Table 1

Baseline characteristic of the studies
Author Study design Recruitment Inclusion criteria Exclusion criteria n all (n female), subgroups Age, mean (SD) Disease duration
Symptoms suggesting gastroesophageal reflux (GERD)-related non-cardiac chest pain (NCCP)
Kim et al., 2007 [24] Cross-sectional, funding NR Inpatients with NCCP, referred by a cardiologist after negative cardiac evaluation. Tertiary care, Seoul, Korea. NCCP was defined when patients were admitted for chest pain to the coronary unit for ≥1 episode of unexplained chest pain/week for ≥3 months. Cardiac chest pain was ruled out by electrocardiogram (ECG), normal enzymes, negative treadmill exercise testing, normal or insignificant ECG changes after intravenous ergonovine injection in coronary angiograms. Severe liver, lung, renal or hematological disorders. History of peptic ulcer or gastrointestinal (GI) surgery, connective tissue disorder and chest pain originating in a musculoskeletal disorder. 58 (female 37), NCCP with GERD symptoms (sy) 24, NCCP without GERD sy 34 54.6 (10.4) 17% <6 months, 17% 6 to 12 months, 51% 1 to 5 years, 16% >5 years
Hong et al., 2005 [25] Retrospective data analysis, funding NR Patients with a clinical suspicion of esophageal motility abnormalities and pathological acid exposure within 1 month were included in this analysis. Tertiary care, Seoul, Korea. Patients with suspicion of esophageal motility abnormalities and pathological acid exposure. NCCP was defined as recurrent angina-like or substernal chest pain believed to be unrelated to the heart, after comprehensive evaluation by the cardiologist. Obstructive lesions, previous esophageal balloon dilatation, botulism toxin injection, or anti-reflux surgery. No complaints associated with symptoms centered on the esophagus. Connective tissue diseases. 462 (female 269), dysphagia 53, NCCP 186, GERD sy 117 47.6 (10.9) NR
Netzer et al., 1999 [26] Retrospective data analysis, funding NR First-time referrals to esophageal function testing laboratory. Tertiary care, Bern, Switzerland. First-time referrals to esophageal function testing laboratory. NCCP group included all patients referred for GI testing because of NCCP. Additional information was obtained by contacting the general practitioner (GP) and interviews. NR 303 (female 145), GERD 143, dysphagia 56, NCCP 45 50 (15) NR
Mousavi et al., 2007 [27] Prospective observational, funding NR Outpatient referral by cardiologist after non-invasive diagnostic evaluation and exclusion of a cardiac or other source. Semnan, Iran. Patients with NCCP referred to the gastrointestinal clinic. NCCP was diagnosed when chest pain was believed to be unrelated to the heart after an evaluation by a cardiologist including non-invasive testing and no apparent other diagnosis was present. Non-steroidal anti-inflammatory drug (NSAID) use, peptic stricture, duodenal/gastric ulcer. History of upper GI surgery, scleroderma, diabetes mellitus, neuropathy, myopathy or functional bowel disorders, any condition that may affect lower esophageal sphincter pressure or decrease acid clearance time. 78 (female 37), NCCP with GERD sy. 35, NCCP without GERD 43 50.4 (2.3) 3 to 30 days (mean 9.3 ± 4.2 days)
Singh et al., 1993 [28] Retrospective data analysis, funding NR All consecutive outpatients referred to Esophageal Laboratory for evaluation of upper gastrointestinal complaints. Alabama, USA. 61 patients had NCCP and were analyzed in comparison to reflux patients for findings in upper gastrointestinal endoscopy and ambulatory 24 h pH monitoring NR 153 (female 40) NR NR
Ho et al., 1998 [29] Cross-sectional, research grant, National University of Singapore Outpatient referral for NCCP to the gastroenterology service. Tertiary care, Singapore. Recurrent NCCP ≥3 months. Normal cardiac evaluation (non-obstructed coronary arteries (<50% diameter narrowing), dobutamine stress echocardiography, exercise ECG). Cardiologist evaluation not cardiac. No history of esophageal disorder or esophageal surgery 61 (NR) NR ≥3 months
