Non-cardiovascular chest pain (NCCP) has a high healthcare cost, but insufficient guidelines exist for its diagnostic investigation. The objective of the present work was to identify important diagnostic indicators and their accuracy for specific and non-specific conditions underlying NCCP.
Methods
A systematic review and meta-analysis were performed. In May 2012, six databases were searched. Hand and bibliography searches were also conducted. Studies evaluating a diagnostic test against a reference test in patients with NCCP were included. Exclusion criteria were having <30 patients per group, and evaluating diagnostic tests for acute cardiovascular disease. Diagnostic accuracy is given in likelihood ratios (LR): very good (LR+ >10, LR- <0.1); good (LR + 5 to 10, LR- 0.1 to 0.2); fair (LR + 2 to 5, LR- 0.2 to 0.5); or poor (LR + 1 to 2, LR- 0.5 to 1). Joined meta-analysis of the diagnostic test sensitivity and specificity was performed by applying a hierarchical Bayesian model.
Results
Out of 6,316 records, 260 were reviewed in full text, and 28 were included: 20 investigating gastroesophageal reflux disorders (GERD), 3 musculoskeletal chest pain, and 5 psychiatric conditions. Study quality was good in 15 studies and moderate in 13. GERD diagnosis was more likely with typical GERD symptoms (LR + 2.70 and 2.75, LR- 0.42 and 0.78) than atypical GERD symptoms (LR + 0.49, LR- 2.71). GERD was also more likely with a positive response to a proton pump inhibitor (PPI) test (LR + 5.48, 7.13, and 8.56; LR- 0.24, 0.25, and 0.28); the posterior mean sensitivity and specificity of six studies were 0.89 (95% credible interval, 0.28 to 1) and 0.88 (95% credible interval, 0.26 to 1), respectively. Panic and anxiety screening scores can identify individuals requiring further testing for anxiety or panic disorders. Clinical findings in musculoskeletal pain either had a fair to moderate LR + and a poor LR- or vice versa.
Conclusions
In patients with NCCP, thorough clinical evaluation of the patient’s history, symptoms, and clinical findings can indicate the most appropriate diagnostic tests. Treatment response to high-dose PPI treatment provides important information regarding GERD, and should be considered early. Panic and anxiety disorders are often undiagnosed and should be considered in the differential diagnosis of chest pain.
The online version of this article (doi:10.1186/1741-7015-11-239) contains supplementary material, which is available to authorized users.
Competing interests
The authors declare that they have no competing interests. This study was not funded.
Authors’ contributions
MW and KR carried out data extraction, participated in the analysis and drafted the manuscript. UH participated in the design of the study and performed the statistical analysis. JS conceived the study, and participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.
Background
In the USA, 6 million patients present to emergency departments with chest pain each year, at an annual cost of $8 billion [1, 2]. In emergency departments, roughly 60% to 90% of the patients presenting with chest pain have no underlying cardiovascular disease [3‐6]. The proportion of patients with cardiovascular disease may be higher in specialized units (cardiology emergency departments, cardiac care units (CCUs), intensive care units (ICUs)) [7] and lower in the primary care setting [6, 8‐10]. Physicians generally assume that patients with non-cardiovascular chest pain (NCCP) have an excellent prognosis after ruling out serious diseases. However, patients with NCCP have a high disease burden; most patients that seek care for NCCP complain of persisting symptoms on 4-year follow-up [11]. Furthermore, compared to patients with cardiac pain, patients with non-cardiac chest pain have a similarly impaired quality of life and similar numbers of doctor visits [12].
In patients with chest pain, the diagnostic investigation focuses primarily on cardiovascular disease diagnosis and is often performed by cardiologists. Upon ruling out cardiovascular disease, only vague recommendations exist for further diagnostic investigation, often delaying diagnosis and appropriate treatment and causing uncertainty for patients [13]. Limited data are available regarding efficient diagnostic investigations for patients with NCCP. Most studies investigate gastrointestinal diseases, and extensive provocation testing has been proposed [14]. Some report that almost half of the patients with NCCP will have gastrointestinal disorders [12], while others attribute more than a third of cases to psychiatric disorders, as diagnosed by the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSMIV). Referred pain from the spine and the chest wall are also likely substantial contributors to NCCP. Information is scarce regarding the appropriate diagnostic tests, and their sensitivity and specificity to discriminate different non-cardiac diseases.
Anzeige
The present systematic review aimed to identify relevant diagnostic tests for patients with NCCP, and to summarize their positive and negative likelihood ratios for underlying disease identification.
Methods
Literature search and study selection
This review, conducted in May 2012, followed the QUADAS quality assessment checklist for diagnostic accuracy studies [15]. We searched six databases (PubMed/Medline, Biosis/Biological Abstracts (Web of Knowledge), Embase (OvidSP), INSPEC (Web of Knowledge), PsycInfo (OvidSP), and Web of Science (Web of Knowledge)) using the following search terms as medical subject headings (MeSH) and other subject headings: thoracic pain, chest pain, non-cardiac chest pain, atypical chest pain, musculoskeletal chest pain, esophageal chest, and thoracic spine pain. The findings were limited to studies investigating ‘diagnosis’, ‘sensitivity and specificity’, ‘sensitivity specificity’, or chest pain/diagnosis. We applied no limits for study setting or language; however, one potentially eligible Russian language article was excluded due to lack of language proficiency [16]. Appendix 1 depicts three detailed search strategies.
To ensure search completeness, one reviewer (MW) conducted a hand search of the last 5 years in the four journals that published most articles about patients with NCCP (Gastroenterology, Chest, Journal of the American College of Cardiology and American Journal of Cardiology). Potentially eligible references not retrieved by the systematic search in the six databases were added. Bibliographies of included studies were also searched, and potential eligible references included in the full text review.
Eligibility criteria
Eligible studies included non-screening studies on diagnostic accuracy published between 1992 and May 2012. Inclusion criteria were studies reporting on patients of 18 years and older, seeking care for NCCP. NCCP was defined as chest pain and cardiac or other vascular disease was ruled out (that is, cardiovascular disease, aortic dissection, pulmonary embolism). Exclusion criteria included studies with <30 patients per group due to concerns about sample size [17]. This group size was arbitrarily chosen to exclude studies with the highest risk of bias, while allowing a comprehensive literature overview. Based on the nomogram proposed by Carley et al. a sample size of more than >150 patients are needed to accurately assess a diagnostic test [18]; however, with this sample size cut-off, very few studies (mainly retrospective data analyses) would have been eligible.
Anzeige
Study selection, data extraction, and synthesis
Two reviewers (MW and KR) independently screened 6,380 references by title and abstract. Both reviewers independently reviewed the full text of 260 studies meeting the eligibility criteria. Disagreements were discussed and resolved by consensus or third party arbitration (JS). Researchers with specific language proficiencies reviewed non-English language references. When the same study was included in several publications without change in diagnostic measure, the most recent publication was chosen and missing information was added from previous publications.
All information regarding the diagnostic test, reference test, and considered differential diagnosis was extracted and grouped according to the disease investigated. The methods used to assess accuracy, sensitivity, and specificity were also extracted.
Quality assessment
Study quality was assessed using the Scottish Intercollegiate Guidelines Network (SIGN) methodology checklist for diagnostic studies [19]. Overall bias risk and study quality was rated according to the SIGN recommendations. The ratings included high quality (++; most criteria fulfilled and if not fulfilled, the study conclusions are very unlikely to be altered), moderate quality (+; some criteria fulfilled and if not fulfilled, the study conclusions are unlikely to be altered), low quality (−; few or no criteria fulfilled, conclusions likely to be altered). Studies rated as low quality by both reviewers were excluded from further analysis.
Reference standards and test evaluation
Information about method validity, reliability, practicability and value for clinical practice of the reference and the standard test was extracted and critically assessed. When several reference standards were used, all measurements were extracted and used for further analysis.
