Aspirin;

Do proton pump inhibitors (PPIs) reduce the risk of bleeding from lower gastrointestinal tract?

FA Manian MD, MPH, , , , , , , , , , , , , , Leave a comment

The short answer is “No”!  Although proton pump inhibitors (PPIs) are effective in reducing the risk of upper gastrointestinal bleed (GIB) in high-risk patients, they do not protect against lower GIB. 1 In fact, their use has been associated with an increased risk of small bowel injury related to non-steroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin.2,3

A 2015 case-control study involving over 1,000 patients hospitalized for GIB found that although concomitant use of PPI in patients on NSAIDs, low-dose aspirin, other antiplatelet agents or anticoagulants was associated with a reduced risk of UGIB, it was not associated with reduced risk of lower GIB.  Interestingly, in this study, PPIs were associated with higher risk of lower GIB which might have been related to confounding factors and not necessarily a direct causal effect.4 Lack of an impact of PPIs on lower GIB among patients on aspirin or NSAIDS has also been supported by others. 5-7

The fact that PPIs don’t seem to reduce the risk of GIB distal to the duodenum should not be surprising given their primary mechanism of action through inhibition of acid production by gastric parietal cells. 8  What is perhaps more intriguing is how they may potentially increase the risk of small intestinal injury while still protecting the gastro-duodenum from NSAID-induced mucosal damage.

In a cool laboratory study involving rats, treatment with a PPI was associated with exacerbation of NSAID-induced intestinal ulceration and bleeding; by itself treatment with PPI was not associated with intestinal mucosa injury.9 Interestingly, in this study, a marked shifts in numbers and types of enteric bacteria with a significant reduction in jejunal Bifidobacteria spp was noted with PPI therapy. Restoration of small intestine Bifididobacteria during treatment with a PPI along with an NSAID prevented intestinal ulceration/bleeding. The investigators concluded that when used along with an NSAID, PPIs may cause small intestinal injury through alteration in the microbiome of the gut.  Fascinating!

Bonus Pearl: Did you know that the 2022 American Gastroenterological Association (AGA) clinical practice update on de-prescribing of PPIs lists several conditions for which acute/short term use of PPIs are NOT indicated, such as isolated lower GI symptomatology, acute nausea and vomiting not believed to be related to GERD/esophagitis, acute undifferentiated abdominal pain, and empiric treatment of laryngopharyngeal symptomatology? 10 

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References

  1. Lue A, Lanas A. Proton pump inhibitor treatment and lower gastrointestinal bleeding: Balancing risks and benefits. World J Gastroenterol 2016;22:10477-10481. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5192259/#:~:text=PPIs%20do%20not%20prevent%20NSAID,and%20the%20risk%20of%20LGB.
  2. Endo H, Sakai E, Taniguchi L, et al. Risk factors for small-bowel mucosal breaks in chronic low-dose aspirin users: data from a prospective multicenter capsule endoscopy registry. Gastrointes Endosc 2014;80:826-34. https://pubmed.ncbi.nlm.nih.gov/24830581/
  3. Washio E, Esaki M, Maehata Y, et al. Proton pump inhibitors increase incidence of nonsteroidal anti-inflammatory drug-induced small bowel injury: A randomized, placebo-controlled trial. Clin Gastroenterol Hepatol 2016;14:809-815. https://pubmed.ncbi.nlm.nih.gov/26538205/
  4. Lanas A, Carrera-Lasfuentes P, Arguedas Y, et al. Risk of upper and lower gastrointestinal bleeding in patients taking nonsteroidal anti-inflammatory drugs, antiplatelet agents, or anticoagulants. Clin Gastroenterol Hepatol 2015;13:906-12. https://pubmed.ncbi.nlm.nih.gov/25460554/
  5. Nagata N, Niikura R, Aoki T, et al. Effect of proton-pump inhibitors on the risk of lower gastrointestinal bleeding associated with NSAIDs, aspirin, clopidogrel, and warfarin. J Gastroenterol 2015;50:1079-1086. https://pubmed.ncbi.nlm.nih.gov/25700638/
  6. Garcia Rodriguez LA, Lanas A, Soriano-Gabarro M, et al. Effect of proton pump inhibitors on risks of upper and lower gastrointestinal bleeding among users of low-dose aspirin: A population-based observational study. J Clin Med 2020;9:928. https://www.mdpi.com/2077-0383/9/4/928
  7. Casado Arroyo R, Polo-Tomas M, Roncales MP, et al. Lower GI bleeding is more common than upper among patients on dual antiplatelet therapy: long-term follow-up of a cohort of a patients commonly using PPI co-therapy. Heart 2012;98:718-723. https://pubmed.ncbi.nlm.nih.gov/22523056/
  8. Engevik AC, Kaji I, Goldenring JR. The physiology of the gastric parietal cell. Physiol Rev 2020;100:573-602. The Physiology of the Gastric Parietal Cell – PMC (nih.gov)
  9. Wallace JL, Syer S, Denou E, et al. Proton pump inhibitors exacerbate NSAID-induced small intestinal injury by inducing dysbiosis. Gastroenterology 2011;141:1314-22. https://www.gastrojournal.org/action/showPdf?pii=S0016-5085%2811%2900926-7
  10. Targownik LE, Fisher DA, Saini SD. AGA clinical practice update on de-prescribing of proton pump inhibitors: expert review. Gastroenterology 2022;162:1334-1342. https://www.gastrojournal.org/article/S0016-5085(21)04083-X/fulltext

