Prognostic value of vasodilator stress perfusion cardiovascular magnetic resonance after inconclusive stress testing

Background While current guidelines recommend noninvasive testing to detect coronary artery disease, stress tests are deemed inconclusive in a quarter of cases. The strategy for risk stratification after inconclusive stress testing is not well standardized. To assess the prognostic value of vasodilator stress cardiovascular magnetic resonance (CMR) parameters and CMR-based coronary revascularization in patients after inconclusive stress testing. Methods Between 2008 and 2020, consecutive patients with a first non-CMR inconclusive stress test referred for vasodilator stress perfusion CMR were followed for the occurrence of major adverse cardiovascular events (MACE), defined by cardiovascular death or nonfatal myocardial infarction. CMR-related coronary revascularization was defined as any revascularisation occurring within 90 days after CMR. Univariable and multivariable Cox regressions were performed to determine the prognostic value of each parameter. Results Of 1563 patients who completed the CMR protocol, 1402 patients (66.7% male, 69.5 ± 11.0 years) completed the follow-up (median [interquartile range], 6.5 [5.6–7.5] years); 197 experienced a MACE (14.1%). Vasodilator stress CMR was well tolerated without severe adverse events. Using Kaplan–Meier analysis, inducible ischemia and late gadolinium enhancement (LGE) were significantly associated with the occurrence of MACE (hazard ratio, HR: 2.88 [95% CI 2.18–3.81]; and HR: 1.46 [95% CI 1.16–1.89], both p < 0.001; respectively). In multivariable Cox regression, the presence and extent of inducible ischemia were independent predictors of a higher incidence of MACE (HR: 2.53 [95% CI 1.89–3.40]; and HR: 1.58 [95% CI 1.47–1.71]; both p < 0.001; respectively). After adjustment, the extent of inducible ischemia showed the best improvement in model discrimination above traditional risk factors (C-statistic 0.75 [95% CI 0.69–0.81] with C-statistic improvement: 0.12). The study suggested no benefit of CMR-related coronary revascularization in reducing MACE. Conclusions In patients with a first non-CMR inconclusive stress test, vasodilator stress CMR has good prognostic value to predict MACE offering an incremental prognostic value over traditional risk factors. Supplementary Information The online version contains supplementary material available at 10.1186/s12968-021-00785-6.

guidelines recommend a non-invasive stress testing or coronary computed tomography angiography (CTA) for the initial diagnostic management of patients with angina and suspected CAD (class IA) [2,3], stress tests are deemed inconclusive in up to 15% to 29% of cases [4,5]. The management of patients with inconclusive stress test is not well standardized and studies reported that < 25% of patients with inconclusive stress test underwent an additional stress test in clinical practice [4,6]. Moreover, it has been shown that inconclusive stress testing leads to a 140% increase in medical costs at 2 years and a worse prognosis compared to patients with conclusive negative tests [6,7]. Although some reports support that further testing after first inconclusive stress test may improve diagnostic accuracy of obstructive CAD and risk stratification [6], the management of such patients remain controversial because data are scarce [7]. Vasodilator stress cardiovascular magnetic resonance (CMR) is recognized as an accurate technique to depict inducible myocardial ischemia and infarction with high sensitivity and specificity [8,9]. A first-line stress CMR-based strategy was recently shown to be non-inferior in terms of outcomes compared to an invasive approach with fractional flow reserve in patients with stable angina [10]. Although several large studies have shown the prognostic value of stress CMR [11,12], no studies have specifically assessed the prognostic value of stress CMR in targeted patients with a first inconclusive stress test.
The aim of this study was to assess the prognostic value of stress CMR parameters and CMR-based coronary revascularization in consecutive patients referred for stress CMR after a first inconclusive noninvasive stress test.