Statistical analysis
Descriptive statistics were used to summarize findings across all diagnostic studies. Sensitivity, specificity, positive and negative predictive values (PPV and NPV, respectively), and positive and negative likelihood ratios (LR + and LR-, respectively) were calculated based on a 2 × 2 table (true/false positives, true/false negatives). Pretest probabilities (prevalence) and the positive and negative post-test probability of the disease were calculated. If one field contained the value 0, 0.5 was added to each field to enable value calculation. Test diagnostic accuracy was assessed as follows [20]: very good (LR+ >10, LR- <0.1); good (LR + 5 to 10, LR- 0.1 to 0.2); fair (LR + 2 to 5, LR- 0.2 to 0.5); or poor (LR + 1 to 2, LR- 0.5 to 1).
When more than four unbiased studies were available in clinically similar populations and with comparable index and reference tests, we performed joined meta-analysis of the diagnostic test sensitivity and specificity. We used a hierarchical Bayesian model, as proposed by Rutter and Gatsonis [21], which accounts for the within-study and between-study variability and the potentially imperfect nature of the reference test. The hierarchical Bayesian model was set up as follows: we assumed J diagnostic studies in the meta-analysis, with crosstabulation between index test (T1) and reference test (T2) available for each study, and both tests assumed to be dichotomous (1 = positive test result, 0 = negative test result). Each study was assumed to use a different cut-off value (θj) to define a positive test result. The diagnostic accuracy of each study was denoted by αj. The model structure implied a within-study level for study-specific parameters (θj and αj), and a between-study level for parameters common among all studies. The model could theoretically be extended to include study-specific covariates such as percentage of female patients or mean age to reduce heterogeneity on study level.
Appendix 2 gives details of the model set up and prior distributions. The results of the Bayesian analysis are samples from the posterior distribution of the parameters, and estimates are presented as posterior means (50% quantile), and lower (2.5% quantile) and upper (97.5% quantile) bounds, resulting in a 95% credible region. Analyses were performed using R statistical software and the ‘HSROC’ package [22, 23].
Ethics statement
For this study no ethical approval was required. No protocol was published or registered. All methods were determined a priori.
Anzeige
Results
Study selection
Figure 1 summarizes the search and inclusion process. Out of 6380 records, 260 were reviewed in full text, resulting in exclusion of 232 studies. In total, the analysis included 28 studies. The reasons for exclusion of the 232 studies are given in Figure 1 and overview of excluded studies reviewed in full text is give in Appendix 3.
Figure 1
Study flow.
×
Study characteristics
Table 1 presents the study characteristics, and included patients. In all, 20 studies (71%) evaluated diagnostic tests to identify gastrointestinal disease, mainly gastroesophageal reflux disorders (GERD), underlying NCCP. Musculoskeletal chest pain was investigated in three studies (11%), and psychiatric conditions in five studies (18%). Study quality was good in 15 studies (54%) and moderate in 13 (46%; Appendix 4). No study had to be excluded because of poor study quality.
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
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
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.
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
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
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
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
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
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
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
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
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
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.
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.
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.
Accuracy of symptoms for the diagnosis of GERD
Table 2 summarizes the diagnostic accuracy of the diagnostic tests relevant for clinical practice. A comprehensive overview of all evaluated diagnostic tests is provided in Appendix 5. For diagnosis of GERD, the most common reference tests (endoscopy and/or 24-h pH-metry) are reported.
Table 2
Summary of diagnostic accuracy of tests used in non-cardiac chest pain
≥3 of 5 palpation findings: (1) sitting motion of end-play restriction in lateral flexion and rotation segment C4 to C7 and Th1 to Th8. (2) Prone motion joint-play restriction segment Th1 to Th8. (3) Prone evaluation paraspinal tenderness segment Th1 to Th8. (4) Supine manual palpation muscular tenderness of 14 points anterior chest wall. 5) Supine evaluation of tenderness of the costosternal junctions of costa 2 to 6 and xiphoid process
Diagnosis using a standardized examination protocol:
37
1.52
0.03
(1) A semistructured interview: pain characteristics, lung and gastrointestinal symptoms, past medical history, height, weight, cardiovascular risk factors
(2) A general health examination: blood pressure, pulse, heart and lung stethoscopy, abdominal palpation, neck auscultation, signs of left ventricular failure, neurological examination
(3) Manual examination of the muscles and joints (neck, thoracic spine and thorax): active range of motion, manual palpation 14 points muscular tenderness of the anterior chest wall and segmental paraspinal muscles, motion palpation for joint-play restriction of the thoracic spine (Th1 to 8), and end play restriction of the cervical and thoracic spine
The Panic Screening Score (derivation population); does the patient have a history of anxiety disorders? Please indicate how often this thought occurs when you are nervous: ‘I will choke to death’. Did the patient arrive in the ED by ambulance? Please answer the statement by circling the number that best applies to you: ‘When I notice my heart beating rapidly, I worry that I might be having a heart attack’. Sum score 22, A total score ≥6 indicates probable panic.
Panic disorder Diagnosis (structured Anxiety Disorders Interview Schedule for Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) (ADIS-IV))
Panic disorder (structured clinical interview of Diagnostic and Statistical Manual of Mental Disorders, based on DSM-III-R)
55
0.82
1.02
LR+: >10; LR-: <0.1; good: LR + 5 to 10, LR- 0.1 to 0.2; fair: LR + 2 to 5, LR- 0.2 to 0.5; poor: LR + 1 to 2, LR- 0.5 to 1.
aBiomechanical dysfunction defined as chest pain presumably caused by mechanical joint and muscle dysfunction related to C4 to Th8 somatic structures of the spine and chest wall established by means of joint-play and/or end-play palpation.
Reference tests are as follows. Endoscopic classification: LA classification: grade A, ≥1 mucosal break ≤5 mm, that does not extend between the tops of two mucosal folds; grade B, ≥1 mucosal break >5 mm long that does not extend between the tops of two mucosal folds; grade C, ≥1 mucosal break that is continuous between the tops of two or more mucosal folds but which involves <75% of the circumference; grade D, ≥1 mucosal break which involves at least 75% of the esophageal circumference [52]. Savary-Miller system: grade I, single or isolated erosive lesion(s) affecting only one longitudinal fold; grade II multiple erosive lesions, non-circumferential, affecting more than one longitudinal fold, with or without confluence; grade III, circumferential erosive lesions; grade IV, chronic lesions: ulcer(s), stricture(s) and/or short esophagus. Alone or associated with lesions of grades 1 to 3; grade V, columnar epithelium in continuity with the Z line, non-circular, star-shaped, or circumferential. Alone or associated with lesions of grades 1 to 4 [53]. Hentzel-Dent grades: grade 0, no mucosal abnormalities; grade 1, no macroscopic lesions but erythema, hyperemia, or mucosal friability; grade 2, superficial erosions involving <10% of mucosal surface of the last 5 cm of esophageal squamous mucosa; grade 3, superficial erosions or ulceration involving 10% to 50% of the mucosal surface of the last 5 cm of esophageal squamous mucosa; grade 4, deep peptide ulceration anywhere in the esophagus or confluent erosion of >50% of the mucosal surface of the last 5 cm of esophageal squamous mucosa [54]. pH-metry: De Meester criteria: (1) total number of reflux episodes; (2) number of reflux episodes with pH <4 for more than 5 minutes; (3) duration of the longest episode; (4) percentage total time pH <4; (5) percentage upright time pH <4; and (6) percentage recumbent time pH <4. [55]. Manometry: Spechler criteria is diagnosis of ineffective esophageal motility, nutcracker esophagus, spasm, achalasia based on basal lower esophageal sphincter pressure, relaxation, wave progression, distal wave amplitude [56].