Disclosures/Disclaimers: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Do proton pump inhibitors (PPIs) reduce the risk of bleeding from lower gastrointestinal tract?

Are NSAIDS contraindicated in patients with 2019 novel Coronavirus infection (Covid-19)?

FA Manian MD, MPH, , , , , , , , , , , , , , , , , 1 Comment

Despite recent internet reports of the association of non-steroidal anti-inflammatory drugs (NSAIDs) with worsening symptoms among patients with Covid-19 (1), firm clinical evidence to support such claims is currently lacking. However, there are some theoretical reasons why it may still be best to avoid NSAIDs in this condition due to their potential adverse impact on the innate and adaptive immune responses as well as their antipyretic properties (2-9).

 
Blunting of the innate immune response: Certain NSAIDs (eg, ibuprofen, naproxen and celecoxib) inhibit cyclooxygenase enzyme-2 (COX-2) and impair production of several pro-inflammatory cytokines important in fighting infections, such as tumor necrosis factor, interleukin 1 and 6, as well as interferon, an antiviral cytokine (2,6,8). COX-2 has been shown to be important in controlling viral replication in influenza (4). Ibuprofen has been associated with inhibitory effects on a variety of polymorphonuclear functions, including chemotaxis (2).

 
Impact on adaptive immune response: COX-2 inhibition may be associated with impaired neutralizing antibody production (3,4,8). Potential mechanisms include modulation of cytokine expression, nitric-oxide production, and antigen processing/presentation and T lymphocyte activation (3,8).

 
Antipyretic effect: NSAIDs are often given for treatment of fever which is an evolutionary host response to infection. A meta-analysis of animal studies evaluating the impact of antipyretics (including aspirin, NSAIDs, and acetaminophen) in influenza found lower survival in animals treated with antipyretics (9). Longer duration of viral shedding has also been associated with the use of aspirin or acetaminophen in rhinovirus infection (9).

 
Formal epidemiologic and experimental studies are sorely needed to evaluate the safety of NSAIDS in Covid-19.  

 

