Dr. Kornelija Adomaitytė

Introduction

According to the latest recommendations, patients with acute coronary syndromes are treated with dual antiplatelet therapy using two drugs, especially those who have undergone percutaneous coronary angioplasty (PCA) and/or stenting (1–2). Dual antiplatelet therapy refers to the combination of aspirin and clopidogrel, to which individual response may vary (3–5). As is well known, aspirin is not only a nonsteroidal anti-inflammatory drug (NSAID) used to relieve pain, suppress inflammation, and reduce fever, but is also widely used in patients with cardiovascular disease. However, aspirin increases the risk of gastrointestinal complications, such as erosions, bleeding, and ulcers. Therefore, patients who have experienced acute coronary syndromes (including those who have undergone PCA and/or stenting) and are treated with dual antiplatelet therapy are recommended to receive gastroprotective medication (20).

NSAIDs and their Mechanism of Action

NSAIDs are first-line medications for the treatment of many rheumatic joint diseases, soft tissue inflammatory conditions, acute and chronic pain, and similar pathological conditions. According to the World Health Organization pain ladder, they are considered first-line analgesics (6). Aspirin occupies a unique position among NSAIDs because, in addition to relieving pain, inflammation, and fever, it is also widely used in patients with cardiovascular disease due to its antithrombotic properties.

According to their mechanism of action, NSAIDs are classified as selective or non-selective cyclooxygenase (COX)-1 and COX-2 inhibitors. Aspirin, diclofenac, indomethacin, piroxicam, naproxen, and several other agents belong to the non-selective group because they inhibit both COX-1 and COX-2, although to varying degrees. Cyclooxygenase enzymes are essential for prostaglandin (Pg) synthesis, which is increased during inflammation and pain. By inhibiting COX, NSAIDs reduce prostaglandin production.

The anti-inflammatory and analgesic effects of aspirin result from its systemic inhibition of prostaglandin synthesis. Like other NSAIDs, it is highly effective in relieving pain and inflammation, but it also shares their most common adverse effect—gastrointestinal injury (10, 11, 13). Selective COX-2 inhibitors generally cause fewer gastrointestinal adverse effects than non-selective NSAIDs.

Gastrointestinal injury caused by NSAIDs may remain clinically silent for a long time and often becomes apparent only after complications such as erosions, ulcers, or bleeding have developed. In the United States, NSAID-related gastrointestinal adverse effects account for more than 100,000 hospitalizations each year (12–13).

It was previously believed that gastrointestinal damage resulted primarily from the direct irritating effect of NSAIDs on the gastric and duodenal mucosa. It is now recognized that the systemic reduction of prostaglandin synthesis also plays an important role. To improve gastrointestinal protection during NSAID treatment, particularly with non-selective agents such as aspirin, H2 receptor antagonists (H2RAs) or proton pump inhibitors (PPIs) are commonly prescribed.

The goals of treating NSAID-induced ulcers are to relieve symptoms and promote ulcer healing (14). Whenever possible, NSAIDs should be discontinued and treatment with H2RAs, PPIs, or sucralfate initiated. If discontinuation is not possible, NSAIDs should be prescribed at the lowest effective dose for the shortest possible duration, together with H2RAs, PPIs, or sucralfate (15–17). If Helicobacter pylori infection is present, eradication therapy should be initiated. In patients at high risk of NSAID-induced ulcers, prophylactic treatment with PPIs or switching to selective COX-2 inhibitors is recommended (18). However, although selective COX-2 inhibitors produce fewer gastrointestinal adverse effects, they have been associated with an increased risk of myocardial infarction and other thrombotic cardiovascular events (21).

In 2012, the journal Clinical Gastroenterology and Hepatology highlighted concerns regarding the long-term use of high-dose PPIs in the treatment of gastroesophageal reflux disease (GERD), drawing attention to alternative treatment strategies, including H2 receptor antagonists, intermittent or on-demand PPI regimens, and antireflux surgery (25).

After reviewing data from several epidemiological studies, the U.S. Food and Drug Administration concluded that long-term (>1 year) use of high-dose PPIs may slightly increase the risk of hip, wrist, or spine fractures, particularly in elderly individuals and those with additional risk factors. Therefore, the FDA recommends the following before prescribing PPIs to elderly patients:

• prescribe PPIs only for approved indications, such as GERD, gastric or duodenal ulcers, and esophagitis (26);
• consider whether a lower dose and shorter treatment duration would provide sufficient benefit (26);
• monitor patients at increased risk of osteoporosis according to current clinical guidelines and ensure adequate calcium and vitamin D supplementation (27).

