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Several caveats on Proton Pump Inhibitors (PPIs) after 20 years of experience: Time to rethink?

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Several caveats on Proton Pump Inhibitors (PPIs) after 20 years of experience: Time to rethink? Published on November 15, 2015

PAWAN V. KULKARNI


General Manager - Marketing @ J B Chemicals & Pharmaceuticals (Unique Division)

Review of alerts on PPIs based on studies published recently !

http://www.slideshare.net/PAWANVKULKARNI/review-of-new-alerts-on-proton-pump-inhibitors-ppi-adverse-effects-2015-55022824


We know it,

We see it,

We might as well have induced it.

I happen to hear this from a colleague some time back who is a B Pharm and also a brand manager working in reputed pharmaceutical company. She said once while leaving on tour for a couple of days when her mom complained of severe back ache. Before leaving she ordered a pain killer and a PPI over phone from the nearby chemist for her mom & left for the tour directing about the dosage of both the brands. 3 to 4 days later when she returned, her mom was happy that back pain had subsidized 2nd day itself. Later that day, the mom informs the daughter that the chemist has called her back then after the daughter left, telling that 1 out 2 medicines was not available and was asking for a substitute. Not knowing any other brand name, the mother had asked to deliver only one which is ordered by daughter & available. When the daughter saw it, her mom since 4 days was ONLY taking the PPI and it was the pain killer brand was not available with the chemist so he had not delivered. The pain had subsidized.

In pharmaceutical business we often see this happening. Use, abuse & Overuse of several drugs. Be it by patient self medicating or may be by a doctor trying hard not to lose a patient and there by prescribing an unnecessary drug, or a strong drug, or even some combination which may not make an actual sense in the particular condition.

The recent most being the TOI Mumbai report (15th Nov 2015) of India ranking No 1 in the world for highest anti-biotic resistance. A few days earlier (3rd Nov 2015) was the news that rocked the world- “Common antacids leading to incident kidney diseases/failure”.

USE, OVERUSE, ABUSE

Let’s talk a little on antacid news which practically are taken chronically and are considered as one of the OVERUSED class of drugs worldwide today. Antacid though is a name given to class of drugs which are anti-acidic, those which acts against acid. There are different class and even creed of antacids. Different antacids have different types of actions. The news reports that garnered a lot of media (Social too) attention across the world was PPI (Proton pump inhibitors). A PPI is a class of antacid which are called as PROTON PUMP INHIBITORs where in have different molecules namely PANTOPRAZOLE, RABEPRAZOLE, OMEPRAZOLE, LANSOPRAZOLE, ILAPRAZOLE, ESOMEPRAZOLE etc. Today, it is bound that one of these above molecule brand in plain or in combination can be found practically in almost every household in India.

Recently in their edition of July – September issue, the journal “Pharmacy Practice” (2015 Jul-Sep;13(3):633) published. Studies emerged claiming up to 68% of hospital inpatients did not have appropriate indication for PPI therapy in developed countries such as US, Australia, New Zealand, Italy, and Ireland. Moreover, inappropriate PPI prescription noted (Hospitalized)

  • USA (65%),
  • Australia (63%),
  • New Zealand (40%),
  • Italy (68%) and
  • Ireland (33%)

A similar situation was also apparent in our setting, whereby 52.5% of all prophylactic PPIs prescribing were unnecessary according to guidelines used in this study.

Trying to derive some unusual yet meaningful conclusions or inferences by correlating the market data, some of my observations are below. Before landing to some twisting facts, let me tell you which some of you industry personnel might already know. Out of all the categories in pharmaceuticals, it is an ANTI-ULCERANT brand that is the highest sold Pharmaceutical drugs in Indian market in terms of units. So…

As per Sept’2015 IMS MAT figures
1342039305 units (Strips) of antipeptic ulcerants are sold in India in a year. Now, for a moment compare this with the population of the country as per the 2011 census. Practically everyone takes a antipeptic ulcerant.

At the same time as per CMARC prescription data (CPR-Mar-Jun 2015) on a PPI, 52% of Pantoprazole prescription is for more than 7 days period.