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References
1. Kolata G. Is ibuprofen really risky for Coronavirus patients? NY Times, March 17, 2020. https://www.nytimes.com/2020/03/17/health/coronavirus-ibuprofen.html
2. Graham NMH, Burrell CJ, Douglas RM, et al. Adverse effects of aspirin, acetaminophen and ibuprofen on immune function, viral shedding, and clinical status in rhinovirus-infected volunteers. J Infect Dis 1990;162:1277-1282. https://academic.oup.com/jid/article/162/6/1277/918184
3. Culbreth MJ, Biryunkov S, Shoe JL, et al. The use of analgesics during vaccination with a live attenuated Yersinia pestis vaccine alters the resulting immune response in mice. Vaccines 2019;7, 205; doi:10.3390/vaccines7040205 https://www.mdpi.com/2076-393X/7/4/205
4. Ramos I, Fernandez-Sesma A. Modulating the innate immune response to influenza A virus:potential therapeutic use of anti-inflammatory drugs. Frontiers in Immunology. July 2015. Volume 6. Article 361. https://www.ncbi.nlm.nih.gov/pubmed/26257731
5. Falup-Pecurariu O, Man SC, Neamtu ML, et al. Effects of prophylactic ibuprofen and paracetamol administration on the immunogenicity and reactogenicity of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugated vaccine(PHID-CV) co-administered with DTPa-combined vaccines in children:An open-label, randomized, controlled, non-inferiority trial. Human Vaccines & Immunotherapeutics 2017;13: 649-660. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5360152/
6. Housby JN, Cahill CM, Chu B, et al. Non-steroidal anti-inflammatory drugs inhibit the expression of cytokines and induce HSP70 in human monocytes. Cytokine 1999;11:347-58. https://www.ncbi.nlm.nih.gov/pubmed/30186359
7. Agarwal D, Schmader KE, Kossenkov AV, et al. Immune response to influenza vaccination in the elderly is altered by chronic medication use. Immunity & Ageing 2018;15:19. https://www.ncbi.nlm.nih.gov/pubmed/30186359
8. Bancos S, Bernard MP, Topham DJ, et al. Ibuprofen and other widely used non-steroidal anti-inflammatory drugs inhibit antibody production in human cells. Cell Immunol 2009;258:18-28. https://www.ncbi.nlm.nih.gov/pubmed/19345936
9. Eyers S, Weatherall M, Shirtcliffe P, et al. The effect on mortality of antipyretics in the treatment of influenza infection: systematic review and meta-analysis. J R Soc Med 2010;103:403-11. https://www.ncbi.nlm.nih.gov/pubmed/20929891

 

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Are NSAIDS contraindicated in patients with 2019 novel Coronavirus infection (Covid-19)?

My elderly patient on anticoagulation for non-valvular atrial fibrillation was admitted for evaluation of a fall. Should I discontinue her anticoagulation long term because of potential for intracranial hemorrhage from future falls?

FA Manian MD, MPH, , , , , , , , , Leave a comment

Although there may always be hesitation in resuming anticoagulation (AC) in patients with non-valvular atrial fibrillation (NVAF) and recent fall(s), the weight of the evidence suggests that most patients are still more likely to benefit from AC than be adversely impacted by intracranial hemorrhage.

 
An often-quoted systematic review article on the risks and benefits of anti-thrombotic (AC or aspirin) therapy in patients with NVAF at risk estimated that persons taking warfarin must fall 295 times in 1 year for warfarin to not be the optimal therapy for reducing the risk of stroke (1). The authors concluded that “a history of and/or the presence of risk factors for falls should not be considered important factors in the decision whether to offer antithrombotic (especially warfarin) therapy to elderly patients with atrial fibrillation”.

 
In another study involving older adults with NVAF, although a history of falls or documented high risk of falling was associated with a risk of intracranial hemorrhage, this risk did not differ among patients treated with warfarin, aspirin or no antithrombotic therapy (2).

 
Ultimately, the decision to prescribe AC in patients with NVAF at risk for falls should be made based on shared decision making with patients and caregivers. However, in the absence of absolute contraindications for AC in these patients (eg, intracranial hemorrhage or neurosurgical procedure with high risk for bleeding within the past 30 days, an intracranial neoplasm or vascular abnormality with high risk of bleeding, recurrent life-threatening gastrointestinal or other bleeding events, and severe bleeding disorders), perceived or actual risk of falls by itself should not automatically exempt a patient from receiving AC in NVAF (3).

 

Although much of the data on the relative risk of bleeding against prevention of strokes has been derived from studies involving warfarin, it is reassuring that the risk of intracranial bleed has been lower than that of warfarin for several newer non-vitamin K antagonist direct oral anticoagulants (NOACs or DOACs),  including dabigatran, rivaroxaban, edoxaban and apixaban (4). 

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References

1. Man-Son-Hing M, Nichol G, Lau A, et al. Choosing antithrombotic therapy for elderly patiets with atrial fibrillation who are at risk for falls. Arch Intern Med 1999;159:677-685.
2. Gage BF, Birman-Deych E, Kerzner R, et al. Incidence of intracranial hemorrhage in patients with atrial fibrillation who are prone to fall. Am J Med 2005;118:612-617.
3. Hagerty T, Rich MW. Fall risk and anticoagulation for atrial fibrillation in the elderly: a delicate balance. Clev Clin J 2017;84:35-40.

4. Lopez RD, Guimaraes PO, Kolls BJ, et al. Intracranial hemorrhage in patietns with atrial fibrillation receiving anticoagulation therapy. Blood 2017;129:2980-87. 

