attributable to acid reflux [26]. Importantly, following eight weeks of acid suppression, 65% of patients (13/20) had marked improvement or resolution of their symptoms [26].
Further exploring this relationship in a prospective trial of 100 consecutive patients undergoing esophageal manometry with acid infusion provocative testing (Bernstein test) and ambulatory pH monitoring, Hewson et al. found that 48% of patients had abnormal acid exposure times; and among the 83 patients who experienced chest pain, 46% had abnormal reflux parameters, with 60% having a positive symptom index [24]. Interestingly, however, acid provocation testing was positive in only 19% of patients. The authors also prospectively compared the test results of 75 consecutive NCCP patients with both a positive acid perfusion test and CP during a 24‐hour pH monitoring to assess for a positive “symptom index,” whereby pH monitoring identifies reflux events that correlate with patient symptoms [27]. Notably, only 26% of patients (9/34) with abnormal reflux had a positive acid perfusion test, whereas 59% (45/75) had a positive symptom index with pH monitoring.
Another mechanism that may be contributing is the cardio‐esophageal reflex, which occurs when esophageal acid perfusion results in a decreased coronary blood flow velocity [28]. This was explored by Rosztoczy et al. in 51 patients with CP undergoing pH monitoring, esophageal manometry, and acid perfusion testing combined with echocardiography (transesophageal doppler echocardiographic coronary flow measurement in the left anterior descending artery) [25]. Results showed 49% of patients (25/51) had decreased coronary flow velocity during acid perfusion, which was more likely to occur in patients with more severe reflux disease (increased number of reflux episodes, fraction of time below pH 4, and prolonged acid reflux times) (p < 0.05) [25]. These authors therefore suggested that patients with prolonged acid reflux episodes, erosive esophagitis, and coronary spasm may be at higher risk for the development of linked angina.
Finally, another postulated mechanism for GERD in ECP is that of esophageal sensitization of mechanoreceptors. Hu et al. found that in healthy volunteers, acid infusion reduced the first perception (p = 0.05) and pain threshold (p = 0.05) to balloon distension, which was not noted with saline infusion [29]. This relationship between GERD and esophageal hypersensitivity is further discussed in detail in the following section.
Diagnosis and treatment
The mainstay of treatment for ECP due to GERD is acid suppression. Among the earliest trials on the treatment of GERD in NCCP patients, Achem et al. randomized 36 patients to omeprazole 20 mg by mouth twice daily or placebo for eight weeks and found that omeprazole resulted in improvement in chest pain days (p = 0.006), pain severity (p = 0.032), individual daily pain scores (p = 0.03), and overall symptomatic improvement (p = 0.001) [30].
A proton pump inhibitor (PPI) trial for suspected GERD‐related cause of NCCP can be both diagnostic and therapeutic. This was first shown by Fass et al. in a trial of 39 NCCP patients randomized to receive either placebo or omeprazole (40 mg qAM and 20 mg qPM) for seven days before crossing over to the other arm after a washout period. All patients completed baseline symptom assessments along with 24‐hour pH monitoring and upper endoscopy prior to the trial [31]. Results identified that 62.2% (23/37) of patients were GERD‐positive, and 78% (18/23) of these patients had a positive response to omeprazole compared to only one of the GERD negative patients (p = 0.01) [31]. The “omeprazole test” had a sensitivity/specificity of 78.3% and 85.7%, respectively. Economic analysis, even at a time when omeprazole was not generic, showed an average savings of $573 per patient and a 59% reduction in the number of diagnostic procedures [31]. Another study shortly after confirmed these economic benefits, noting an 11% improvement in diagnostic accuracy, 43% reduction in the use of invasive diagnostic tests, and an average savings of $454 per patient [32].
This initial finding was replicated in randomized trials with other PPIs, including lansoprazole and rabeprazole [33, 34]. The only significant difference noted was that potentially the duration of PPI may need to be two weeks to improve diagnostic accuracy [35]. Meta‐analyses including randomized trials on the use of PPI testing for the diagnosis of GERD‐responsive NCCP found a pooled overall sensitivity/ specificity of 80% (95% CI, 71–87%) and 74% (95% CI, 64–83%), respectively [36,37].