Study population
Between December 2008 and January 2020, we conducted a single-centre longitudinal study with retrospective enrollment of consecutive patients with a first non-CMR inconclusive noninvasive stress test as the main indication for vasodilator stress perfusion CMR. Inconclusive stress test was defined by exercise electrocardiogram (ECG) or stress echocardiography or single photon emission computed tomography (SPECT) without positive or negative conclusion regarding the diagnosis of CAD [6,13]. Two expert physicians reviewed the first stress test, using the definitions of positive or negative tests presented in Additional file 1, in accordance with previous studies [6]. Patients without angina or dyspnea on exertion underwent the first stress test during the work-up of known CAD, or because of relatively high CVD risk defined by the presence of at least 2 CVD risk factors (age > 50 years for men or > 60 years for women, diabetes, hypertension, smoking, dyslipidemia, family history of CAD and obesity defined by body mass index (BMI) ≥ 30 kg/m 2 ). Exclusion criteria were: (i) contraindication to CMR (cerebral clips, metallic eye implant); (ii) contraindication to dipyridamole (severe asthma or chronic obstructive pulmonary disease, second-or thirddegree atrioventricular block); (iii) known cardiomyopathy (e.g. hypertrophic, dilated, or infiltrative) and acute or chronic myocarditis; (iv) known allergy to gadoliniumbased contrast medium; and (v) glomerular filtration rate < 30 ml/min/1.73 m 2 . Clinical data were collected according to medical history and clinical examination on the day of stress CMR. All patients gave informed written consent for clinical CMR examination and enrolment in the clinical research study at baseline. The study was approved by the local ethic committee of our institution and conducted in accordance with the Declaration of Helsinki. This study followed the STROBE reporting guidelines for cohort studies.

Patients follow-up and clinical outcome
The follow-up consisted of a clinical visit as part of usual care (72%) or by direct contact with the patient or the referring cardiologist (28%). Data collection was ended on June 2020. Cardiovascular events were checked by medical reports collected from the corresponding hospitals. The primary composite endpoint was the occurrence of at least one of the combined major adverse clinical events (MACE) defined as cardiovascular mortality or nonfatal myocardial infarction (MI). The secondary endpoints were all-cause mortality, hospitalizations for heart failure (HF), late coronary revascularizations and sustained ventricular arrhythmias. All these clinical events were defined according to standardized definitions [14,15], and are detailed in Additional file 2. Annualized event rates were expressed as the number of patients having the event as a proportion of the number of patients at risk divided by the number of patient-years followup. The adjudication of the cause of death between cardiovascular and non-cardiovascular was performed by two senior cardiologists (TP and MK), with a third cardiologist (JG) to reach final consensus. For patients who underwent percutaneous coronary intervention (PCI) < 90 days after index examination, the nine periprocedural events (seven nonfatal MI or two CVD mortality) were excluded from the analysis.

CMR protocol
The detailed stress CMR protocol has been previously published [16,17], and is described in Additional file 3. Briefly, CMR was performed on a 1.5T CMR scanner (Siemens Healthineers, Erlangen, Germany). Vasodilation was induced with dipyridamole injected at 0.84 mg/kg during 3 min [18]. Then, a bolus of gadolinium-based contrast agent (Dotarem ® , Guerbet LLC, France, 0.1 mmol/kg) was injected at a rate of 5.0 ml/s. Stress perfusion imaging was performed using an ECG-triggered saturation-prepared balanced steadystate free-precession sequence. A series of six slices (four short-axis views, a 2-chamber, and a 4-chamber view) were acquired every other heartbeat. No motion compensation was performed before analysis. Ten minutes after contrast injection, breath-hold contrastenhanced 3D T1-weighted inversion-recovery gradientecho sequence was acquired to detect late gadolinium enhancement (LGE). CMR sequence parameters are detailed in Additional file 4.

CMR image analysis
Left ventricular (LV) end-diastolic volume (LVEDV), end-systolic volume (LVEDV) and systolic function were quantified on the short-axis cine stack. Stress perfusion and LGE images were evaluated according to the American Heart Association 17-segment model [19]. The analysis of perfusion images was done visually by two experienced physicians blinded to clinical and follow-up data. Inducible ischemia was defined as a subendocardial perfusion defect that (1) occurred in at least one myocardial segment, (2) persisted for at least three phases beyond peak contrast enhancement, (3) followed a coronary distribution, (4) in the absence of co-location with LGE in the same segment [11,12]. An MI was defined by subendocardial or transmural LGE [20]. A myocardial segment was considered viable if LGE thickness was < 50% and nonviable when LGE thickness was ≥ 50% of the myocardial wall [21]. The total number of ischemic and LGE segments was assessed for each patient.