24-h pH-metry 24-h pH monitoring, GERD gastroesophageal reflux disease, GP general practitioner, IHD ischemic heart disease, QA questionnaire, Sensory McGill McGill Pain Questionnaire sensory subscale, SIS symptom index score calculated by adding the reported daily severity (mild = 1; moderate = 2; severe = 3; and disabling = 4) multiplied by the reported daily frequency values during each week).
Patients with the main complaint of NCCP were less likely to have GERD (LR + 0.83, 0.43; LR- 1.13, 1.23) compared to patients with the main complaint of dysphagia (LR + 1.27, 1.16; LR- 0.97, 0.97) or GERD typical symptoms without chest pain (LR + 1.26, 1.53; LR- 0.93, 0.74) in two studies [25, 26]. Two further studies compared the accuracy of NCCP and typical GERD symptoms (LR + 2.70 [27], 2.75 [24]; LR- 0.42 [24], 0.78 [27]) with NCCP without GERD symptoms (LR + 0.49; LR- 2.71 [24]) or with NCCP and a history of heart burn (LR + 2.15; LR- 0.74 [27]).
Anzeige
Accuracy of response to proton pump inhibitor (PPI) treatment for diagnosis of GERD in NCCP
The effect of treatment with PPI was measured by using a symptom intensity score (SIS) at baseline and follow-up. The SIS was calculated by adding the reported daily severity (mild = 1; moderate = 2; severe = 3; and disabling = 4) multiplied by the reported daily frequency values obtained during each week of symptom recording.
Table 2 summarizes the results. Three studies compared the treatment response after high doses of PPI (rabeprazole [31], lansoprazole [32], omeprazole [33]) for 1 week to placebo. A reduction of the SIS score of ≥50% was associated with a good LR + and a fair LR- (LR + 5.48 [33], 7.13 [31], 8.56 [32]; LR- 0.24 [32], 0.25 [33], 0.28 [31]) for the presence or absence of GERD. The likelihood ratios in the placebo groups with a reduction of the SIS score of ≥50% were: LR + 0.89 [31], 0.61 [32], 3.04 [33]; LR- 1.03 [31], 1.22 [32], 0.84 [33]. A reduction of the SIS score of ≥65% resulted in a very good LR + (18.33), and a good LR- (0.17) [32]. A treatment duration of 4 weeks (lasoprazole) resulted in a better LR- (LR + 2.75; LR- 0.13) [36] when compared to 2 weeks (omeprazole [34], LR + 2.7; LR- 0.15).
For joint meta-analysis only studies were considered with similar study design. Therefore, the active treatment arms of six studies were available for further analysis [31‐36]. The model could be extended to include study-specific covariates such as the percentage of female patients or mean age to reduce unexplained heterogeneity on study level. However, due to the small number of studies available for pooling we refrained from including covariates. Figure 2 shows the summary receiver operating characteristic (ROC) curve. Considering the GERD prevalence and the fact that no perfect reference test is available for GERD (sensitivity of the 24-h pH-metry in endoscopy-negative patients <71% [57]), the posterior mean sensitivity of what was 0.89 (95% credible interval, 0.28 to 1). The posterior mean of the specificity was 0.88 (95% credible interval, 0.26 to 1), respectively.
Using a treadmill test during the 24-h pH-metry (reference test) showed highest LR + for GERD when chest pain was provoked by exercise (LR + 14.4; LR- 0.79 [39]). In all patients who underwent treadmill test, a high number of false negative test results during the treadmill test were observed.
Anzeige
For joint meta-analysis only studies were considered with similar study design, again. Five patient groups from four original studies were included in the analysis [38‐41]. Figure 3 shows the summary ROC curve. Considering the prevalence and imperfect nature of the reference test, posterior mean sensitivity and specificity were 0.53 (95% credible interval, 0.02 to 1) and 0.93 (95% credible interval, 0.25 to 1), respectively. For all provocation tests (Tensilon test, Bernstein test, or balloon distension test) high numbers of false negative results were found [29, 42].
Figure 3
Summary receiver operating characteristic (ROC) for treadmill test during 24 h pH-metry.
×
Accuracy of patient characteristics for eosinophilic esophagitis diagnosis
Eosinophilic esophagitis is a rare but important differential diagnosis for NCCP. In a retrospective analysis the likelihood for histologically proven eosinophilic esophagitis (reference test) was fair when current GERD symptoms were present (LR + 2.36, LR- 0.71 (poor)). Male gender or the presence of typical endoscopic findings for eosinophilic esophagitis were associated with a poor LR + (1.78) but a very good LR- (0.09) No information was available about eosinophilia that responds to PPI treatment compared to eosinophilic esophagitis.
Accuracy of clinical signs for musculoskeletal chest pain diagnosis
In one study in a cardiology emergency department specific clinical signs or symptoms compared to a standardized examination protocol showed either fair LR + and poor LR- (for example, pain worse with movement of the torso, pain relief on pain medication, no sudden pain start, age ≤49 years) or a poor LR + and a very good LR- (for example, anterior chest wall tenderness, biomechanical dysfunction) [44]. A score of 3 or more points in a sum score (1 point for each of five palpation findings: restriction in C4 to 7/Th1 to Th8 when sitting; prone restriction Th1 to 8; paraspinal tenderness; anterior chest wall tenderness; costosternal junction tenderness) showed an LR + of 1.52 and very good LR- of 0.03. A score of 1 or more points in a sum score for the diagnosis of a chest wall syndrome (CWS) in the GP setting (1 point for each positive finding: localized muscle tension; stinging pain; pain reproducible by palpation; absence of cough) showed a LR + of 1.82 and LR- of 0.20 [45]. A score of 2 or more points in the sum score showed a LR + of 3.02 and LR- of 0.47.
Accuracy of patient characteristics for psychiatric disease diagnosis
For the diagnosis of an anxiety disorder the anxiety subscale of the Hospital Anxiety and Depression Score (HADS-A, cut-off ≥8) compared to a neuropsychiatric interview (reference test) showed a very good LR- (0.03) and a fair LR + (2.03). In further studies the HADS-A was used as reference test for the diagnosis of anxiety disorder. Specific symptoms showed a fair LR + and a poor LR-: fear of dying (LR + 4.04; LR- 0.82); light-headedness, dizziness, or faintness (LR + 3.03; LR- 0.84); diaphoresis (LR + 3.49; LR- 0.69); and chills or hot flushes (LR + 4.85; LR- 0.81).
For panic disorders a four-item panic screening score validated in patients presenting to an ER showed fair LR + (3.44 and 3.89) and poor-to-fair LR- (0.44 and 0.55) [49]. A combination of different questionnaires and pain patterns (Agoraphobia Cognitions Questionnaire; Mobility Inventory for Agoraphobia; McGill Pain Questionnaire sensory) showed a fair LR + (2.6) and fair LR- (0.46) [50]. In patients presenting to their primary care physician with NCCP the presence of a panic disorder was rarely diagnosed. Clinician consultations in this setting had poor accuracy for panic disorder diagnosis (LR + 0.8; LR- 1.02) [51].
Discussion
Main findings
The included studies showed that most studies investigated tests for gastroesophageal reflux disease (GERD) as the underlying disease in non-cardiovascular chest pain (NCCP). Few studies investigated diagnostic tests for other illnesses. The diagnostic value of a PPI treatment test was confirmed, with a ≥50% symptom reduction under PPI treatment showing posterior sensitivity and specificity of almost 90%. Together with the favorable adverse effect profile of PPIs, a high dose (double reference dose, twice daily) can quickly provide important diagnostic information in patients with unexplained chest pain. History or presence of typical GERD-associated symptoms increases the likelihood of GERD.
Only limited evidence was available for other prevalent illnesses manifesting with chest pain. Screening tools for panic and anxiety disorders are valuable for identifying patients requiring further diagnostic evaluation. The likelihood for musculoskeletal chest pain increased when the pain was reproducible or relieved by pain medication. Among studies investigating musculoskeletal disease, the major limitation was the lack of a reference test (‘gold standard’).
