What is the association between PPIs and non-cardiac or cardiac chest pain, but not GERD symptom chest pain?

Comment by InpharmD Researcher

There appears to be a scarcity of data assessing the association between proton pump inhibitors (PPIs) and non-gastroesophageal reflux disease (GERD) chest pains. Pooled data suggests that PPI therapy may have little to no response in patients with non-GERD chest pains. While case studies describe the occurrence of PPI-induced chest pains that resolve after discontinuing the agent, definitive associations cannot be made due to the anecdotal nature of the evidence.


A 2011 systematic review and meta-analysis aimed to assess the response of unexplained chest pain to proton pump inhibitor (PPI) therapy in patients with and without objective evidence of gastroesophageal reflux disease (GERD). A total of six randomized controlled trials (RCTs) were included, five of which were considered eligible for meta-analysis. All included trials utilized 24-hour pH monitoring and/or endoscopy to identify GERD-positive patients, and defined response as >50% improvement in chest pain (5 RCTs) or >20% improvement (1 RCT). The analysis revealed that PPIs demonstrated a therapeutic gain of 56-85% in GERD-positive patients (>50% improvement relative risk [RR] 4.3; 95% confidence interval [CI] 2.8 to 6.7; p<0.0001), and 0-17% in GERD negative patients (>50% improvement RR 0.4; 95% CI 0.3 to 0.7; p= 0.0004). Criteria for concomitant heartburn varied among included trials, but generally correlated with GERD-positive status. Notably, the authors highlighted that patients without conclusive evidence of GERD were more likely to respond to placebo than to PPI therapy. Based on these findings, it was suggested that unexplained chest pain in patients with evidence of GERD on endoscopy or pH-monitoring tends to improve but not resolve with PPI therapy, while patients without GERD evidence show little to no response. While these findings provide insights into the response of unexplained chest pain to PPI therapy in patients with and without GERD, examining the association of PPIs leading to PPI-induced chest pains was not within the scope of the analysis. [1]


[1] Kahrilas PJ, Hughes N, Howden CW. Response of unexplained chest pain to proton pump inhibitor treatment in patients with and without objective evidence of gastro-oesophageal reflux disease. Gut. 2011;60(11):1473-1478. doi:10.1136/gut.2011.241307

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What is the association between PPIs and non-cardiac or cardiac chest pain, but not GERD symptom chest pain?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→

Please see Tables 1-2 for your response.


The Unknown Association of PPIs With Chest Pain in Patients With Known, Treated Coronary Artery Disease-A Diagnostic Dilemma


Case series

Case presentation 1

A 61-year-old man presented with recurrent episodes of exertional chest pain starting approximately 4 months prior. The pain was described as deep, pressure-like sensation, rated to be 4 on 10-point scale. The patient reported radiation of pain to left shoulder, with relief after few minutes of rest. The patient's medical history included hypertension, hyperlipidemia, hypothyroidism, gastroesophageal reflux disease (GERD), and coronary artery disease (CAD). The patient underwent percutaneous coronary intervention (PCI) with placement of drug eluting stents in his distal right coronary artery (RCA) and proximal left anterior descending artery 10 years earlier. For the current illness, a recent electrocardiogram (ECG), conducted 3 months prior, indicated no changes from baseline and negative cardiac enzyme assays. Similarly, exercise stress test found no evidence of stress-induced myocardial ischemia.

The patient's medications included aspirin 81 mg, clopidogrel 75 mg, irbesartan 300 mg, atorvastatin 80 mg, atenolol 25 mg, amlodipine 5 mg, levothyroxine 88 mcg, and multivitamins, all taken daily. The patient also started taking pantoprazole 40 mg orally daily x 4 months after being diagnosed with GERD. 

With his current presentation, vital signs were normal and he was normotensive, with regular heart rhythm and normal rate with no murmurs, rubs, or gallops. All other lab and ECG evaluations were also found to be normal. Based on these examinations, the authors suspected pantoprazole to be causative of the patient's chest pain. Pantoprazole was discontinued and the patient was initiated on ranitidine 150 mg orally twice daily for GERD. Upon follow-up, the patient reported symptoms to have resolved within a few days of pantoprazole discontinuation, with no recurrence at 8 months of follow-up. 

