Michael J. Zellweger

Incremental cost-effectiveness of drug-eluting stents compared with a third-generation bare-metal stent in a real-world setting: randomised Basel Stent Kosten Effektivitäts Trial (BASKET)

BACKGROUND No prospective trial-based data are available for incremental cost-effectiveness of drug-eluting stents (DES) compared with bare-metal stents (BMS) in unselected patients, as treated in everyday practice. METHODS The Basel stent cost-effectiveness trial (BASKET) included 826 consecutive patients treated with angioplasty and stenting for 1281 de-novo lesions, irrespective of indication for angioplasty. Patients were randomised to one of two DES (Cypher, n=264; Taxus, n=281) or to a cobalt-chromium-based BMS (Vision, n=281) and followed up for 6 months for occurrence of major adverse cardiac events and costs. Analysis was by intention-to-treat. The primary endpoint was cost-effectiveness after 6 months, with effectiveness defined as reduction of major adverse cardiac events. FINDINGS Cardiac death, myocardial infarction, or target vessel revascularisation occurred in 39 of 544 (7.2%) patients with DES and 34 of 280 (12.1%) with BMS (odds ratio 0.56, 95% CI 0.35-0.91; p=0.02), without significant differences between the two DES. Total costs at 6 months were higher with DES (mean 10,544, SD 6849) than with BMS (9639, 9067; p<0.0001); higher stent costs of DES were not compensated for by lower follow-up costs. Incremental cost-effectiveness ratio of DES compared with BMS to avoid one major event was 18,311, and costs per quality-adjusted life-year gained were more than 50 000. Subgroup analyses showed that DES were more cost-effective for elderly patients in specific high-risk groups. INTERPRETATION In a real-world setting, use of DES in all patients is less cost effective than in studies with selected patients. Use of these stents could be restricted to patients in high-risk groups.

Direct comparison of cardiac troponin I and cardiac troponin T in the detection of exercise-induced myocardial ischemia

BACKGROUND It is unknown, whether cardiac troponin (cTn) I or cTnT is the preferred biomarker in the detection of exercise-induced myocardial ischemia. METHODS We investigated patients with suspected myocardial ischemia referred for exercise or pharmacological rest/stress myocardial perfusion single-photon emission computed tomography (SPECT) to directly compare the diagnostic accuracy of high-sensitivity cTnI (hs-cTnI) and hs-cTnT. Diagnostic performance was analyzed separately according to stress modality. Hs-cTnI and hs-cTnT were measured before, immediately after, as well as 2h and 4h after maximal exercise in a blinded fashion. Further, all clinical information available to the treating cardiologist was used to quantify the clinical judgment regarding the presence of myocardial ischemia using a visual analog scale twice: once prior and once after stress-testing. The presence of stress-induced myocardial ischemia was adjudicated using SPECT combined with coronary angiography findings. RESULT A total of 403 consecutive patients were enrolled in our study, of which 229 underwent exercise stress and 174 patients pharmacological stress. Exercise-stress-induced myocardial ischemia was detected in 90 patients (39.3% of 229). Levels of hs-cTnI and hs-cTnT were both significantly higher at all time-points examined in patients with exercise-induced myocardial ischemia as compared to patients without myocardial ischemia (all p<0.001). Correlation of hs-cTnI and hs-cTnT was high in direct comparison of time-points (Spearmans rho all ≥0.7). The AUCs for baseline/peak/2h/4h for hs-cTnI and hs-cTnT were 0.71/0.71/0.72/0.69 vs. 0.74/0.73/0.71/0.72, respectively (all p=ns for hs-cTnI versus hs-cTnT). In patients undergoing pharmacological stress, the AUCs for baseline/peak/2h/4h for hs-cTnI and hs-cTnT were 0.66/0.66/0.68/0.67 and 0.61/0.62/0.64/0.59, respectively (all p=ns for hs-cTnI versus hs-cTnT). Also the combinations including clinical judgment or changes during serial sampling were similar for hs-cTnI and hs-cTnT (all p=ns). CONCLUSIONS Hs-cTnI and hs-cTnT provide comparable diagnostic information regarding exercise-induced myocardial ischemia. Overall, their diagnostic accuracy seems moderate. UNIQUE IDENTIFIER NCT01838148.