Results in light of existing literature
To the best of our knowledge, this is the first systematic review summarizing the current evidence on the accuracy of diagnostic tests in patients with NCCP. Several non-systematic reviews have suggested various diagnostic and therapeutic approaches [14, 58‐61], often with algorithms focused on gastrointestinal diseases [14, 58, 59], sometimes recommending extensive testing, such as provocation tests. Here, we found no additional value of provocation testing for diagnosing underlying gastroesophageal conditions, as provocation tests failed to identify many patients that would have reflux during a 24-h pH measurement period. While meta-analyses of PPI treatment studies compared to placebo have been previously conducted [62, 63], compared to this analyses we excluded studies of poor quality and small sample sizes [64‐67]. Our study is the first to assess study quality and to use a hierarchical Bayesian approach that accounts for within-study and between-study variability and the imperfect nature of the reference test.
Cremonini et al. [62] previously used a bivariate model, and found a lower pooled sensitivity and specificity (sensitivity 80% vs 89%, specificity 74% vs 88%) of a positive PPI treatment response for the diagnosis of GERD. Harbord et al. [68] showed that the likelihood functions of the two model formulations are algebraically identical in the absence of covariates. However, for assessing a summary ROC curve, the hierarchical Bayesian model is more natural than the model for pooled sensitivity and specificity [69]. Without a broadly accepted standard reference test, it is important to adjust for conditional dependence between multiple tests (index test and reference test) carried out in the same subjects [69]. The hierarchical Bayesian model can be adapted to this situation by introducing covariance terms between the sensitivities and specificities of the index and reference tests. A previous simulation study [69] demonstrated that if a model does not address an imperfect reference test, bias will be around 0.15 in overall sensitivity and specificity [69]. No systematic review has examined diagnostic studies of musculoskeletal chest pain or chest pain as part of a psychiatric disease.
Strengths and limitations
This review comprehensively evaluates the currently available studies. The search was inclusive, no language restrictions were applied, and a thorough bibliographic search was conducted to identify all relevant studies. The extraction process was performed in accordance with current guidelines and supported by an experienced statistician. Potential factors influencing diagnostic test accuracy were identified by a multidisciplinary team (an internist, general practitioner, statistician, and methodologist).
The study was limited by the small number of studies available for most diseases presenting with NCCP. Furthermore, many studies were only of moderate quality and most cross-sectional or prospective studies did not meet the required sample size criterion for reliable estimates of sensitivity and specificity. Small studies on diagnostic accuracy are often imprecise, with wide confidence intervals, making it difficult to assess test informativeness [17]. The lack of a gold standard reference test is another limitation, which we addressed within the Bayesian model formulation; however, the resulting posterior credible intervals for overall sensitivity and specificity of the index test are wider than they would be with a perfect reference test. Further, NCCP is a collective term with potentially different underlying diseases and therefore might present differently. Diagnostic accuracy in one population with high prevalence for one disease is high might be entirely different for another population [70]. Therefore, for most studies no joint meta-analysis could be conducted and results have to be interpreted on a single study level within the context of the study population. We have tried to balance this by providing a thorough description of the studies’ inclusion and exclusion criteria and the study setting. This will allow readers to judge to whom study results apply. In studies included in the joint meta-analyses, we intended to include study-specific covariates such as the percentage of female or mean age into the Bayesian model. The inclusion of covariates can reduce unexplained heterogeneity. However, this was due to the small number of studies available for meta-analysis not feasible.
Research implications
Further research should investigate the combined value of symptoms, clinical findings, and diagnostic tests, including multidisciplinary research aimed at increasing our knowledge about diagnostic processes and making recommendations for diagnostic tests and treatments in patients with NCCP. Most patients with chest pain consult primary care physicians [45], but few studies are performed in this setting. Further research is needed to strengthen the evidence in a primary care setting. The value of screening questionnaires for panic and anxiety disorders should be further evaluated and investigated in clinical practice. The use of a flag system [61], as successfully applied in back and neck pain, could facilitate the diagnostic process allowing systematic assessment of first red flags (acute disease requiring immediate diagnosis and care), then green flags (identifiable diseases), and yellow flags (psychological diseases).
Implication for practice
Patients with NCCP incur high healthcare costs due to the extensive and often invasive diagnostic testing, and NCCP’s impact on quality of life. Early identification of underlying diseases is essential to avoid delayed treatment and chronicity of complaints. Symptoms and clinical findings may provide important information to guide treatment of an underlying illness. In patients with typical GERD symptoms, twice-daily high-dose PPI treatment is the most efficient diagnostic approach. GERD is very likely if a positive treatment response occurs after 1 week, while GERD is unlikely if there is no response after 4 weeks of PPI treatment. In patients not responding to PPI, if an endoscopy shows no pathological findings, other illnesses should be considered before initiating further gastrointestinal testing.
Panic and anxiety disorders are often missed in clinical practice [51]. Symptoms such as expressing ‘fear of dying’, ‘light headedness, dizziness, faintness’, ‘diaphoresis’ and ‘chills or hot flushes’ are associated with anxiety disorders. Screening tests are valuable to rule out panic or anxiety disorders, and positive finding should lead to further investigation.
Conclusions
In patients with NCCP, timely diagnostic evaluation and treatment of the underlying disease is important. A thorough history of symptoms and clinical examination findings can inform clinicians which diagnostic tests are most appropriate. Response to high-dose PPI treatment can indicate whether GERD is the underlying disease and should be considered as an early test. Panic and anxiety disorders are often not diagnosed and should be considered in the differential diagnosis of chest pain.
Appendix 1: Search Strategy May Week 4 2012
In Tables 3 and 4 the detailed search strategy of PubMed, Web of Knowledge (INSPEC, Biosis/Biological Abstracts, Web of Science) and OvidSP (Embase, PsycInfo) are given.
Table 3
Search Strategy May Week 4 2012 (PubMed)
No.
Search
Hits
1
Search thoracic pain OR chest pain OR noncardiac chest pain OR non cardiac chest pain OR atypical chest pain OR musculoskeletal chest pain OR esophageal chest pain OR thoracic spine pain OR chest wall
96,313
2
Search coronary artery disease OR cardiac disease OR coronary heart disease OR coronary thrombosis OR coronary occlusion
929,959
3
Search 1 NOT 2
38,735
4
Search sensitivity OR specificity OR diagnostic tests OR chest pain/diagnosis
1,301,595
5
Search 3 AND 4
2,736
6
Search 5 NOT 2; Filters: publication date from 1992/01/01; humans
2,177
7
Search 5 NOT 2; Filters: publication date from 1992/01/01; humans; adult: 19+ years
1,432
Biological Abstracts/BIOSIS, INSPEC and Web of Science (Web of Knowledge)
Topic = (‘thoracic pain’ OR ‘chest pain’ OR ‘noncardiac chest pain’ OR ‘non cardiac chest pain’ OR ‘atypical chest pain’ OR ‘musculoskeletal chest pain’ OR ‘esophageal chest pain’ OR ‘thoracic spine pain’ OR ‘chest wall’) AND Topic = (sensitivity OR specificity OR diagnostic tests) NOT Topic = (coronary artery disease OR cardiac disease OR coronary heart disease OR coronary thrombosis OR coronary occlusion)
Refined by: Topic = (human*)
Timespan = 1992 to 2012.
Table 4
Database: PsycINFO <1806 to May Week 4 2012>, Embase <1974 to 2012 Week 21> (OvidSP)
No.