Diabetes and Hypertension which are chronic conditions feature in the TOP 7 most frequently prescribed indication for Pantoprazole (and even for most PPIs). Overtly, these two indications are not a prescribed/approved direct indication for PPIs. Moreover being long term conditions makes them more vulnerable that the international bodies do not feature them in a PPI indication lists directly.

CMARC also specifies that 35.9% PRESCRIPTIONS of Pantoprazole in Diabetes & 36.5% of PRESCRIPTIONS in Hypertension are for more than 15 days period. There arise some important questions and concerns, which we may not ascertain an answer right now. A considerable number of prescriptions are given in unapproved indications. How many patients follow it judiciously? How many patients self medicate further even after the completion of the course?

Most commonly, a PPI is prescribed by default when a NSAID is on the prescription. My observation with orthopedicians (who prescribe this most) is many write “S.O.S” or “Only when pain is severe” under a NSAID brand. But fail to write this below the PPI they have prescribed. This often resulting a patient keeps popping in a PPI for weeks even with no reason when NSAID is stopped long back.

Evidence based research conclude the dark side of PPI overuse. PPIs are amongst the most over prescribed drugs in clinical practice. These drugs were purported to have excellent safety profile. However in the recent past, certain adverse events have been reported which are of clinical significance as stated in Tropical Gastroenterology 2011;32(3):175–184.

In 2013, one of the most eminent medical journals on the planet “Circulation” from American Heart Association published a new postulation. The ADMA Pathway. Titled study as "Unexpected Effect of Proton Pump Inhibitors Elevation of the Cardiovascular Risk Factor Asymmetric Dimethylarginine" (Circulation. 2013;128:845-853). The paper is quite interesting especially the ADMA pathway explained is appreciable. It gives a great deal of approach on PPIs in general. Which some eminent doctors are aware, but many are not.

The asymmetrical dimethylarginine (ADMA) pathway. ADMA is derived from proteins (largely nuclear) containing methylated arginine residues. ADMA is largely (80%) metabolized by dimethylarginine dimethylaminohydrolase (DDAH). ADMA is a competitive inhibitor of nitric oxide (NO) synthase (NOS). Endothelial NOS (eNOS) is highly regulated and produces small amounts of NO locally to affect vascular homeostasis. Increased levels of ADMA (such as through possible inhibition by the proton pump inhibitors [PPIs]) could impair eNOS activity, reducing NO generation while increasing superoxide anion generation. The vasoprotective action of eNOS is lost, increasing the risk for adverse vascular events. In this setting, inflammatory cells are attracted into the vessel wall and express inducible NOS (iNOS), which generates superoxide anion and nitric oxide, which combine to form the cytotoxic free radical peroxynitrite anion. L-NMMA indicates NG-monomethyl-l-arginine; and PRMTs, protein arginine methyltransferases.

In connection to this, British Medical Journal (BMJ) Research News of June 2015 has given statement that “PPIs cause 16% increased risk of Myocardial Infarction (MI)” - (BMJ 2015;350:h3220)

Even Medscape on their online portal commented on 10th June 2015…”The investigators reviewed more than 16 million clinical documents on 2.9 million individuals for pharmacovigilance data. They describe their approach as a "novel analytical pipeline" and report that PPIs, but not H2 blockers, appear to be associated with an elevated risk for myocardial infarction (MI)”

BMJ had also published 19000 patients Aspirin based study with PPI. It found that PPI + ASPIRIN had more death rates. Also, in the same journal it showed a chart which mentioned Pantoprazole is most hazardous as compared to all PPIs. Infact all PPIs showed hazard ratios. Only H2RAs were more near to the reference point stating them as safe. (BMJ 2011;342:d2690)

NOT JUST HEART FUNCTION, PPI AFFECTS KIDNEYS TOO.

The bigger blow came in NOV 2015, with the news resonating worldwide and across India from Kidney Week abstract collection. Out of 100s of abstracts finalized to be presented at the American Society of Nephrology, 2 studies derived a marked attention worldwide.