B-type Natriuretic Peptide and Clinical Judgment in the Detection of Exercise-induced Myocardial Ischemia

BACKGROUND Myocardial ischemia has been shown to be associated with increased levels of B-type natriuretic peptide (BNP). However, it remains unclear whether and how BNP levels could be used clinically in patients with suspected exercise-induced myocardial ischemia. METHODS We enrolled 274 consecutive patients with suspected exercise-induced myocardial ischemia referred for evaluation by rest/bicycle myocardial perfusion single-photon emission computed tomography (SPECT). All clinical information available to the treating cardiologist was used to quantify the clinical judgment regarding the presence of myocardial ischemia using a visual analogue scale twice: once before and once after bicycle exercise stress testing. BNP measurements were obtained before, immediately after, and 2 hours after stress testing in a blinded manner. The presence of myocardial ischemia was adjudicated on the basis of perfusion SPECT combined with coronary angiography findings. RESULTS Exercise-induced myocardial ischemia was adjudicated to be present in 103 patients (38%). BNP levels were significantly higher at all time points in patients with myocardial ischemia compared with those without (P < .01 for all). The accuracy of BNP levels as quantified by the area under the receiver operating characteristic curve (AUC) was similar among the time points evaluated (AUC, 0.677-0.697). Combining clinical judgment before exercise testing with BNP levels at rest increased diagnostic accuracy from AUC 0.708 to 0.754 (P = .018). When combining clinical judgment after exercise testing with BNP levels, AUC increased from 0.741 to 0.771 (P = .055). CONCLUSIONS Combining clinical judgment with BNP levels increased the diagnostic accuracy regarding the presence of myocardial ischemia.

Predictors of impaired heart rate recovery: a myocardial perfusion SPECT study

Background Heart rate recovery (HRR) is an established prognostic predictor. However, a number of methodological issues have not been fully explored, including differences in HRR 1 versus 2 min after exercise termination, absolute versus relative HRR, and the impact of β-blockers. Design Cross-sectional study. Methods Predictors of impaired absolute and relative HRR 1 (HRR-1, HRR-1%) and 2 min after exercise termination (HRR-2, HRR-2%), defined as their lowest quartiles, were assessed in 1667 patients undergoing cycle exercise myocardial perfusion single photon emission computed tomography, and measures of HRR were compared between patients undergoing myocardial perfusion single photon emission computed tomography with continued, discontinued, and without β-blockers. Results Higher resting heart rate was an independent predictor of all measures of impaired HRR (P < 0.001 for all). Lower peak heart rate was independently associated with impaired HRR-1, HRR-2, and HRR-2% (P < 0.001 for all) but not HRR-1%. Higher summed rest score as a marker of scar and in part left ventricular dysfunction was an independent predictor of impaired HRR-1 (P = 0.010) and HRR-1% (P = 0.025) but not HRR-2 and HRR-2%, whereas lower stroke volume index was an independent predictor of slow HRR-2 (P = 0.004) and HRR-2% (P = 0.02) but not HRR-1 and HRR-1%. HRR-1 (P = 0.98) and HRR-2 (P = 0.86) were similar in patients with continued, discontinued, and without β-blocker therapy. In contrast, HRR-1% (P = 0.01) and HRR-2% (P = 0.001) were faster in patients on β-blockers than in the other groups. Conclusion HRR-1 and HRR-2 as well as HRR-1% and HRR-2% reflect different pathophysiological processes. Relative but not absolute measures of HRR seem to be enhanced under β-blockers. Eur J Cardiovasc Prev Rehabil 17:303-308

Prospective Validation of a Biomarker-Based Rule Out Strategy for Functionally Relevant Coronary Artery Disease