Search
Hits
1
(thoracic pain or chest pain or noncardiac chest pain or non cardiac chest pain or atypical chest pain or musculoskeletal chest pain or esophageal chest pain or thoracic spine pain or chest wall).mp. [mp = ti, ab, hw, tc, id, ot, tm, sh, tn, dm, mf, dv, kw]
44,196
2
exp thorax pain/di [Diagnosis]
2,481
3
exp thorax pain/
36,580
4
1 or 3
63,756
5
Coronary artery disease or cardiac disease or coronary heart disease or coronary thrombosis or coronary occlusion).mp. [mp = ti, ab, hw, tc, id, ot, tm, sh, tn, dm, mf, dv, kw]
Limit 11 to ‘300 adulthood < age 18 years and older > ‘ [Limit not valid in Embase; records were retained]
3,769
13
Limit 12 to adulthood <18+ years > [Limit not valid in Embase; records were retained]
3,769
Appendix 2: Set up of the hierarchical Bayesian models for the summary receiver operating characteristic (ROC) curves
Model 1: proton pump inhibitor (PPI) studies
Assumption: imperfect reference standard
Prior distributions:
Prior of prevalence (pi) is beta (12, 12), <= > pi in [0.3, 0.7]
Prior of beta is uniform (−0.75, 0.75)
Prior of THETA is uniform (−1.5, 1.5)
Prior of LAMBDA is uniform (−3, 3)
Prior of sigma_alpha is uniform (0, 2)
Prior of sigma_theta is uniform (0, 2)
Prior of S2 (sensitivity of reference test) is:
Study(ies) 1 to 7 beta (172.55, 30.45), <= > S2 in [0.8, 0.9]
Prior of C2 (specificity of reference test) is:
Study(ies) 1 to 7 beta (50.4, 12.6), <= > C2 in [0.7, 0.9]
Model 2: exertional 24 h pH-metry
Assumption: imperfect reference standard
Prior distributions:
Prior of prevalence (pi) is beta (5.2318, 6.0194), <= > pi in [0.18, 0.75]
Prior of beta is uniform (−0.75, 0.75)
Prior of THETA is uniform (−1.5, 1.5)
Prior of LAMBDA is uniform (−3, 3)
Prior of sigma_alpha is uniform (0, 2)
Prior of sigma_theta is uniform (0, 2)
Prior of S2 (sensitivity of reference test) is:
Study(ies) 1 to 5 beta (172.55, 30.45), <= > S2 in [0.8, 0.9]
Prior of C2 (specificity of reference test) is:
Study(ies) 1 to 5 beta (50.4, 12.6), <= > C2 in [0.7, 0.9]
Appendix 3: Summary of excluded studies during full-text review
In Table 5 summarizes the studies reviewed in full-text and excluded from the systematic review. For each study the reason for exclusion is provided.
Table 5
Summary of excluded studies during full-text review
Author
Year
Design
Comments
Aanen
2008
cohort, prospective
No diagnostic study. No NCCP. GERD, reproducibility of reflux symptoms only
Abbass
2009
randomised clinical trial
No diagnostic study. No NCCP. General pain patients
Achem
1993
retrospective, review
Prevalence of nutcracker esophagus in NCCP. For treatment outcome open label trial with small sample
Achem
1997
randomised, controlled trial
No diagnostic study. GERD patients only received PPI
Achem
2000
review article
Review article about atypical chest pain
Adams
2001
retrospective review
no NCCP. Spiral CT in pulmonary embolism
Adamek
1995
cross-sectional study
No reference test. Description of coexistence of motility disorders and pathologic acid reflux
Aikens
2001
cross-sectional study
No diagnostic study, presence of fear in NCCP patients. Correlation of fear with symptoms
Aizawa
1993
cross-sectional study
no NCCP, acetylcholine provocation test for coronary arterial spasm
Ajanovic
1999
cross-sectional study
no NCCP. Pulmonary embolism
Aksglaede
2003
experimental
Experimental. Small sample (n = 5) chest pain.
Alexander
1994
cross-sectional study
Prevalence and nature of mental disorders in NCCP and IHD
Amarasiri
2010
cross-sectional study
GERD patients not NCCP
Anzai
2000
cross-sectional study
No reference test, coronary flow reserve with dopler in patients with no significant coronary stenosis
Armstrong
1992
review article
Review article about atypical chest pain
Arnold
2009
randomised clinical trial
No diagnostic study. Treatment outcome
Aufderheide
1996
validation
Validation of ACI-TIPI probabilities for MI
Bak
1994
cohort, prospective
No diagnostic study. Comparison of prevalence of findings
Balaban
1999
experimental
No diagnostic study. Small sample (n = 10)
Baniukiewicz
1997
cross-sectional study
No diagnostic study. Description of findings in upper GI studies
Barham
1997
observational
No NCCP. Description of presence of esophageal spasm in patients undergoing upper GI studies
Barki
1996
cohort, prospective
No diagnostic study. Description of clinical presentation in painful rip syndrome
Basseri
2011
experimental
Experimental. No NCCP. Different techniques swallow studies
Bassotti
1998
cohort, retrospective
No NCCP. Nutcracker esophagus and the symptoms and findings investigated.
Bassotti
1992
cohort, prospective
No diagnostic study. Prevalence
Beck
1992
cross-sectional study
No diagnostic study. Charasteristics of NCCP patients compared to general pain patients
Belleville
2010
cross-sectional study
No diagnostic study. Characteristics of patients with panic disorders in the ER
Berkovich
2000
cohort, retrospective
No NCCP
Bernstein
2002
validation
GOLDmineR: improvement of a risk model
Berthelot
2005
cohort, retrospective
No diagnostic study. Pain referral study after injection
Bjorksten
1999
cross-sectional study
No patients, workers with muscoloskeletal complaints
Blatchford
1999
cross-sectional study
No NCCP. Emergency medical admission rates
Borjesson
1998
cross-sectional study
Small sample (n = 18), prevalence of esophageal findings
Borjesson
1998
non-randomised controlled trial
No diagnostic study. Small sample size (n = 20 per group). Intervention = TENS
Bortolotti
2001
experimental
No diagnostic study, small sample (n = 9)
Bortolotti
1997
randomised clinical trial
No diagnostic study. L-Arginine in patients with NCCP. Small sample (n = 8)
Bovero
1993
cohort, prospective
Duplicate of same study Bovero 1993 included in the analysis under different titel
Bovero
1993
cohort, prospective
Duplicate of same study Bovero 1993 included in the analysis under different titel
Brims
2010
review article
Review article about atypical chest pain
Broekaert
2006
experimental
Experimental trial in volunteers (no patients, n = 10)
Brunse
2010
cohort, prospective
No diagnostic study. Prevalence
Brusori
2001
cross-sectional study
Mixed sample, diagnosis of esophageal dysmotility in fluoroscopy vs. Manometry
Budzynski
2010
cross-sectional study
Mixed patients sample with significant and non significant coronary leasons not responding to PPI treatment
Bruyninckx
2009
cross-sectional study
No diagnostic study. GP's reasons for referral
Cameron
2006
case series
Case series, selected sample by gastroenterologist. Not all patients had all investigation. Small samples for each group
Cannon
1994
randomised clinical trial
Treatment outcome (imipramine vs. placebo)
Carter
1997
review article
Review article about atypical chest pain
Cremonini
2005
review article
Systematic Review PPI
Castell
1998
Editorial
Editorial
Chambers
1998
observational
Small sample size: n = 23, SI in 7 patients not calculated
Cheung
2007
cross-sectional study
No diagnostic study. Questionnaire to doctors to see what kind of patients they see, what diagnostic tests they use and how they treat.
Christenson
2004
cohort, prospective
Chest discomfort inappropriately not diagnosed ACS. Different research question
Crichton
1997
experimental
Experimental statistical rule out
Cossentino
2012
randomised clinical trial
No diagnostic study. Baclofen in gastro-esophageal diseases
Dekel
2003
cohort, retrospective
No diagnostic study. Prevalence of esophageal motility disorders.