CMR-related coronary revascularization
CMR-related coronary revascularization was defined as all procedures (coronary artery bypass grafting [CABG] or PCI performed within 90 days after stress CMR. All patients were treated with optimal medical therapy according to current guidelines in patients with chronic coronary syndromes [2]. Decision-making regarding initial coronary revascularization was based on the presence of myocardial ischemia in at least two contiguous segments in symptomatic patients, and the choice between PCI or CABG was made by the Heart Team of the Institutions. All clinical data, CMR parameters and CMRrelated coronary revascularization were prospectively recorded into a dedicated database (Clinigrid software, Hemolia, France).

Statistical analysis
Continuous variables were expressed as mean ± standard deviation (SD), categorical variables as frequency with a percentage, and follow-up as a median and interquartile range (IQR). Patients with and without inducible ischemia were compared using the Student's t-test or the Wilcoxon rank-sum test for the continuous variables and the Chi-square or Fisher's exact test for the  categorical variables. Cumulative incidence rates of the outcomes were estimated using the Kaplan-Meier method and compared with the log-rank test. The data of patients who were lost to follow-up were censored to the time of the last contact. Cox proportional hazards methods were used to identify the predictors of MACE among patients with and without inducible ischemia.
The assumption of the proportional hazards ratio (HR) was verified. To assess the incremental prognostic value of both the inducible ischemia and CMR-related coronary revascularization, different multivariable models were used, as follows: The discriminative capacity of each model for predicting MACE was determined according to Harrell's C-statistic before and after the addition of inducible ischemia. The additional predictive value of the inducible ischemia was calculated using Harrell's C-statistic increment. In addition, the global χ 2 statistic was calculated for models with or without stress CMR parameters and compared using the likelihood ratio (LR) test for predicting MACE.
In the competitive risk analysis, cumulative incidence functions were used to display the proportion of patients with the event of interest or the competing event (nonfatal MI or CV mortality) as time progressed, and the Fine and Gray regression model was used for the sub-distribution hazard. A two-tailed p-value < 0.05 was considered statistically significant. Statistical analysis was performed using R software, version 3.3.1 (R Project for Statistical Computing, Vienna, Austria).

Study population
Of the 35,280 patients referred for stress CMR during the inclusion period, 1584 (4.5%) patients were referred for dipyridamole vasodilator stress CMR because of a first inconclusive noninvasive stress test. Among those, 1563 (98.7%) completed the stress protocol, as detailed in the flowchart (Fig. 1). Of the 1563 patients who successfully underwent stress CMR, the diagnosis of ischemia was Bold empasis means that the P value has reached statistical significance, with 2-tailed P value < 0.05 Values are n (%), mean ± SD, or median (interquartile range) BMI body mass index, CABG coronary artery bypass graft, CAD coronary artery disease, CMR cardiovascular magnetic resonance, CVD cardiovascular disease, ECG electrocardiogram, HF heart failure, LGE late gadolinium enhancement, LV left ventricle, MI myocardial infarction, PCI percutaneous coronary intervention, RPP ratepressure product (pressure mmHg × Heart rate bpm)/1000, SD standard deviation a Defined by BMI ≥ 30 kg/m 2 b Defined by glomerular filtration rate < 60 ml/min/1.73 m 2 c Defined by Framingham Risk Score > 20% of risk of CAD at 10 years d Based on a modified SCORE project (https:// www. escar dio. org/ Educa tion/ Pract ice-Tools/ CVD-preve ntion-toolb ox/ SCORE-Risk-Charts) that did not take into account the total cholesterol level [22,23] e Defined by the presence of LGE with < 50% transmurality Fig. 2 Annualized rates of major adverse cardiovascular events (MACE) stratified by the extent of myocardial ischemia. Annualized rates of MACE stratified by the extent of myocardial ischemia. Mild, moderate, and severe ischemia were defined as the involvement of 1-2, 3-5, and ≥ 6 myocardial segments, respectively. Test comparing the groups was based on the Cochran-Armitage test for trend inconclusive in 24 patients (1.5%) due to nondiagnostic image quality, arrythmias or artifacts. Out of these 1563 patients, 61 failed to respond to dipyridamole injection as assessed by the rate-pressure product (3.9%). No patient died during or shortly after CMR, and detailed safety results are presented in Additional file 5. Overall, 1402 patients completed the clinical follow-up and constituted our study cohort. Baseline subject characteristics and baseline CMR data are shown in Table 1 Among the 1402 patients, 485 (34.6%) were asymptomatic without angina or dyspnea. These asymptomatic patients were older and had a higher rate of known CAD (87.0% vs 33.3%, p < 0.001), diabetes mellitus, hypertension and smoking than symptomatic patients with angina or dyspnea (Additional file 6). Consistently, asymptomatic patients presented a higher CV risk than symptomatic using the ESC SCORE 10-year risk for fatal CAD [22]  The study cohort had a mean LV ejection fraction (LVEF) of 50.4 ± 12.1%. LGE was present in 556 (39.7%) and presence of inducible ischemia was detected in 414