My elderly patient on anticoagulation for non-valvular atrial fibrillation was admitted for evaluation of a fall. Should I discontinue her anticoagulation long term because of potential for intracranial hemorrhage from future falls?

My patient just developed a fixed drug reaction from ibuprofen. What is the mechanism of this type of skin reaction?

FA Manian MD, MPH, , , , , , , , Leave a comment

Although its mechanism is not full elucidated, fixed drug eruption (FDE) is thought to result from the drug-induced cytotoxic activation of CD8+ memory T cells.1 ,2

In this context, the culprit medication behaves as a hapten that adheres to basal keratinocytes which in turn results in the recruitment of T cells and inflammation.  However, as the inflammation resolves, CD8+  effector-memory T cells remain in the area in question,  setting the stage for more rapid immunologic reaction when the drug is reintroduced.

Why a systemic drug triggers a reaction only at specific sites in the body is a fascinating question. Prior herpes simplex virus (HSV) infection (eg, on the lips or genitalia) may explain some cases.1 Interestingly, despite the absence of prior herpetic lesions, most patients with FDE are seropositive for HSV. Previously traumatized body sites (e.g. from burns or insect bites) may also create an immune microenvironment conducive to FDE.

The classic presentation of FDE is reappearance of a rash in the genitals, perianal areas, hands, and feet within 30 min to 8 hours of taking the culprit medication.3 Look specifically for NSAIDs, tetracyclines, sulfonamides, and aspirin on the patient’s drug list. 4

References

  1. Shiohara, T. Fixed drug eruption: Pathogenesis and diagnostic tests. Curr Opin Allergy Clin Immunol 2009; 9:316-21. https://www.ncbi.nlm.nih.gov/pubmed/19474709
  2. Butler, DF. Fixed Drug Eruptions. Medscape. http://emedicine.medscape.com/article/1336702-overview#a4. Accessed March 26, 2018.
  3. Korkij W, Soltani K. Fixed drug eruptions: A brief review. Arch Dermatol 1984;120:520. https://www.ncbi.nlm.nih.gov/pubmed/6231004
  4. Oakley, A. Fixed Drug Eruption. https://www.dermnetnz.org/topics/fixed-drug-eruption Accessed March 26, 2018.

 

Contributed by Amir Hossein Ameri, Medical Student, Harvard Medical School

My patient just developed a fixed drug reaction from ibuprofen. What is the mechanism of this type of skin reaction?

In my patient on oral anticoagulation about to undergo coronary stenting, will triple therapy (an oral anticoagulant plus two antiplatelet agents) be necessary or can I get away with double therapy (an oral anticoagulant plus a single antiplatelet agent)?

FA Manian MD, MPH, , , , , , , , , , Leave a comment

 

Patients with atrial fibrillation (AF) who need percutaneous coronary intervention (PCI) after acute coronary syndrome or for stable angina pose a treatment challenge as oral anticoagulants (OACs) and dual antiplatelet therapy (DAPT) are often used concurrently to decrease the risk of systemic thromboembolism and stent thrombosis. However, “triple therapy”, including aspirin, a P2Y12 inhibitor, and an OAC (eg, warfarin or a direct oral anticoagulant-DOAC), also increases the risk of bleeding, necessitating several recent landmark trials to better address the subject.

Two modest-sized RCTs (WOEST and ISAR-TRIPLE) reported that when compared to triple therapy (DAPT plus warfarin), double therapy (single antiplatelet agent plus INR-targeted warfarin) is associated with reduced risk of bleeding complications without an increased risk of thrombotic events. 1,2

Two larger RCTs, PIONEER AF-PCI and RE-DUAL PCI, studied rivaroxaban and dabigatran, respectively, in patients with non-valvular AF undergoing PCI and found a reduction in bleeding events in patients receiving double therapy (single antiplatelet agent plus DOAC) compared to triple therapy (DAPT plus warfarin), without an increased risk of thrombotic complications. 3,4

Collectively, these studies suggest that it may be safe to treat patients with increased risk of bleeding with double therapy (even immediately following PCI) without an increase in thrombotic events. If triple therapy is elected, duration should be minimized, clopidogrel should be preferred over more potent P2Y12 inhibitors, and a PPI should be considered.