Dekel
2004
Not randomised, not controlled trial
PPI trial only 14 patients included (only GERD positive treated)
Deng
2009
cross-sectional study
No NCCP. Combination between cardiac ischemia and esophageal spasms
De Vries
2006
cross-sectional study
Mixed patient sample with cardiac and non-cardiac chest pain
Dickman
2007
cohort, prospective
No diagnostic study. Prevalence of GI findings in NCCP vs. patients with GERD
Disla
1994
cohort, prospective
No diagnostic study, prevalence
Domanovits
2002
cross-sectional study
Rule out cardiovascular disease. No diagnostic study for NCCP
Ellis
1992
cohort, prospective
No diagnostic study. Treatment outcome in patients with esophageal spasm
Elloway
1992
cross-sectional study
provocative radionuclide esophagealNo comparison to reference test, radionuclide esophageal transit (P-RET) investigation, small sample (n = 30)
Elloway
1992
cross-sectional study
Same study under different title
Erhardt
2002
Guideline
Task force on the management of chest pain
Esayag
2008
retrospective review
Pleuritic chest pain. No reference test, description of presentation and outcome
Esler
2001
randomized clinical trial
Dissertation, same as following.
Esler
2003
randomized clinical trial
Treatment intervention in NCCP. CBT in NCCP seems to reduce chest pain episodes
Fass
1999
cohort, prospective
No diagnostic study. Treatment outcome study
Fleischmann
1997
cross-sectional study
No NCCP. Echokardiographic findings in acute chest pain and health status
Fletcher
2011
cohort, prospective
Sample size: 8 patients with NCCP
Fornari
2008
cohort, retrospective
No NCCP. Only nutcracker esophagus investigated
Fournier
1993
cross-sectional study
No NCCP. Ergovine test during coronary angiogram and induction of coronary spasm
Fournier
1993
cross-sectional study
Same study under different titles
Foldes
2011
cross-sectional study
No comparison of test with reference test. Prevalence of panic disorders
Frobert
1996
cross-sectional study
No diagnostic study. Comparison of characteristics between NCCP with positive treadmill test compared to negative treadmill test.
Gentile
2003
cross-sectional study
Patients with pneumococcal pneumonia. No reference test, description of presentation, microbiological findings and mortality
Gignoux
1993
experimental
No diagnostic study, experimental study
Goehler
2011
experimental
Simulation model of CT scan
Goodacre
2004
randomized clinical trial
No diagnostic study. Comparison of treatments
Gustafsson
1997
non-randomised controlled trial
Sample size: intravenous edrophonium chloride test in 16 patients
Ha
1998
cross-sectional study
No only NCCP. Patients with suspected coronary artery spasm. Ergonovine provocation test and scintigrafic findings. Small sample (n = 26)
Hamm
2011
Guideline
ESC Guidelines
Herbella
2009
cross-sectional study
No NCCP. Presentation of GERD patients
Hess
2008
validation
Diagnostic accuracy to exclude coronary artery disease
Hillis
2003
observational
Correlation of predictors and long term outcome. No diagnostic study
Hick
1992
cohort, retrospective
No diagnostic study. Comparison of characteristics
Hirano
2001
cross-sectional study
No NCCP. Coronary artery spasm
Ho
2001
cross-sectional study
No diagnostic study. Difference between cardiovascular disease and non-cardiovascular disease
Hobson
2006
experimental
Experimental for pain threshold.
Hobson
2006
experimental
Same study under different titels
Howarth
2003
cohort, prospective
Ischemic heart disease and GERD
Hu
2000
experimental
Experimental trial in volunteers
Hughes
2007
cohort, retrospective
No diagnostic study. Risk factors for Reflux or NCCP
Hung
2010
review article
Review article about atypical chest pain
Ilgen
2011
validation
Diagnostic accuracy to exclude coronary artery disease
Jacobs
2007
Guideline
executive summary of management patients with ischemic heart disease
Jerlock
2005
qualitative study
No diagnostic study. Qualitative study
Johnston
1993
cohort, retrospective
No diagnostic study, prevalence
Jones
1999
cross-sectional study
Pleuritic chest pain. Review article
Kahrilas
2011
systematic review
Systematic Review PPI Trial in NCCP, reference publication for included studies
Kao
1993
cross-sectional study
No diagnostic study, prevalence
Karamanolis
2008
experimental
Healthy volunteers
Karlson
1994
observational
No diagnostic study. Prognosis and outcome after discharge for ER
Ke
1993
cohort, prospective
No diagnostic study, prevalence of GERD in NCCP
Keefe
2011
randomised clinical trial
No diagnostic study. Coping skills training, sertraline, placebo
Keogh
2004
cross-sectional study
No diagnostic study. Presence of various psychological factors in the ER in cardiac vs. NCCP on cardiac chest pain
Kisley
1997
cohort, prospective
No diagnostic study. Prognosis after discharge after first admission with acute chest pain
Klingerman
2011
cross-sectional study
Rule out cardiovascular disease. No diagnostic study for NCCP
Klopocka
2005
cohort, prospective
No diagnostic study. Only 24 patients with NCCP
Klopocka
2005
cohort, prospective
Same study under different titles
Koop
2005
journal article
GERD. No diagnostic study in NCCP
Kumarathurai
2008
cohort, prospective
No diagnostic study.
Kushner
1992
cross-sectional study
small sample: n = 27. Presence of panic disorders in relatives.
Lacy
2009
cross-sectional study
Prevalence study
Lam
1994
cohort, prospective
No diagnostic procedure. Only patients included that chest pain was reproduced during the investigation
Lanzarini
1994
cross-sectional study
Description of findings in dobutamine stress echocardiography in patients with positive exercise stress test and negative coronar angiography including ergonovine stress test.
Lauenbjerg
1997
observational
No diagnostic study. Long term prognosis in patients with NCCP of various etiologies
Lee
2011
randomised clinical trial
Conference proceeding. No diagnostic study
Lee
2005
cross-sectional study
Prevalence study
Lehtola
2010
randomised, controlled trial
Treatment outcome (manipulation, acupuncture vs. placebo. No diagnostic study
Lessard
2012
Patients with NCCP with Panic disorders. Two different interventions, no diagnostic study
Lien
2011
cohort, prospective
NCCP not investigated
Lin
2004
cross-sectional study
No NCCP. GERD symptoms and underlying conditions. Differences between women and men
Liu
2006
cross-sectional study
No NCCP patients. Correlation analysis between psychological factors and findings
Lopez Gaston
1994
cross-sectional study
Only esophageal pain investigated not NCCP
Lopez Gaston
1994
cross-sectional study
Same study under different titles
Lopez Gaston
1994
cross-sectional study
Same study under different titles
Loten
2009
observational
No diagnostic study. Adverse outcome / prognosis of mixed patient population
Lyer
2009
retrospective review
Spontaneous pneumomediastinum. Presentation and findings. No diagnostic study
MacPherson
2007
cross-sectional study
No diagnostic study. Survey of patients after ER diagnosis NCCP about interest in acupuncture
Maev
2007
randomised clinical trial
Conference proceeding
Maev
2007
randomised clinical trial
Same study under different titles
Makk
2000
experimental
Experimental study. No diagnostic study. Comparison of acid infusion and cardiac vs. non-cardiac chest pain. Small sample
Manchikanti
2003
observational
No NCCP. Medial branch blocks for musculoskeletal pain
Manterola
2004
cross-sectional study
No diagnostic study. Clinical presentation of patients with NCCP
Martina
1997
cross-sectional study
All patients presenting in primary care. NCCP not as subgroup investigated
Matthews
2005
Meta-analysis
Meta-analysis for PPI-Trial
Mayou
1994
cohort, prospective
No diagnostic study. Comparison of NCCP vs. IHD patients
Mayou
2002
cohort, prospective
No diagnostic study. One year follow-up in comparison to cardiac chest pain. Comparison of costs to the CVD patients
Mearin
1998
cohort study, prospective
No diagnostic study. Change of habits during manometry
Mehta
1995
experimental
No reference test as “true positive” defined.