Prognostic value of stress CMR parameters
In univariable analysis, age, male gender, hypertension, diabetes mellitus, dyslipidemia, known CAD, LVEF value, LV end-diastolic volume (LVEDV) and end-systolic volume (LVESV) indexed (LVEDVI, LVESVI, respectively) and the presence and extent of both inducible ischemia and LGE were all significantly associated with MACE (  Survival curves for MACE stratified by the presence of inducible ischemia. The univariable analysis for MACE (a) was performed using the log-rank test to compare patients with ischemia and without ischemia. The adjusted survival curve for MACE (b) was performed with the final model including: age, male, hypertension, diabetes, dyslipidemia, known CAD, LVEF per 10%, LV end-diastolic volume index, modified SCORE project, the presence of LGE and the presence of ischemia. HR indicates hazard ratio non-obese, and regardless of LVEF value or the presence of LGE (Fig. 4).
In multivariable stepwise Cox regression analysis, age, male gender, the presence of inducible ischemia and the number of ischemic segments were independent predictors of a higher incidence of MACE  (Table 3). In competitive risk analysis, the presence of inducible ischemia was independently associated with nonfatal MI and CV mortality (HR: 4.26, 95% CI 2.60-6.89, p < 0.001 and HR: 1.80, 95% CI 1.27-2.56, p < 0.001; respectively) ( Fig. 5 and Additional file 13).

Incremental prognostic value of stress CMR
For the prediction of MACE, the baseline C-statistic value was 0.63 (95% CI 0.60-0.68) for model 1 with stepwise variable selection. The addition of inducible ischemia or the number of ischemic segments significantly improved the C-statistic to 0.73 (95% CI 0.66-0.79; C statistic improvement for model 1: 0.10) and 0.75 (95% CI 0.69-0.81; C statistic improvement for model 1: 0.12), respectively. Furthermore, the addition of both presence of inducible ischemia and CMR-related coronary revascularization did not improve the C-statistic compared to the model with only the presence of inducible ischemia (C-statistic 0.73 for both) ( Table 4).