Lam et al., 1992 [30] Cross-sectional, funding NR Patients referred to the gastroenterologist after being released from a cardiac care unit (CCU) where they were admitted with suspected myocardial infarction but negative cardiac evaluation. Secondary care, Haarlem, The Netherlands. Patients were eligible for the study when a cardiologist determined the chest pain to be of non-cardiac origin. Episode of acute, prolonged retrosternal chest pain. Cardiac chest pain was ruled out when no abnormalities on admission ECG, negative results on heart enzyme tests, negative exercise test. Further cardiac testing (coronary angiography) was only performed when considered necessary by the cardiologist. Age >80 years, ECG ischemic alterations on the admission, arrhythmias, or signs of congestive heart failure 41 (female 41) 61.4 (range 40 to 75) Acute episode of chest pain
Studies investigating the efficacy and diagnostic value of proton pump inhibitor (PPI) trials in GERD-related NCCP
Dickman et al., 2005 [31] Randomized, controlled trial (RCT), double-blind, crossover, Janssen Pharmaceutica und Eisai Inc. Outpatient referral by a cardiologist after negative cardiac evaluation. Tertiary care, Arizona, USA. NCCP ≥3 episodes/week (angina-like) for ≥3 months. Normal/insignificant findings coronary angiogram, or insufficient evidence for ischemic heart disease (IHD) in non-invasive tests. Severe comorbidity, previous empirical anti-reflux regimen, history of peptic ulcer disease or gastrointestinal surgery 35 (female 12), GERD + 16 (45.7%), GERD- 19 (54.3%) 55.6 (10.10) ≥3 months
Bautista et al. 2004 [32] RCT, double-blind, crossover, TAP Pharmaceuticals Outpatient referral by a cardiologist after negative cardiac evaluation. Tertiary care, Arizona, USA. NCCP ≥3 episodes (angina-like) for ≥3 months. Normal/insignificant findings coronary angiogram, or insufficient evidence for IHD in non-invasive tests. Severe comorbidity, previous empirical anti-reflux regimen, history of peptic ulcer disease or gastrointestinal surgery 40 (female 9), placebo 40, GERD + 18, GERD- 22 54.4 (2.78) ≥3 months
Fass et al. 1998 [33] RCT, double-blind, crossover, Astra-Merck research grant Outpatient referral by a cardiologist after negative cardiac evaluation. Tertiary care, Arizona, USA. NCCP ≥3 episodes (angina-like) for ≥3 months. Normal/insignificant findings coronary angiogram, or insufficient evidence for IHD in non-invasive tests. Previous empirical anti-reflux regimen, history of peptic ulcer disease or gastrointestinal surgery 37 (female 1), GERD + 23, GERD- 14 58.2 (2.3) ≥3 months
Pandak et al., 2002 [34] RCT, double-blind, crossover, Astra Zeneca Patients presented with recurrent chest pain, whose chest pain was determined by cardiologist to be of non-cardiac origin with the aid of methoxyisobutylisonitrile (MIBI) testing. Tertiary care, Arizona, USA. Unexplained recurrent chest pain determined to be of non-cardiac origin by a cardiologist and had negative results on MIBI testing Previous empirical anti-reflux regimen, gastric or duodenal ulcer, prior gastric surgery, abnormalities on physical exam or chest x-ray that would explain the chest pain 42 (female 24), GERD + 20, GERD- 18 Range 22 to 77 ≥6 months
Kim et al., 2009 [35] Prospective observational, Janssen Pharmaceuticals Inpatients referred after negative cardiac examination by cardiologists to gastroenterology. Tertiary care, Seoul, Korea. NCCP was defined when patients were admitted for chest pain to the coronary unit for ≥1 episode of unexplained chest pain/week for ≥3 months. Cardiac chest pain was ruled out by ECG, normal enzymes, negative treadmill exercise testing, normal or insignificant ECG changes after intravenous ergonovine injection in coronary angiograms. Severe comorbidity, history of peptic ulcer disease or gastrointestinal surgery, history of connective tissue disorder and chest pain originating from musculoskeletal disorder 42 (female 17), GERD + 16, GERD- 26 53.9 (12.8) ≥3 months: n = 12 3 to 12 months; n = 23 1 to 5 years; n = 7 >5 years
Xia et al., 2003 [36] RCT, single blind, Simon KY Lee Gastroenterology Research Fund Referred by a cardiologist after negative cardiac evaluation. Tertiary care, Hong Kong, China. NCCP ≥12 weeks during last 12 months. Normal coronary angiograph, chest pain considered by a cardiologist to be NCCP. Pathologic endoscopic finding, previous anti-reflux regimen, apparent heartburn, acid reflux, dysphagia and dyspepsia 68 (female 42), placebo 32, lansoprazole 36 58.2 (10.0) ≥12 weeks