Benjamin Lazarus et al followed 10,482 participants in the Atherosclerosis Risk in Communities study with an eGFR of ≥60mL/min/1.73m2 from a baseline visit (1996-1999) to December 31, 2011. Baseline PPI use was associated with incident CKD in unadjusted (hazard ratio [HR], 1.45, 95% CI, 1.11, 1.90; P=0.006) and fully adjusted analyses (HR, 1.50, 95% CI, 1.14, 1.96; P=0.003). There was no significant association between baseline H2-antagonist use and incident CKD (P=0.2). The study concluded saying “PPI use is an independent risk factor for CKD. Caution against unnecessary use is warranted” Another study was by Pradeep Arora et al. which had more number of patients. Here the population included 99,351 patients who were seen in primary care VISN2 clinics from 4/2001 until 4/2008. For evaluation of CKD outcome, 27,835 patients with baseline CKD were excluded. This study was establishing similarly to what Lazarus et al pointed out. Patients receiving PPI were more likely to have vascular disease, COPD, cancer and hypertension. Of the total of 99,251 patients analyzed for mortality outcome, 36,290 died. Propensity score analysis showed higher odds for development of CKD ( OR 1.29 95% CI 1.24-1.34) and mortality (OR 1.97, 95% CI 1.88- 2.06) among patients taking PPIs versus those not on PPIs and concluding Use of proton pump inhibitors are associated with increased risk of development of CKD. In a 2007 paper published, the abstract of Clin Nephrol. 2007 Aug; 68(2):65-72. was the paper that critically reviewed the effect of PPIs on the kidney in 2007 saying…

Proton pump inhibitors (PPIs) are widely prescribed; most concerning is the ever increasing number of cases of acute interstitial nephritis (AIN) associated with PPI therapy. The study stated it to be a class effect as all PPIs have been documented to cause AIN. Several adverse drug event registries now note PPIs as the most common cause of drug-induced AIN. While most patients recover kidney function, many are left with some level of chronic kidney disease.

Another recent study Misra et al. BMC Nephrology (2015) 16:136, titled “The relationship between proton pump inhibitor use and serum magnesium concentration among hemodialysis patients: a cross-sectional study” arrived at conclusion about PPI being a prime cause of hypomagnesemia stated In this cross-sectional study of prevalent HD patients, we found that serum Mg levels among PPI users were significantly lower than Mg levels of those who were not on PPIs, even after adjustment for relevant covariates. These results suggest that the effect of PPI use on GI loss of Mg is likely present in a substantial proportion of patients, and may therefore be an under-recognized entity that only comes to clinical attention when the hypomagnesemia is severe enough to cause symptoms.

There are several earlier studies which linked PPI usage issues with Clopidogrel, Iron, Calcium, Vitamin B12 absorption hampered, Hyperparathyroidism, Hypomagnesiemia, Anemia in CVD/CKD patients etc.

20 years of PPI experience

Caveats apply now.

PPI use is not, however, without shortcomings. Significant attention has been given to the potential interaction between clopidogrel and PPIs because Clopidogrel requires biotransformation via CYP2C19 to become active, which is the same pathway through which PPIs are primarily metabolized. In many cases of controlling and managing the overt acid problems, lifestyle modifications (e.g. avoiding precipitating foods, weight loss) may be all that are required. H2RAs – Get green signal as safe from the same Studies & journals that alert us on PPI.

PPIs are not without significant adverse effects; therefore, their long-term use must be re-evaluated periodically and discontinued when appropriate. After 20 years of experience with these drugs, many caveats apply to their use.

Nutshell

PPI are effective in management of GERD, acute acid peptic bleeding and stress ulcer prophylaxis but carry CV ricks, significant infectious risks, possible risk of pathologic fractures

ADMA pathway of PPI is class effect increasing the CV risks.

H2RAs have no association of CV events.

Question the indication and risks of chronic PPI usage on a regular basis.

Avoid use of Long Term PPI.