BACKGROUND This study aimed to prospectively advance a rule-out strategy for functionally significant coronary artery disease (CAD) by use of high-sensitivity cardiac troponin I (hs-cTnI) from bench to bedside, by application of a 3-step approach: validation in serum, correlation in plasma, and application on a clinical platform. METHODS Patients without known CAD referred for rest/stress myocardial perfusion single-photon emission tomography/computer tomography (MPI-SPECT/CT) were assigned to 3 consecutive cohorts: validation, correlation, and application. Functionally relevant CAD was adjudicated with the use of expert interpretation of MPI-SPECT/CT and, if available, coronary angiography. In the validation cohort resting hs-cTnI was measured in serum before stress testing with the research Erenna system, in serum and plasma in the correlation cohort with the research Erenna system, and in plasma in the application cohort with the clinical Clarity system. RESULTS Overall, functionally relevant CAD was adjudicated in 21% (304/1478) of patients. In the validation cohort (n = 613), hs-cTnI concentrations were significantly higher in patients with functionally relevant CAD (median 2.8 ng/L vs 1.9 ng/L, P < 0.001) as compared to patients without functionally relevant CAD and allowed a rule out with 95% sensitivity in 14% of patients. In the correlation cohort (n = 606), hs-cTnI concentrations in serum and plasma strongly correlated (Spearman r = 0.921) and had similar diagnostic accuracy as quantified by the area under the receiver operating characteristic curve (0.686 vs 0.678, P = 0.425). In the application cohort (n = 555), very low hs-cTnI plasma concentrations (< 0.5 ng/L) ruled out functionally relevant CAD with 95% sensitivity in 10% of patients. CONCLUSIONS A single resting plasma hs-cTnI measurement can safely rule out functionally relevant CAD in around 10% of patients without known CAD.

MR-imaging of the thoracic aorta: 3D-ECG- and respiratory-gated bSSFP imaging using the CLAWS algorithm versus contrast-enhanced 3D-MRA

OBJECTIVE To compare a contrast-enhanced 3D angiography (CE-3D-MRA) with the ECG- and respiratory gated 3D balanced steady state free precession (bSSFP) sequence using the CLAWS algorithm (3D-bSSFP-CLAWS) with respect to acquisition time, image quality, signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR). METHODS 14 patients (4 women, mean age ± SD: 52 ± 18) with known or suspected thoracic aortic disease were imaged on a 1.5T scanner with both sequences. Two readers scored image quality of predefined levels of the thoracic aorta. Acquisition time, SNR and CNR were calculated for each examination. RESULTS Image quality achieved with the 3D-bSSFP-CLAWS was scored significantly better than with the CE-3D-MRA for the aortic annulus (P = 0.003), the sinuses of Valsalva (P = 0.001), the proximal coronary arteries (P = 0.001) and the sinotubular junction (P = 0.001). Effective acquisition time for the 3D-bSSFP-CLAWS and corrected acquisition time (corrected for imaging parameters) was significantly longer compared to the CE-3D-MRA (P = 0.004 and P = 0.028). SNR and CNR were significantly higher for the CE-3D-MRA (P = 0.007 and P = 0.001). CONCLUSIONS Providing the highest scan efficiency for a given breathing pattern, image quality for the proximal ascending aorta achieved with the 3D-bSSFP-CLAWS is significantly superior in contrast to the CE-3D-MRA.

Diagnostic value of ST-segment deviations during cardiac exercise stress testing: Systematic comparison of different ECG leads and time-points

BACKGROUND Exercise ECG stress testing is the most widely available method for evaluation of patients with suspected myocardial ischemia. Its major limitation is the relatively poor accuracy of ST-segment changes regarding ischemia detection. Little is known about the optimal method to assess ST-deviations. METHODS A total of 1558 consecutive patients undergoing bicycle exercise stress myocardial perfusion imaging (MPI) were enrolled. Presence of inducible myocardial ischemia was adjudicated using MPI results. The diagnostic value of ST-deviations for detection of exercise-induced myocardial ischemia was systematically analyzed 1) for each individual lead, 2) at three different intervals after the J-point (J+40ms, J+60ms, J+80ms), and 3) at different time points during the test (baseline, maximal workload, 2min into recovery). RESULTS Exercise-induced ischemia was detected in 481 (31%) patients. The diagnostic accuracy of ST-deviations was highest at +80ms after the J-point, and at 2min into recovery. At this point, ST-amplitude showed an AUC of 0.63 (95% CI 0.59-0.66) for the best-performing lead I. The combination of ST-amplitude and ST-slope in lead I did not increase the AUC. Lead I reached a sensitivity of 37% and a specificity of 83%, with similar sensitivity to manual ECG analysis (34%, p=0.31) but lower specificity (90%, p<0.001). CONCLUSION When using ECG stress testing for evaluation of patients with suspected myocardial ischemia, the diagnostic accuracy of ST-deviations is highest when evaluated at +80ms after the J-point, and at 2min into recovery.

