric oxide synthase (NOS), which might impair endothelial function, increase vascular resistance, and\u00a0promote inflammation and thrombosis. (This is the explanation offered by the authors of \u00a0the study, though the data are\u00a0based on animal studies and cultured human endothelial cells)<\/p>\n

    –perhaps there is an associated chronic inflammatory state created by the increase in\u00a0GI infections from PPI use, and this inflammatory state is associated with CAD (as found with rheumatoid arthritis, in\u00a0a couple of new studies on psoriasis, perhaps in\u00a0HIV??)<\/p>\n

    –or, the explanation I\u00a0favor, is that a small but significant proportion of patients being treated for GERD in fact have GERD-like\u00a0symptoms from\u00a0CAD which are falsely ascribed to GERD. I did just see a patient who epitomized this: he had GERD-like symptoms, treated by H2 blockers which did not work, augmented\u00a0to a PPI which still did not work. And on further questioning, his GERD symptoms were exertional. He\u00a0will be getting worked-up for this, but he presents the case of approximately\u00a010% of angina patients present with predominantly GI symptoms, including typical GERD symptoms (even more classical than his, with postprandial and not exertional symptoms). Therefore, the relationship of PPI to MI may be really from the error of using PPIs to treat GI symptoms which really come from the heart…<\/p>\n

    So, I\u00a0bring this up mostly as a means to reinforce my sense that we use too many PPIs (my other big concern is overuse of NSAIDs, but that is a side issue here…). And also to highlight\u00a0a new mechanism in medical research\u00a0for doing quick and dirty epidemiologic associations through data-mining.\u200b<\/p>\n

     <\/p>\n","protected":false},"excerpt":{"rendered":"

    By: Dr. Geoffrey Modest There was a recent article published online and hitting the press\u00a0regarding a possible association between the use of\u00a0proton-pump inhibitors (PPIs)\u00a0and subsequent MIs\u00a0(see\u00a0DOI:10.1371\/journal.pone.0124653\u200b). The article was unusual in that it used a new technique for medical research: data-mining. \u00a0The bottom line is that if there were a real association between PPI use […]<\/p>\n

    Read More…<\/a><\/p>\n","protected":false},"author":148,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_jetpack_memberships_contains_paid_content":false,"footnotes":""},"categories":[14283],"tags":[],"class_list":["post-754","post","type-post","status-publish","format-standard","hentry","category-archive"],"jetpack_featured_media_url":"","jetpack_sharing_enabled":true,"_links":{"self":[{"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/posts\/754","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/users\/148"}],"replies":[{"embeddable":true,"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/comments?post=754"}],"version-history":[{"count":0,"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/posts\/754\/revisions"}],"wp:attachment":[{"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/media?parent=754"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/categories?post=754"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/wp-json\/wp\/v2\/tags?post=754"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}