For patients who do not respond to the PPI trial, the next step in evaluation is the performance of pH or pH‐impedance monitoring. Relating to this, there are a few key clinical questions including selection of pH vs. combination pH‐impedance monitoring, duration of pH monitoring, and performance on or off PPI therapy.
In the evaluation of NCCP, we advocate for combined pH‐impedance monitoring over pH monitoring alone, as conventional pH monitoring cannot reliably detect nonacid reflux, whereas impedance monitoring allows for the detection of reflux events regardless of pH level [38]. This ability to discern acid vs. nonacid reflux has been shown to result in a greater positive symptom association probability (SAP) for combination pH‐impedance monitoring than for pH monitoring alone (77.1 vs. 66.7%, p < 0.05) [39]. If pH monitoring alone is selected, choices include traditional 24‐hour pH monitoring vs. wireless pH monitoring up to 96 hours (Bravo™, Medtronic, Minneapolis, MN). Early studies using this Bravo wireless pH monitoring system in patients with NCCP showed an increase in the percentage of patients with elevated acid exposure time after two days (35.5%, 22/62) vs. one day of monitoring (25.8%, 16/62) (gain of 9.7%, 95% CI 4.6–19.6%) [40]. Additionally, 4 patients developed chest pain symptoms only on day 2, and a positive SAP was identified in an additional 13 patients with the extra day of monitoring (21% increase, 95% CI 12.7–32.7%) [40]. A similar percentage was also reported in a retrospective review of 190 patients undergoing both 24‐hour pH monitoring and 48‐hour Bravo pH monitoring in which abnormal esophageal acid exposure was identified in a total of 115 patients, 21 of whom (22%) were detected on day 2 only [41]. Another benefit of wireless pH monitoring is that the duration can be extended up to 96 hours in select patients while still maintaining high completion rates (80–89%) [42, 43]. The added diagnostic benefit of studying three or four days vs. two days remains unclear, however, as prolongation beyond 48 hours may not increase diagnostic yield [42]; on this basis, the Esophageal Diagnostic Working Group in their summary on the utilization of wireless pH monitoring technologies suggests at least 48 hours in order to increase the diagnostic yield and reduce false negative studies [38]. More recent consensus guidelines on the diagnosis of GERD have recommended the use of extended wireless pH monitoring when there is strong clinical suspicion of GERD in the setting of negative 24‐hour reflux monitoring [44].
Another key clinical question is whether to perform pH‐impedance monitoring on or off PPI therapy. For patients with PPI‐refractory symptoms, Hemmink et al. suggested that in order to exclude GERD as a cause of symptoms, 24‐hour pH‐impedance monitoring should be performed off PPI therapy, as 42% (8/19 patients) with no symptoms or a negative SAP while on PPI had a positive SAP off PPI therapy [45]. In contrast, others have suggested that combination pH‐impedance monitoring is still accurate for the detection of persistent symptoms among patients taking PPIs. This was demonstrated in 168 patients undergoing combined pH‐impedance monitoring while on at least a twice‐daily PPI [46]. In total, 86% (144/168) of patients recorded symptoms during the study, with 48% (69/144) noting a positive symptom index for at least one symptom – acid reflux 11% (16/144), nonacid reflux 37% (53/144) – with a positive SAP in 46% (66/144) and negative SAP in 54% (78/144) [46]. These findings highlight that the use of pH monitoring alone would not have identified the 37% of patients on twice‐daily PPI with a positive symptom index due to nonacid reflux and also that a very low proportion of patients on PPI therapy will have symptoms attributable to acid reflux. [46]. Similar findings are shared by a study that combined pH‐impedance in patients both on and off PPI therapy [47]. Among 79 patients off PPI therapy, a positive SAP was identified in 55.4% of patients, with 31.1% attributable to acid reflux, 4.1% to nonacid reflux, and 20.3% a combination of acid and nonacid reflux [47]. For those on PPI therapy (n = 71), the overall positive SAP was lower at 36.7% (acid reflux in 5%, nonacid reflux in 16.7%, and combination of acid and nonacid reflux in 15%) [47]. Despite the lower overall SAP, these results do highlight that the performance of pH‐impedance monitoring on therapy allows for greater detection of nonacid reflux than performance off PPI.
In summary, consensus guidelines recommend that testing off PPI is most