Mendelson
1997
cohort, prospective
Reference test are cancer patients. Comparison of Szintigraphy for the diagnosis of costochondritis
Mitchell
2006
cross-sectional study
Prevalence of risk factors and pretest probability
Miniati
1999
cross-sectional study
no NCCP. Pulmonary embolism
Miniati
2001
cross-sectional study
no NCCP. Pulmonary embolism
Miniati
2003
cross-sectional study
no NCCP. Prediction model for pulmonary embolism
Mujica
2001
cohort, prospective
No diagnostic study in patients. Healthy volunteers
Mulero
1999
cross-sectional study
Small sample (n = 24). No reference test. Descriptive findings in SPECT
Munk
2008
cohort, prospective
No diagnostic study. Risk of death in patients with unexplained chest pain
Nanbu
1997
cross-sectional study
Focus on difference between IHD and NCCP patients. Valdity of the medical interview for patients with NCCP
Nasr
2010
experimental
Experimental study.
Nasr
2010
experimental
Same study under different titels
Nellemann
2000
experimental
Small sample (n = 5 with chest pain)
Nevitt
1999
secondary analysis of an RCT
No NCCP. Vertebral fracture
Nikolic
2010
cross-sectional study
No diagnostic study. Comparison of NCCP to IHD patients
Nilsson
2003
cross-sectional study
Prevalence of Diagnosis of IHD in primary care.
Okada
1993
cross-sectional study
No NCCP. Provocation of myocardial ischemia by hyperventilation
Oliver
1999
cross-sectional study
CT in acute non-cardiac chest pain. No reference. Description of diagnoses found.
Pandak
2002
cross-sectional study
duplicate of the study included in the analysis
Panju
1996
observational
No diagnostic study. Patients prognosis after discharge
Paterson
1993
cohort, prospective
exclude, small sample
Paterson
1995
cross-sectional study
No diagnostic study. Description of finding in balloon distention NCCP in comparison to other pain patients
Paterson
1996
cross-sectional study
Not enough information to populate a two by two table. Small sample (n = 23)
Porter-Moffitt
2006
cross-sectional study
Small sample (Chest pain n = 34). Comparison of findings to other pain diagnosis.
Rasmussen
2009
cohort, prospective
No NCCP. Complex regional pain syndrome
Robertson
2008
cross-sectional study
Comparison of psychological morbidity in cardiac vs. Non-cardiac chest pain
Rosano
1996
randomised clinical trial
No diagnostic study. Treatment of 17-beta-estradiol patches compared to placebo on NCCP in postmenopausal women
Ratnaike
1993
retrospective review
No diagnostic study. Audit for IHD
Rate
1999
experimental
healthy volunteers
Rencoret
2006
cross-sectional study
No diagnostic study. Prevalence of esophageal disorders in patients with NCCP compared to other GI diseases
Repasky
2005
validation
ED chest pain pathway
Rokkas
1992
cross-sectional study
Not enough information to populate the two by two table
Rose
1994
cohort, prospective
No diagnostic study. Does esophageal testing prevent persistence of symptoms? No control group
Rose
1994
cohort, prospective
Same study under different titles
Rosengren
2008
Editorial
Editorial
Rousset
2011
retrospective review
No NCCP. Catammenial pneumothorax and endometriosis-related pneumothorax
Ruigomez
2004
cohort study
No diagnostic study. Description of risk factors, incidence and comorbidities
Sakata
1996
cross-sectional study
No reference test. Description of homeostasis and fibrinolysis in patients with coronary artery spasm. Not sure only NCCP patients
Sakamoto
2011
cross-sectional study
Acute chest pain, rule out aortic dissection or pulmonary embolism
Salles
2011
cohort, retrospective
No diagnostic study: SAPHO syndrome, clinical characteristics.
Sanchis
2008
cross-sectional study
clinical risk profile of patients with acute chest pain without ST-segment deviation or troponin elevation
Scarinci
1994
cohort, prospective
No NCCP. Women with GERD clinical presentation
Schima
1992
cohort, prospective
Small sample (n = 4 NCCP)
Schima
1992
cohort, prospective
Same study under different titles
Schmidt
2002
cross-sectional study
No NCCP. General pain patients
Schmulson
2004
review article
Review article about atypical chest pain
Shahid
2005
cross-sectional study
No diagnostic study. Prensentation of young adults with chest pain
Shapiro
2006
No NCCP patients. Functional heart burn (pH Man normal) vs. NERD (ph manometry pathologic) incl. psychometric profile).
Sharma
2010
experimental
healthy volunteers
Shelby
2009
randomized clinical trial
Same sample as 210 and 217. Description of psychological factors at baseline.
Sigurdsson
2009
retrospective review
Retrospective analysis of lung biopsy. No NCCP group
Singh
1993
retrospective review
duplicate of the included study
Smith
2000
retrospective review
Feasibility study based on records in a chiropractic clinic.
Smout
1992
experimental
experimental. Small sample (n = 10)
Sobralske
2005
review article
Review article about atypical chest pain
Spencer
2006
observational
No NCCP. GI patients long term outcome
Sporer
2007
cross-sectional study
Rule out cardiovascular disease. No diagnostic study for NCCP
Stahl
1994
cohort, prospective
Small sample (n = 13 NCCP patients)
Steurer
2010
Metaanalysis
clinical value of diagnostic instruments to rule out IHD
Stochkendahl
2008
randomised clinical trial
Study protocol
Stochkendahl
2012
randomised, controlled trial
No diagnostic study. Treatment outcome
Stochkendahl
2012
randomised, controlled trial
No diagnostic study. Same study as previous. Treatment outcome 1 year follow-up
Stollman
1997
cross-sectional study
Small sample (n = 14 patients)
Taylor
2002
cross-sectional study
Rule out strategy cardiovascular patients. No diagnostic study in NCCP
Taniguchi
2009
cross-sectional study
Chest pain in asthma. Treatment response to bronchodilatators
Tew
1995
cross-sectional study
No diagnostic study. Outcome cardiovascular patients
Tougas
2001
experimental
Experimental. Autonomic reaction to acid infusion in NCCP patients (n = 28) compared to controls
Triadafilopoulos
1997
cohort, prospective
GERD patients. Description of spectrum of patients. Only a few with NCCP
Tutuian
2006
cross-sectional study
Not enough information to populate a two by two table in NCCP patients with esophageal spasm
Valdovinos
2004
experimental
No reference test. pH Bravo- capsule. Safety, efficacy and experience in 11 patients
Van Kleef
1995
observational
No diagnostic study. Intervention success comparison after radiofrequency lesion of the dorsal root ganglion
Van Peski-Oosterbaan
1998
cross-sectional study
Survey about how people are interested in psychological treatment after discharge after cardiac unit admission. Mixed patients sample.
van Ravensteijn
2012
systematic review
Diagnostic test efficacy in various pain patients
Varia
2000
randomised, controlled trial
No diagnostic study. Comparison efficacy Sertraline vs. Placebo.
Vent
2010
journal article
dysphagia cause of chest pain
Verdon
2010
observational
Chest pain early diagnostic guess accuracy in GP’s
Vermeltfoort
2009
cross-sectional study
Mixed patient sample with cardiac and non-cardiac chest pain
Volpicelli
2008
cohort, prospective
Pleural sonography for the diagnosis of pulmonary embolism
Wang
2011
cross-sectional study
Conference proceeding
Watkins
2011
journal article
Diagnosis and management of community-acquired pneumonia
Weiner
2006
journal article
Cardiac markers in low-risk patients. No study
Weingarten
1993
cross-sectional study
No diagnostic study for NCCP. Reduction of length of stay by complying the guidelines
White
2011
cross-sectional study
no diagnostic study. Prevalence
Wong
2002
cohort, prospective
no comparison to a reference test. Descriptive information only.