Predictors and prognostic impact of silent coronary artery disease in asymptomatic high-risk patients with diabetes mellitus

AIMS Evaluation of predictors of silent coronary artery disease (SCAD) in high-risk asymptomatic diabetic patients and to evaluate their two-year outcome. METHODS AND RESULTS Four hundred diabetic patients without prior CAD but at high CAD risk underwent myocardial perfusion scintigraphy (MPS) in this prospective multicentre outcome trial. MPS were abnormal in 22% of patients. Male sex (OR 2.223, 1.152-4.290; p=0.017), diabetes duration (OR 1.049,1.015-1.085; p=0·005), peripheral artery disease (OR 2.134, 1·150-3.961; p=0.016), smoking (OR 2.064, 1.109-3.839; p=0·022), systolic blood pressure (OR 1.014, 1.00-1.03, p=0·056), brain natriuretic peptide (OR 1.002, 1.001-1.004, p=0·005) independently predicted an abnormal MPS: if <2 and >3 predictors were present, 3.2% and 47% patients had an abnormal MPS, respectively (p<0·001). Two-year major adverse cardiac event rates increased from 2·9% to 14·6%, cardiac death rates from 0·6% to 4·1% in patients with summed stress scores ≤10 and >10%, respectively (each p<0.045). CONCLUSIONS Male sex, diabetes duration, peripheral artery disease, smoking, elevated systolic blood pressure and increased brain-natriuretic peptides independently predicted SCAD. In presence of >3 predictors, almost 50% of patients had an abnormal MPS. They may benefit from screening by MPS since the extent of the MPS abnormality discriminated clearly between a favourable compared to a bad 2-year outcome. However, even highest risk patients without objective evidence of CAD had a benign prognosis without need for specific evaluation or therapy. TRIAL REGISTRATION NUMBER ISRCTN87953632.

Despite some caveats: a normal myocardial perfusion result is still a strong value!