Recent publications (19) indicate that H2 receptor antagonist therapy is effective both for the prevention and treatment of ulcers induced by low-dose aspirin and has efficacy comparable to PPIs. Given the potential risks associated with prolonged PPI use, H2RAs may represent an appropriate option for ulcer prevention and treatment.

H2 receptor antagonists reduce gastric acid secretion by approximately 70% (22, 23). The most commonly used H2RA in clinical practice is ranitidine (e.g., Raniberl®). At the standard dose of 150 mg twice daily, ranitidine suppresses approximately 60–70% of gastric acid secretion over 24 hours. It is particularly effective in reducing nocturnal acid secretion. When administered as a 300 mg dose at bedtime, it suppresses nearly 90% of nighttime acid secretion and 50–60% of daytime acid secretion (24).

The effects of ranitidine begin within 30–60 minutes after administration and last for approximately 12 hours, making it particularly suitable for relieving episodic heartburn when used on an as-needed basis (24).

Summary

The use of NSAIDs, including aspirin, is associated with gastrointestinal adverse effects. Early superficial mucosal damage of the stomach and duodenum is often asymptomatic, and complications such as gastric or duodenal ulcers may be the first clinical manifestation. In severe cases, these complications may result in life-threatening gastrointestinal bleeding, indicating that gastroprotective therapy may not have been initiated in time.

To provide optimal protection of the upper gastrointestinal mucosa during NSAID therapy, H2 receptor antagonists (e.g., Raniberl®) or proton pump inhibitors may be prescribed.

H2 receptor antagonists are generally well tolerated, rarely cause adverse effects, and effectively reduce gastric acid secretion and gastrointestinal symptoms. By lowering gastric acidity, they create favorable conditions for ulcer healing and reduce the risk of ulcer recurrence.

LT/Ranib/2014/17

LITERATURE 1. Steinhubl S.R., Berger P.B., Mann J.T. et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary interven¬tion: a randomized controlled trial. JAMA, 2002, 288, 2411–2420. 2. King S.B., Smith S.C., Hirshfeld J.W. et al. 2007 Focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardio¬logy/American Heart Association Task Force on Practice guidelines. Journal of the American College of Cardiology, 2008, 51, 172–209. 3. Gurbel P.A., Bliden K.P., Hiatt B.L. et al. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pre¬treatment platelet reactivity. Circulation, 2003, 107, 2908–2913. 4. Blindt R., Stellbrink K., de Taeye A. et al. The significance of vasodila¬tor-stimulated phosphoprotein for risk stratification of stent thrombosis. Journal of Thrombosis and Haemostasis, 2007, 98, 1329–1334. 5. Paniccia R., Antonucci E., Gori A.M. et al. Different methodologies for evaluating the effect of clopidogrel on platelet function in high-risk coronary artery disease patients. Journal of Thrombosis and Haemostasis, 2007, 5, 1839–1847. 6. Koch K. Acute pain management in general practice: steps to effective pain control. Review Article. South African Family Practice, 2013, 55 (6), 520–524. 7. Gumbrevičius G., Milašius A., Sveikata A. Nonsteroidal anti-inflammatory drugs - choosing between harmful effects on the digestive tract and possible damage to the heart and blood vessels. Continuing Medical Studies. Medicine, 2006, 42 (5), 429–439. 8. Lanas A. A review of the gastrointestinal safety data-a gastroentero¬logist’s perspective. Rheumatology, 2010, 49, ii3–ii10. 9. Castellsague J., Riera-Guardia N., Calingaert B., Varas-Lorenzo C. et al. Individual NSAIDs and upper gastrointestinal complications: a systematic review and meta-analysis of observational studies (the SOS project).; Safety of Non-Steroidal Anti-Inflammatory Drugs (SOS) Project. Source RTI Health Solutions, Barcelona, Spain. Drug Safety, 2012 Dec. 1, 35 (12), 1127–1146. 10. Airtal preparato charakteristikų santrauka. Accessed online (viewed 2014 02 02): <https://extranet.vvkt.lt/paieska/details. php?id=21752&thislanguage=lang_lt>. 11. The place of NSAIDs in pain management. Lithuanian Doctor's Journal, 2011 (3). Accessed online (viewed 2014 02 02): <https://www.pasveik.lt/ naujausi-medicinos-straipsniai/dolmen--neselektyvus-nesteroidinis-vaistas-nuo-uzdegimo-uminiam-skausmui-malsinti/69124>.