 

References:

  1. Dewilde WJ, Oirbans T, Verheugt FW, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet. 2013;381:1107-15. https://www.ncbi.nlm.nih.gov/pubmed/23415013
  2. Fiedler KA, Maeng M, Mehilli J, et al. Duration of triple therapy in patients requiring oral anticoagulation after drug-eluting stent Implantation: The ISAR-TRIPLE Trial. J Am Coll Cardiol. 2015;65:1619-29. https://www.ncbi.nlm.nih.gov/pubmed/25908066
  3. Gibson CM, Mehran R, Bode C, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med. 2016;375:2423-2434. http://www.nejm.org/doi/pdf/10.1056/NEJMoa1611594
  4. Cannon CP, Bhatt DL, Oldgren J, et al. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med. Published online, Aug, 27, 2017. http://www.nejm.org/doi/pdf/10.1056/NEJMoa1708454

 

Contributed by Amulya Nagarur, MD, Mass General Hospital, Boston, MA

In my patient on oral anticoagulation about to undergo coronary stenting, will triple therapy (an oral anticoagulant plus two antiplatelet agents) be necessary or can I get away with double therapy (an oral anticoagulant plus a single antiplatelet agent)?

My patient with atrial fibrillation (AF) with a CHA2DS2-VASc score ≥2 is not a candidate for anticoagulation due to excessive bleeding risk. Does high-dose aspirin provide an effective alternative for stroke prevention in this setting?

FA Manian MD, MPH, , , Leave a comment

 The SPAF (Stroke Prevention in Atrial Fibrillation) trial1 found a 42% reduction in overall risk of stroke with daily aspirin (325 mg). However, critics note that no benefit was observed among patients > 75 y or those with severe stroke.

7 other studies on the topic failed to confirm reduction in the risk of stroke at a range of aspirin doses (25mg bid-1,300mg qd) 2. These studies reported that aspirin is associated with a 19% reduction in stroke incidence (similar to patients with vascular disease), with a 95% CI that crosses zero (-1% to 35%), raising doubts about its actual benefit in AF3. For secondary prevention, aspirin was associated with a 2.5% reduction in the annual risk of stroke. However, these results were influenced by the only trial with a favorable outcome, SPAF-14.

In short, even at higher doses, aspirin may not be the answer for stroke prevention in patients with AF.

 References

  1. Stroke Prevention in Atrial Fibrillation Study. Final results. Circulation 1991;84, 527–39.
  2. January CT, Wann LS, Alpert  JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Circulation  2014;130, e199–e267.
  3. European Heart Rhythm Association et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Europace  2010; 12, 1360–420.
  4. Sabir IN, Matthews GDK,  Huang, CL-H. Antithrombotic therapy in atrial fibrillation: aspirin is rarely the right choice. Postgrad Med J 2013; 89, 346–51.

 

Contributed by Jacqueline Boehme, M.D., Medical Resident, Mass General Hospital

My patient with atrial fibrillation (AF) with a CHA2DS2-VASc score ≥2 is not a candidate for anticoagulation due to excessive bleeding risk. Does high-dose aspirin provide an effective alternative for stroke prevention in this setting?

Is aspirin effective in reducing the risk of cancer?

FA Manian MD, MPH, , Leave a comment

Yes, at least for certain types of cancer! A recent report based on 2 ongoing prospective studies (Nurses’ Health Study and Health Professionals Follow-up Study) assessed the risk of cancer in non-regular and regular users of aspirin at a dose of at least 0.5-1.5 standard tablets (325 mg) per week or a low daily dose of 81 mg.  It involved nearly 136,000 subjects while taking into account many potential confounders, including age and cancer screening1.

Compared to non-regular use, aspirin use for at least 6 years was associated with a 3% lower risk of overall cancer, and 15% lower incidence of gastrointestinal cancers, especially colorectal cancers (19% risk reduction); the incidence of breast, advanced prostate or lung cancer was not affected. The irreversible inhibition of cyclooxygenase-2 (COX-2), the principle enzyme that produces pro-inflammatory prostaglandins such as prostaglandin E2 (PGE2) found in human colorectal adenomas and carcinomas2, may explain aspirin’s protective effect1.

 

References

  1. Cao Y, Nishihara R, Wu K, et al. The population impact of long-term use of aspirin and risk of cancer. JAMA Oncol 2016;2:762-769
  2. Greenhough A, Smartt HJM, Moore, et al. The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment. Carcinogenesis 2009;30:377-386.

 

Contributed by Katarzyna Orlewska, Medical Student, Warszawski Uniwersytet Medyczny

Is aspirin effective in reducing the risk of cancer?