A normal myocardial perfusion [single photon emission computed tomography (SPECT)] (MPS) is consistent with a low probability of haemodynamically relevant coronary stenosis, an excellent prognosis, and a warranty period of up to 2 years. These facts have been demonstrated extensively in thousands of patients. However, we all know the sobering effect of disappointment when a patient with normal myocardial perfusion is diagnosed with severe triple vessel disease. In these cases, we are going back to see if we have missed anything, if the stress test was really adequate, if the perfusion was absolutely normal, and if there were any discordant findings besides the perfusion findings (typical angina during the stress test, ischaemic electrocardiogram (ECG) changes, transient ischaemic dilation, and increased tracer uptake in the lungs). Yokota et al. describe 133 patients who had normal perfusion findings on MPS but had persistent or worsening chest pain after the test. They underwent subsequent coronary angiography and fractional flow reserve (FFR) testing. These 133 (2%) patients are part of 6603 consecutive patients who had normal perfusion on MPS and underwent the evaluation at the Isala Hospital, Zwolle, in the Netherlands between 2009 and 2014. Of these 6603 patients, only 47 (0.7%) had lesions with an FFR <_ 0.80 and therefore were haemodynamically relevant. The authors conclude, that in selected patients with normal MPS and persistent angina complaints, the prevalence of functionally relevant coronary artery disease (CAD) is very low. These low rates of relevant CAD in patients with normal MPS in patients with chest pain are reassuring, especially in the era in which we often use complimentary information of anatomic and functional testing. How to deal with a normal perfusion and a high calcium score? How to deal with normal perfusion and an obvious stenosis on coronary computed tomography angiography? We still have to learn how to best integrate and weight all the information and variables that may be provided by a contemporary (hybrid) test: pre-test likelihood of CAD, historical and stress test variables, calcium score, coronary computed tomography angiography findings, myocardial perfusion, myocardial blood flow, and ejection fraction. In the current study, it would have been useful to know the baseline characteristics of all 6603 patients with normal MPS and to compare the patients with vs. without persistent symptoms. However, as mentioned by the authors, the lack of this information is one of the several limitations of the study. In addition, the patient group with relevant stenosis is very small (n = 22). As a consequence, the power to detect differences between patients with vs. without relevant stenosis is too low. But still, looking at potential discordant findings, one might think to recognize some hints or slight differences between these groups (Table 1 in the paper of Yokota et al.): patients with relevant stenosis ‘tended’ (in part far away from statistical significance) to have a higher pre-test probability of CAD, to have more often typical angina, ischaemic ECG changes during the stress test, and to have higher calcium scores than patients without relevant stenosis. Ischaemic ECG—changes during physical stress testing in patients with normal perfusion seem to have some prognostic relevance, since the magnitude of ST-depression was a predictor of the composite endpoint of cardiac death, myocardial infarction (MI), or revascularization in a large study of almost 5000 patients. These patients had an intermediate-risk treadmill score (including ST-segment depression in 45% of patients) but with normal perfusion images they were still at low risk for subsequent cardiac death. During pharmacologic stress, the relevance of ECG changes with ST depression is less clear. In a very recent meta-analysis, the rate of cardiac death or MI was increased in patients with transient ischaemic dilation of the left ventricle and normal perfusion, primarily amongst patients with diabetes mellitus, known CAD, and ischaemia. If a coronary calcium score is available it can not only be used for prognostic but also diagnostic purposes. Absent coronary calcifications (calcium score = 0) are consistent with a negative predictive value of 99.5% to exclude coronary stenosis. Normal myocardial perfusion and absent coronary calcium are therefore

Direct Comparison of Cardiac Troponin T and I Using a Uniform and a Sex-Specific Approach in the Detection of Functionally Relevant Coronary Artery Disease

BACKGROUND We aimed to directly compare high-sensitivity cardiac troponin I (hs-cTnI) and high-sensitivity cardiac troponin T (hs-cTnT) in the detection of functionally relevant coronary artery disease (fCAD). METHODS Consecutive patients referred with clinical suspicion of fCAD and no structural heart disease other than coronary artery disease were included. The presence of fCAD was based on rest/stress myocardial perfusion single-photon emission computed tomography/computed tomography and coronary angiography. hs-cTnI and hs-cTnT concentrations were measured in a blinded fashion. Diagnostic accuracy was quantified using the area under the ROC curve (AUC) and evaluated both for uniform use in all patients and for sex-specific use in women and men separately. The prognostic end point was major adverse cardiac events (MACEs; cardiovascular death or myocardial infarction) within 2 years. For the prognostic performance, we used a multivariable model comparison with the Akaike information criterion (AIC). RESULTS fCAD was detected in 613 of 2062 patients (29.7%) overall, 112 of 664 of women (16.9%), and 501 of 1398 of men (35.8%). hs-cTnI and hs-cTnT had comparable diagnostic accuracy when assessed for uniform use in all patients (AUC, 0.68 vs 0.66; P = 0.107) and separately in women (AUC, 0.68 vs 0.63; P = 0.068) and men (AUC, 0.65 vs 0.64; P = 0.475). However, women required lower rule-out cutoffs to achieve high sensitivity, and men needed higher rule-in cutoffs to achieve high specificity. hs-cTnI and hs-cTnT were strongly and independently associated with MACE within 2 years (P < 0.001), with comparable prognostic accuracies by the AIC. CONCLUSIONS hs-cTnI and hs-cTnT provide moderate and comparable diagnostic accuracy. Sex-specific cutoffs may be preferred. The prognostic utility of both troponins is comparable.