Kushnir et al., 2010 [37] Retrospective data analysis, Mentors in Medicine, Washington University, St Louis, MO, USA Outpatients referred for ambulatory pH monitoring for the evaluation of unexplained chest pain. Tertiary care, Missouri, USA. Unexplained chest pain. Cardiac causes were excluded in all instances before referral. Anti-reflux surgery in the past, chest pain was not the dominant symptom, pH manometry data incomplete 98 (female 75) 51.8 (1.1) 7.4 ± 4.1 years
Lacima et al. 2003 [38] Cross-sectional, funding NR Referred by a cardiologist after negative cardiac evaluation. Barcelona, Spain. Normal ECG, cardiac enzymes, treadmill exercise testing, coronary angiography and epicardial coronary arteries or with <25% narrowing, no ECG changes after intravenous ergonovine injection Previous anti-reflux regimen, calcium channel blockers, beta blockers and/or nitrates were withdrawn at least 7 days before the study 120 (female 62), patients 90, volunteers 30 57 (27 to 82) NR
Studies investigating the value of provocation tests for the diagnosis of GERD-related NCCP
Cooke et al., 1994 [39] Cross-sectional, funding NR Patients in whom coronary angiography was performed for the diagnosis of new chest pain. Secondary care, London, UK. New chest pain and normal coronary anatomy with exertional pain as principal complaint Mitral valve prolapse, left ventricular hypertrophy, previous myocardial infarction, abnormalities of resting wall motion on echocardiography, pain at rest only, unable to exercise. Previous anti-reflux regimen, previous gastroenterologist assessment. 66 (female 34), non-cardiovascular disease (CVD) 50, CVD 16 (controls) 53 (non-CVD), CVD 58, range 32 to 72 3.4 years
Bovero et al., 1993 [40] Cross-sectional, funding NR Patients investigated for chest pain. Secondary care, Genova, Italy. Chest pain, no coronaroactive drugs for ≥5 days. No anti-reflux regimen ≥3 days. Chest pain of organic and/or functional cardiologic origin (evaluated by: ECG, two ergometry tests, dynamic ECG, thallium myocardial scintigraphy under physical stress or echodypiridamole test, ergonovine or methyl-ergometrine test, angiography) 67 (female 43), pain at rest 46, exertional pain 21 53 (range 34 to 76) NR
Romand et al., 1999 [41] Cross-sectional, funding NR Referred after negative cardiac evaluation. Secondary care, Lyon, France. Normal coronary anatomy, normal ECG, negative treadmill exercise Cardiologic origin of symptoms, history of upper gastrointestinal surgery, duodenal or gastric ulcer, peptic stricture or stricture by a tumor 43 (female 19) 56 (range 31 to 78) n = 25 <1 year; n = 7 1 to 5 years; n = 11 >5 years
Abrahao et al., 2005 [42] Cross-sectional, funding NR Referred by a cardiologist after negative cardiac evaluation. Tertiary care, Rio de Janeiro, Brazil. ≥1 episode of NCCP/week, normal coronary angiogram or with <30% narrowing Chronic obstructive lung disease, asthma, cardiac arrhythmia, cardiomyopathy, valvular heart disease 40 (female 32) 54.7 (8.4) Mean 24 months (range 1 to 360 months)
Ho et al., 1998 [29] Cross-sectional, research grant from the National University of Singapore Referred for NCCP to the gastroenterology service, Singapore Recurrent chest pain of ≥3 months; cardiologists evaluation normal and symptoms not cardiac (non-obstructed coronary arteries (<50% luminal narrowing), dobutamine stress echocardiography, exercise ECG) No history of proven esophageal disorder or esophageal surgery 80 (female 38) 48 (range 21 to 75) ≥3 months
Eosinophilic esophagitis-related NCCP
Achem et al., 2011 [43] Retrospective data analysis, funding NR Referred for endoscopic evaluation of NCCP, who had esophageal biopsies for suspected eosinophilic esophagitis. Secondary care, Florida, USA. Chest pain suspected of being esophageal origin after negative cardiac evaluation (either by non-invasive stress testing or coronary angiography) Dysphagia (if this was the main reason for endoscopy). Anticoagulant use. 171 (female 104), 24 (female 7) eosinophilia, 147 (female 97) normal histology 59 (24 to 86) normal histology, 55 (21 to 81) eosinophilia NR
Musculoskeletal NCCP