Case presentation 2

A 73-year-old woman presented for coronary angiography to evaluate anomalous RCA due to refractory exertional angina. The patient's medical history included hypertension, hyperlipidemia, CAD, hypothyroidism, arthritis, and diet-controlled diabetes mellitus type 2. Two months prior to presentation, the patient started experiencing constant, nonradiating, pressure-like chest pain in the middle of her chest, lasting for 3-5 minutes, rated as severity of 8 on a 10-point pain scale. The pain was aggravated by exertion and relieved with sublingual nitroglycerin. The patient underwent coronary angiography and PCI after coronary computed tomography (CT) scan found obstructive proximal left circumflex artery stenosis and calcified anomalous RCA. Despite the PCI, chest pain symptoms improved yet continued. An ECG was found to be normal, with no evidence of ischemic changes. 

The patients medications included aspirin 81 mg, prasugrel 10 mg, pravastatin 40 mg, metoprolol succinate 25 mg, levothyroxine 100 mcg, amlodipine 10 mg, and esomeprazole 40 mg daily, omega-3 fatty acid-vitamin E 1000 mg TID, and nitroglycerin as needed. Her cardiovascular examination, as well as laboratory data were found to be normal. Based on angiographic findings, the authors suspected omeprazole to be the causative agent of the angina-like symptoms. The patient's esomeprazole was discontinued and switched to ranitidine 150 mg twice daily due to use of dual antiplatelet therapy. After a one-week follow-up, the patient was reported to be symptom free, which was also confirmed at an 8 month follow-up.  

Study Author Conclusions

It is the authors' opinion that a relationship between PPIs and angina-like chest pain is plausible, as these two cases demonstrate the causative role of PPIs in precipitation of their symptoms. The authors postulate that this association should be considered in differential diagnosis of chest pain. In light of these findings, the authors suggest that this is hypothesis generating and are exploring the role of PPIs in patients with history of CAD and refractory angina-like symptoms despite complete revascularization.  

Javed F, Ramee S. The Unknown Association of PPIs With Chest Pain in Patients With Known, Treated Coronary Artery Disease-A Diagnostic Dilemma. Curr Probl Cardiol. 2016;41(7-8):235-244. doi:10.1016/j.cpcardiol.2016.10.001


Esomeprazole-induced chest pain: a case of an unexpected serious adverse reaction to a rroton rump inhibitor


Case report 

Case presentation

A 57-year-old woman was diagnosed with gastroesophageal reflux disease (GERD) and prescribed oral esomeprazole 20mg daily. Past medical history included hypertension with the management of bisoprolol 5 mg daily, perindopril 2x4 mg daily, and aspirin 100 mg daily. Of note, three years before GERD diagnosis, the patient presented with noncharacteristic chest pressure, palpitations, and shortness of breath during physical activity and completed labs with electrocardiogram (ECG), echocardiography, stress test, and coronarography. All findings including vitals were unremarkable, except for hypertensive reaction to strain on stress test and possible myocardial ischemia impression of ECG. She was subsequently prescribed nitroglycerin (NTG) spray as needed for symptoms.

Three to four hours following omeprazole initiation, the patient complained of chest constrictions identical to anginal difficulties, which were resolved following NTG administration. Vitals, labs, and ECG were unremarkable. She resumed omeprazole, however, due to continued symptoms, the medication was soon discontinued after 19 days. Three months after discontinuation, she did not complain of anginal difficulties. However, GERD symptoms persisted and she was referred to the cardiology unit for observation for esomeprazole initiation. Pre-medication ECG was normal. Within 1 hour of esomeprazole intake, she experienced angina discomfort and an ECG showed shallow negative T-waves with a milder ST-segment depression in V1 – V4 leads. Symptoms resolved a few minutes after 2 sprays of NTG. The following day, she did not take esomeprazole and her ECG was unremarkable.

Study Author Conclusions

Proton pump inhibitors are not among the known causes of ischemic or nonischemic chest pain. Based on the rechallenge and dechallenge effects in this case, the Croatian Agency judged its causal relationship to esomeprazole as certain. Because the patient had ECG changes typical of transient myocardial ischemia and without myocardial damage, we characterized the reaction as microvascular dysfunction.


Radas MR, Knežević A, Trkulja V. Esomeprazole-induced chest pain: a case of an unexpected serious adverse reaction to a proton pump inhibitor. Case Reports in Gastrointestinal Medicine. 2020;2020:1-3. doi: 10.1155/2020/5693545