See the detailed ppt in the link below

Click Below Link For Related Presentation

http://www.slideshare.net/PAWANVKULKARNI/review-of-new-alerts-on-proton-pump-inhibitors-ppi-adverse-effects-2015-55022824

تعليقات

1y Praveen Raj Vice President - Training & Development - Macleods Pharmaceuticals Ltd - Mumbai Dear Chits... PPIs cause interstitial nephritis too.

1y PAWAN V. KULKARNI General Manager - Marketing @ J B Chemicals & Pharmaceuticals (Unique Division) Chalega Chittaranjan saheb - Rantac lelo..."Rantac OD 300" - Naya hai

1y Sanjiv Shrivastava, ACFE Principal Consultant & Director at Risk Analysis Superbly written article PAWAN V. KULKARNI. Its an eye opener for general public with limited knowledge of medical science.

1y Sudeep Bhattacharyya Director, Consulting and Innovation at BioXcel Corporation PPIs have actually been quite revolutionary. On a side note, we rely on them so much ... consumption every Fri or Sat night with religious regularity :).

1y Chittaranjan Deodhar Pharmaceutical Sales & Marketing Pawan... Zinetac lega toh chalega?

1y PAWAN V. KULKARNI General Manager - Marketing @ J B Chemicals & Pharmaceuticals (Unique Division) Chittaranjan Deodhar sir...Best is Lifestyle modification...which we sledom do. The issue cropping up is that "ACID is needed in Body. But nominal amounts and PPIs (90%+ blockage of acid) over/wrong use, long term use is altering the daily physiology. H2RAs doesnt block completely. Those all recent journals/studies that have shown PPI causing issues since 2011 are eminent. BMJ, Circulation, Nephrology, Recent most being Am Assoctn of Nephrology Conference. Patient number range in 10000 plus in many studies that proved PPIs have problem. Cardiac Arrest, Bone resorption, Hypomagnesemia, Anaemia, what not all. The same journals studies give a green signal to H2RAs. So why take risk...?

1y PAWAN V. KULKARNI General Manager - Marketing @ J B Chemicals & Pharmaceuticals (Unique Division) Dear Mr Sudeep Quite rightly said. They are worth. But issue is if you see, studies have shown that almost world wide as many as 65% cases reported the use of PPI for unnecessary indication. Short term is good, but never long term is what studies now showing up. Its like in pretext of QUICK RELIEF, Irreversible damage in invited.

1y PAWAN V. KULKARNI General Manager - Marketing @ J B Chemicals & Pharmaceuticals (Unique Division) I have asked many of my relatives and friends to revisit their doctors with reports i gave. On seeing it, all doctors whom my relatives went, immediately asked to stop and some drs THEN told patients why is that PPIs continued when it was written clearly for only 10-15 days.... So its patient's mistake also most of the times.

11mo Satnam S Chagger General Manager-Mktg. at Alkem Laboratories Ltd. Full of information, one point, a per cmark pantoprazole is written in diabetes an hypertension, it is given by physician to duabetic an hypertensive patients for drug induced gastritis. Hence indications wrongly captured in papers.

11mo Satnam S Chagger General Manager-Mktg. at Alkem Laboratories Ltd. Please ignore auto spell check

11mo PAWAN V. KULKARNI General Manager - Marketing @ J B Chemicals & Pharmaceuticals (Unique Division) Yeah have mentioned that in the article...that they are not not direct indications However, DIAB & HYPERTENSION is featured as "MOST Frequently Rxed" indications for all PPIs.

11mo kapil raj singh AREA MANAGER at J B CHEMICAL AND PHARMACEUTICAL LTD Zintac lengey to nahi chalega !! Rantac Od lengey to lamba chalega !!!

10mo PAWAN V. KULKARNI General Manager - Marketing @ J B Chemicals & Pharmaceuticals (Unique Division) http://www.medscape.com/viewarticle/857060

10mo PAWAN V. KULKARNI General Manager - Marketing @ J B Chemicals & Pharmaceuticals (Unique Division) http://archinte.jamanetwork.com/article.aspx?articleid=2481157

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