Discussion
In this study of consecutive series of patients with a first inconclusive noninvasive stress test referred for vasodilator stress CMR, the main findings are: (1) 29.5% of patients had inducible ischemia and 14.1% had MACE after median follow-up of 6.5 years; (2) inducible ischemia and LGE were long-term predictors of MACE and CVD mortality; (3) the presence and extent of inducible ischemia were independently associated with MACE and CV mortality; (4) the presence or extent of inducible ischemia improved model discrimination for the prediction of MACE, after adjusting for traditional CV risk factors; (5) there was no benefit of CMR-related coronary revascularization in reducing MACE.
The prevalence of inducible ischemia (29.5%) and LGE (39.7%) are consistent with previous large studies in patients with suspected or known CAD [11,12,22]. The rate of MACE reported over the follow-up period (14.1%) is in line with contemporary cohorts of patients  Table 3 Multivariable Cox regression analysis for the prediction of adverse events Bold empasis means that the P value has reached statistical significance, with 2-tailed P value < 0.05 CAD coronary artery disease, CI confidence interval, CMR cardiovascular magnetic resonance, LGE late gadolinium enhancement, MACE major adverse cardiac events, LVEF left ventricular ejection fraction a Covariates in the model 1 by stepwise variable selection with entry and exit criteria set at the p ≤ 0. referred for stress CMR [11,23], a meta-analysis of patients with inconclusive stress echocardiography [24], and the ISCHEMIA trial [25]. Notably, the rate of inducible ischemia in patients referred for inconclusive stress test was higher (29.5%) than in the overall population of 35,280 patients referred for stress CMR during the same inclusion period (12.4%). Besides, the global annualized events rate (4.4%/year) of this study was higher than the annualized rate described in patients with normal CMR in previous larges studies (1%/year) [12,23]. This finding is consistent with a recent study showing that patients with inconclusive stress tests had a higher rate of CV events compared with those with negative results [6].
Although the long-term prognostic value of stress CMR is well established in patients with known or suspected CAD [11,12,26], there is no prognostic data in patients with a first inconclusive stress test [7]. In the current study, the presence of inducible ischemia and LGE were associated with MACE and CVD mortality. In accordance with some recent studies [22,27], the extent of inducible ischemia was a strong and independent predictor of MACE and CVD mortality. In agreement with previous functional imaging studies [28,29], the extent of inducible ischemia assessed by stress CMR had the best incremental prognostic value in predicting MACE, with better discrimination over traditional risk factors than the sole presence of inducible ischemia.
We found the prognostic value of stress CMR for predicting MACE was significant for both symptomatic and asymptomatic patients. Interestingly, asymptomatic patients addressed after a first inconclusive stress test had known CAD in the vast majority of cases (87%) or at high CVD risk (13%). Because patients with silent myocardial ischemia have at least similar risk for CVD events and mortality than symptomatic patients with typical angina [30,31] risk stratification of asymptomatic patients may be useful in managing secondary prevention. Although the current guidelines do not recommend systematic stress testing in the work-up of patients with CAD [2,3], the current data demonstrate a significant prognostic value of stress CMR in asymptomatic patients.
The rate of CMR-related revascularization was 78.0% in patients with inducible ischemia, which is consistent with recent studies [12,27,29]. In line with the ISCHEMIA trial that recently showed the lack of benefit of coronary revascularization in reducing MACE in patients with stable coronary disease [25], the current study suggests no  association between CMR-related coronary revascularization and improved outcome. While the current guidelines recommend to perform an additional noninvasive testing (class IIa) in patients with a first inconclusive stress test [2,3], this strategy is used in < 25% of the cases resulting in significant economic implications with increased healthcare costs [4,6]. Interestingly, a report from the SPINS registry of the Society for Cardiovascular Magnetic Resonance [12] has recently demonstrated that the average cost of ischemic testing was lower for stress CMR than nuclear stress or the use of initial coronary angiography [32]. The current study demonstrates that an improved risk stratification using stress CMR could allow to identify high-risk patients who could benefit from treatment intensification and new therapies. Future studies should prospectively randomize some diagnostic algorithms following an inconclusive stress test to define optimal testing strategies.

Study limitations
First, the study was retrospective with 8.8% patients lost to follow-up, which can be explained by the relatively long follow-up period. The analysis of the CMR perfusion scans was visual, but it represents the most widely accepted clinical method with optimal diagnostic accuracy. Because of the lack of randomization, the prognostic impact of CMR-related revascularization cannot be formally established. Moreover, the reasons for the absence of revascularization in patients with ischemia mostly included non-significant lesions, technical difficulties, small ischemic territory, and coronary arteries < 2 mm diameter, but those data were not formally collected. Also, technical details regarding revascularization such as the type and number of stents or anti-platelet strategy were not collected. However, these limitations were related to patient care and reflect current clinical practice. The Syntax score or other specific predictive models of CVD events after revascularization were not available in this study. The current study was not designed to assess the potential prognostic value of a first inconclusive stress test before stress CMR. Finally, although adenosine or regadenoson is commonly used for vasodilator stress CMR, dipyridamole was used in our center mainly because of medico-economic reasons and very close efficacy/safety profile compared to adenosine.

Conclusion
In consecutive patients with a first inconclusive noninvasive stress test, stress perfusion CMR has good long-term prognostic value to predict MACE and CV mortality. The presence and extent of inducible myocardial ischemia are independently associated with CV mortality and nonfatal MI and offer incremental prognostic value over traditional CVD risk factors.