Wulsin
2002
randomised clinical trial
no diagnostic study. Treatment of paroxetine vs. usual care
Yelland
2010
review article
Review article about atypical chest pain
Yu
1997
cross-sectional study
Not enough information to populate a two by two table for symptom index and the presence of GERD
Zalar
1995
cross-sectional study
Conference proceeding
Zarauza
2003
observational
No diagnostic study. Follow-up after discharge
Zheng
2008
cross-sectional study
Small sample (n = 27)
Zheng
2008
cross-sectional study
Same study under different title
Appendix 4: Summary of the Scottish Intercollegiate Guidelines Network (SIGN) quality assessment [19]
In Table 6 the study quality assessed by using the Scottish Intercollegiate Guidelines Network (SIGN) methodology checklist for diagnostic studies [19] is summarized. Study quality was assessed by two reviewers independently.
Table 6
Summary of the Scottish Intercollegiate Guidelines Network (SIGN) quality assessment [19]
1.1: spectrum of patients is representative of patients who will receive the test; 1.2: selection criteria described; 1.3: reference standard is likely to classify the condition correctly; 1.4: period between reference standard and index test short enough; 1.5: whole sample received verification of diagnosis; 1.6: patients receive same reference test regardless of index test results; 1.7: reference standard independent of index test; 1.8: execution of index test described in detail; 1.9: reference standard described in detail; 1.10: index test interpreted without knowledge of result of reference test; 1.11: reference standard results interpreted without knowledge of result index test; 1.12: uninterpretable or intermediate results are reported; 1.13: explanation is provided for withdrawals; 2.1: reliability of the conclusion of the study. Risk of bias (2.1) is as follows. (++), high quality: most of the criteria have been fulfilled. If not fulfilled, the conclusions of the study are very unlikely to alter. (+), moderate quality: some criteria fulfilled. Criteria not adequately described are unlikely to alter the conclusions. (−), low quality: few or no criteria fulfilled. The conclusions are likely to alter.
AA adequately addressed, N/A not applicable, NA not addressed, NR not reported, PA poorly addressed, WC well covered.
Appendix 5: Summary of all tests evaluated
Table 7 provides a detailed description of all tests and reference tests investigated. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), prevalence, and post test prevalence are given.
Panic disorder diagnosis: formula including Agoraphobia Cognitions QA, Mobility Inventory for Agoraphobia, Zone 12 Dermatome Pain Map, Sensory McGill Pain QA, Gender, Zone 25 (Validation population)
Panic Disorder (ADIS-R structured interview by psychologist)
32
41
17
122
0.65
0.75
0.44
0.88
2.60
0.46
23
44
12
Sensitivity calculated by TP/(TP + FN); specificity calculated by TN/(FP + TN). Biomechanical dysfunction defined as chest pain presumably caused by mechanical joint and muscle dysfunction related to C4 to T8 somatic structures of the spine and chest wall established by means of joint-play and/or end-play palpation.
24-h pH-metry: 24-h pH monitoring measures with a single sensor located above the lower esophageal sphincter (LES) a reflux event and the association of the reflux event with symptoms can also be ascertained from the tracing; manometry: esophageal manometry measures mean pressure of the lower esophageal sphincter and any degree of hypomotility and dysmotility in the esophagus.
LR+, positive likelihood ratio calculated sensitivity/1 - specificity; LR-, negative likelihood ratio calculated 1 - sensitivity/specificity; diagnostic test accuracy. Very good: LR + >10, LR- <0.1; good: LR + 5 to 10, LR- 0.1 to 0.2; fair: LR + 2 to 5, LR- 0.2 to 0.5; poor: LR + 1 to 2, LR- 0.5 to 1.
Reference tests are as follows. Endoscopic classification: LA classification: grade A, ≥1 mucosal break ≤5 mm, that does not extend between the tops of two mucosal folds; grade B, ≥1 mucosal break >5 mm long that does not extend between the tops of two mucosal folds; grade C, ≥1 mucosal break that is continuous between the tops of two or more mucosal folds but which involves <75% of the circumference; grade D, ≥1 mucosal break which involves at least 75% of the esophageal circumference [52]. Savary-Miller System: grade I, single or isolated erosive lesion(s) affecting only one longitudinal fold; grade II, multiple erosive lesions, non-circumferential, affecting more than one longitudinal fold, with or without confluence; grade III, circumferential erosive lesions; grade IV, chronic lesions: ulcer(s), stricture(s) and/or short esophagus. Alone or associated with lesions of grades 1 to 3; grade V, columnar epithelium in continuity with the Z line, non-circular, star-shaped, or circumferential. Alone or associated with lesions of grades 1 to 4 [53]. Hentzel-Dent grades: grade 0, no mucosal abnormalities; grade 1, no macroscopic lesions but erythema, hyperemia, or mucosal friability; grade 2, superficial erosions involving <10% of mucosal surface of the last 5 cm of esophageal squamous mucosa; grade 3, superficial erosions or ulceration involving 10% to 50% of the mucosal surface of the last 5 cm of esophageal squamous mucosa; grade 4, deep peptide ulceration anywhere in the esophagus or confluent erosion of >50% of the mucosal surface of the last 5 cm of esophageal squamous mucosa [54]. pH-metry: De Meester criteria: (1) total number of reflux episodes; (2) number of reflux episodes with pH <4 for more than 5 minutes; (3) duration of the longest episode; (4) percentage total time pH <4; (5) percentage upright time pH <4; and 6) percentage recumbent time pH <4. [55]. Manometry: Spechler criteria: diagnosis of ineffective esophageal motility, nutcracker esophagus, spasm, achalasia based on: basal lower esophageal sphincter pressure, relaxation, wave progression, distal wave amplitude [56].
ACQ Agoraphobia Cognitions Questionnaire, ADIS-R structured interview by psychologist, recommended interview protocol for panic research, CVD cardiovascular disease, DSM-IV (ADIS-IV) Anxiety Disorders Interview Schedule, GERD gastroesophageal reflux disease, GP general practitioner, GPE Ghillibert probability estimate (sum of partial probabilities for exact numbers of reflux associated symptoms within the context of the total number of symptoms), HDR high-degree response, EoE eosinophilic esophagitis (typical abnormal EoE endoscopic findings (rings or furrows)), IHD ischemic heart disease, McGill sensory McGill Pain Questionnaire sensory, MIA Mobility Inventory for Agoraphobia, MINI Mini International Neuropsychiatric Interview (gold standard for anxiety disorders), NPV negative predictive value, PPV positive predictive value, SI symptom index (calculated as the proportion of chest pain symptoms (pH <4) divided by the number of chest pain episodes recorded, expressed as a percentage), SIS symptom index score (calculated by adding the reported daily severity (mild = 1; moderate = 2; severe = 3; and disabling = 4) multiplied by the reported daily frequency values during each week).
Acknowledgements
We thank Dr Martina Gosteli, University of Zurich, for conducting the literature search.
This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Competing interests
The authors declare that they have no competing interests. This study was not funded.
Authors’ contributions
MW and KR carried out data extraction, participated in the analysis and drafted the manuscript. UH participated in the design of the study and performed the statistical analysis. JS conceived the study, and participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.
Akuter Schwindel stellt oft eine diagnostische Herausforderung dar. Wie nützlich dabei eine MRT ist, hat eine Studie aus Finnland untersucht. Immerhin einer von sechs Patienten wurde mit akutem ischämischem Schlaganfall diagnostiziert.
Wenn unter einer medikamentösen Hochdrucktherapie der diastolische Blutdruck in den Keller geht, steigt das Risiko für schwere kardiovaskuläre Ereignisse: Darauf deutet eine Sekundäranalyse der SPRINT-Studie hin.
Beginnen ältere Männer im Pflegeheim eine Antihypertensiva-Therapie, dann ist die Frakturrate in den folgenden 30 Tagen mehr als verdoppelt. Besonders häufig stürzen Demenzkranke und Männer, die erstmals Blutdrucksenker nehmen. Dafür spricht eine Analyse unter US-Veteranen.