Stochkendahl et al., 2012 [44] Cross-sectional, Foundation Chiropractic Research and Postgraduate Education, Government Patients discharged form an emergency cardiology department. Tertiary care, Odense, Denmark. Acute (<7 days) chest pain primary complaint. Pain in the thorax and/or neck. Understand Danish. Age 18 to 75 years, resident of the Funen County. Cardiovascular disease, previous percutaneous coronary intervention or coronary artery bypass graft: other definite cause, inflammatory joint disease, insulin dependent diabetes, fibromyalgia, malignant disease, apoplexy, dementia or unable to cooperate, major osseous anomaly, osteoporosis, pregnancy 302 (female 132) 52.5 (11.0) Acute episode, <7 days before admission
Bosner et al. 2010 [45] Cross-sectional with 6 months follow-up, federal Ministry of Education and Research grant Consecutive recruitment of all patients presenting to chest pain in a GP clinic. An independent interdisciplinary reference panel decided about the etiology of chest pain. Age >35 years, pain (acute or chronic) localized between clavicles and lower costal margins and anterior to the posterior axillary lines Patients whose chest pain had been investigated already and/or who came for follow-up for previously diagnosed chest pain were excluded 1,212 (female 678), chest wall symptom (CWS) 565 (female 330) All 59 (35 to 93), CWS 58 (35 to 90) Acute pain 28.4%
Manchikanti et al., 2002 [46] Cross-sectional, no funding Chronic thoracic pain, managed by one physician and undergoing diagnostic medial branch blocks. Private pain practice, USA. Pain for ≥6 months. Failure of conservative management with physical therapy, chiropractic management and drug therapy. Age 18 to 90 years. No radicular pattern of pain, no disc herniation on MRI 46 (female 31) 46 (2.2) ≥6 months, mean 86 (SD 17.2) months
NCCP related to psychiatric diseases
Kuijpers et al., 2003 [47] Cross-sectional, funding NR Discharged from the hospitals first-heart-aid service with a diagnosis of NCCP received an envelope Chest pain or palpitation presenting to first-heart-aid service, received no cardiac explanation Dementia, live ≥50 km from the hospital. Do not speak Dutch. 344 (female 151), Hospital Anxiety Depression Scale (HADS) ≥8: 266 (female 123); HADS <8: 78 (female 28) HADS ≥8: 55.81 (13.03); HADS <8: 60.55 (10.84) NR
Demiryoguran et al., 2006 [48] Cross-sectional, funding NR Patients admitted to the ER and discharged with a diagnosis of NCCP. Ismir, Turkey. Cardiac chest pain ruled out. Normal ECGs and low or stable levels of cardiac markers. Unstable vital signs, uncooperative and disoriented patients. Established diagnoses. Documented coronary artery disease, history of trauma to chest wall, back or abdomen within the previous week. 157 (female 89), HADS <10: 108 (female 55), HADS >10: 49 (female 34) 41.6 (11.7) NR
Foldes-Busque et al., 2011 [49] Cross-sectional, Groupe interuniversitaire de recherche sur les urgences (GIRU) and Fonds de Recherche en Santé du Québec Emergency department (ED), Monday to Friday between 8 AM and 4 PM. Tertiary care, Quebec, Canada. Low-risk unexplained chest pain, ≥18 years old. English or French speaking, normal serial ECG, normal cardiac enzymes. Explained chest pain (for example, ischemic, cause identifiable by radiography). Medical condition that could invalidate the interview (for example, psychosis, intoxication, or cognitive deficit), any unstable condition, or any trauma. 507 (NR), derivation sample 201 (female 101); validation sample 306 (female 173) Derivation condition 54.2 (13.9), validation condition 53.3 (14.4) NR
Fleet et al. 1997 [50] Cross-sectional, Fonds de Recherché en Santé Québec Consecutive patients presenting to ambulatory walk in ED, patients with or without IHD, Québec, Canada Complaint of chest pain, understand French, able to complete evaluation in the ED Cognitive impairment, psychotic state Derivation sample 180 (female 63), validation sample 212 Development 57.6 (12.6), validation 56 (12.2) NR
Katerndahl et al., 1997 [51] Cross-sectional, public health and service Establishment of Departments of Family Practice Presented to the GP with a chief compliant of new-onset chest pain. Primary care, Texas, USA. Adults 18 years and older, new-onset chest pain, only one complaint (chest pain) as well as those with several symptoms that included chest pain Previous investigation for chest pain at the practice 51 (NR) 42.6 (14.6) New onset

NR not reported.

Wertli et al.

Wertli et al. BMC Medicine 2013 11:239   doi:10.1186/1741-7015-11-239

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