Routine revascularization with percutaneous coronary intervention in patients with coronary artery disease undergoing transcatheter aortic valve implantation - the third nordic aortic valve intervention trial - NOTION-3.

BACKGROUND: Coronary artery disease (CAD) frequently coexists with severe aortic valve stenosis (AS) in patients planned for transcatheter aortic valve implantation (TAVI). How to manage CAD in this patient population is still an unresolved question. In particular, it is still not known whether fractional flow reserve (FFR) guided revascularization with percutaneous coronary intervention (PCI) is superior to medical treatment for CAD in terms of clinical outcomes. STUDY DESIGN: The third Nordic Aortic Valve Intervention (NOTION-3) Trial is an open-label investigator-initiated, multicenter multinational trial planned to randomize 452 patients with severe AS and significant CAD to either FFR-guided PCI or medical treatment, in addition to TAVI. Patients are eligible for the study in the presence of at least 1 significant PCI-eligible coronary stenosis. A significant stenosis is defined as either FFR ≤0.80 and/or diameter stenosis >90%. The primary end point is a composite of first occurring all-cause mortality, myocardial infarction, or urgent revascularization (PCI or coronary artery bypass graft performed during unplanned hospital admission) until the last included patient have been followed for 1 year after the TAVI. SUMMARY: NOTION-3 is a multicenter, multinational randomized trial aiming at comparing FFR-guided revascularization vs medical treatment of CAD in patients with severe AS planned for TAVI.

Drug-coated balloon for treatment of de-novo coronary artery lesions in patients with high bleeding risk (DEBUT): a single-blind, randomised, non-inferiority trial.

BACKGROUND: The optimal technique of percutaneous coronary intervention in patients at high bleeding risk is not known. The hypothesis of the DEBUT trial was that percutaneous coronary intervention with drug-coated balloons is non-inferior to percutaneous coronary intervention with bare-metal stents for this population. METHODS: The DEBUT trial is a randomised, single-blind non-inferiority trial done at five sites in Finland. Patients were eligible if they had an ischaemic de-novo lesion in a coronary artery or bypass graft that could be treated with drug-coated balloons, at least one risk factor for bleeding, and a reference vessel diameter of 2·5-4·0 mm. Those with myocardial infarction with ST-elevation, bifurcation lesions needing a two-stent technique, in-stent restenosis, and flow-limiting dissection or substantial recoil (>30%) of the target lesion after predilation were excluded. After successful predilation of the target lesion, patients were randomly assigned (1:1), by use of a computer-generated random sequence, to percutaneous coronary intervention with a balloon coated with paclitaxel and iopromide or a bare-metal stent. The primary outcome was major adverse cardiac events at 9 months. Non-inferiority was shown if the absolute risk difference was no more than 3%. All prespecified analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01781546. FINDINGS: Between May 22, 2013, and Jan 16, 2017, 220 patients were recruited for the study and 208 patients were assigned to percutaneous coronary intervention with drug-coated balloon (n=102) or bare metal stent (n=106). At 9 months, major adverse cardiac events had occurred in one patient (1%) in the drug-coated balloon group and in 15 patients (14%) in the bare-metal stent group (absolute risk difference -13·2 percentage points [95% CI -6·2 to -21·1], risk ratio 0·07 [95% CI 0·01 to 0·52]; p<0·00001 for non-inferiority and p=0·00034 for superiority). Two definitive stent thrombosis events occurred in the bare metal stent group but no acute vessel closures in the drug-coated balloon group. INTERPRETATIONS: Percutaneous coronary intervention with drug-coated balloon was superior to bare-metal stents in patients at bleeding risk. The drug-coated balloon-only coronary intervention is a novel strategy to treat this difficult patient population. Comparison of this approach to the new generation drug-eluting stents is warranted in the future. FUNDING: B Braun Medical AG, AstraZeneca, and Competitive State Research Funding of the Kuopio University Hospital Catchment Area.

Long-Term Changes in Invasive Physiological Pressure Indices of Stenosis Severity Following Transcatheter Aortic Valve Implantation.

BACKGROUND: Patients with severe aortic stenosis frequently have coexisting coronary artery disease. Invasive hyperemic and nonhyperemic pressure indices are used to assess coronary artery disease severity but have not been evaluated in the context of severe aortic stenosis. METHODS: We compared lesion reclassification rates of fractional flow reserve (FFR) and resting full-cycle ratio (RFR) measured before and 6 months after transcatheter aortic valve implantation using the conventional clinical cutoffs of ≤0.80 for FFR and ≤0.89 for RFR. This was a substudy of the ongoing NOTION-3 trial (Third Nordic Aortic Valve Intervention). Two-dimensional quantitative coronary analysis was used to assess changes in angiographic lesion severity. RESULTS: Forty patients were included contributing 50 lesions in which FFR was measured. In 32 patients (36 lesions), RFR was also measured. There was no significant change in diameter stenosis from baseline to follow-up, 49.8% (42.9%-57.1%) versus 52.3% (43.2%-57.8%), P=0.50. RFR improved significantly from 0.88 (0.83%-0.93) at baseline to 0.92 (0.83-0.95) at follow-up, P=0.003, whereas FFR remained unchanged, 0.84 (0.81-0.89) versus 0.86 (0.78-0.90), P=0.72. At baseline, 11 out of 50 (22%) lesions were FFR-positive, whereas 15 out of 50 (30%) were positive at follow-up, P=0.219. Corresponding numbers for RFR were 23 out of 36 (64%) at baseline and 12 out of 36 (33%) at follow-up, P=0.003. CONCLUSIONS: In patients with severe aortic stenosis, physiological assessment of coronary lesions with FFR before transcatheter aortic valve implantation leads to lower reclassification rate at 6-month follow-up, compared with RFR.

Microcirculatory Function in Nonhypertrophic and Hypertrophic Myocardium in Patients With Aortic Valve Stenosis.

Background Left ventricular hypertrophy (LVH) has often been supposed to be associated with abnormal myocardial blood flow and resistance. The aim of this study was to evaluate and quantify the physiological and pathological changes in myocardial blood flow and microcirculatory resistance in patients with and without LVH attributable to severe aortic stenosis. Methods and Results Absolute coronary blood flow and microvascular resistance were measured using a novel technique with continuous thermodilution and infusion of saline. In addition, myocardial mass was assessed with cardiac magnetic resonance imaging. Fifty-three patients with aortic valve stenosis were enrolled in the study. In 32 patients with LVH, hyperemic blood flow per gram of tissue was significantly decreased compared with 21 patients without LVH (1.26±0.48 versus 1.66±0.65 mL·min-1·g-1; P=0.018), whereas minimal resistance indexed for left ventricular mass was significantly increased in patients with LVH (63 [47-82] versus 43 [35-63] Wood Units·kg; P=0.014). Conclusions Patients with LVH attributable to severe aortic stenosis had lower hyperemic blood flow per gram of myocardium and higher minimal myocardial resistance compared with patients without LVH.

Enhanced predictive power of quantitative TWA during routine exercise testing in the Finnish Cardiovascular Study.

INTRODUCTION: We examined whether quantification of T-wave alternans (TWA) enhances this parameter's capacity to evaluate the risk for total and cardiovascular mortality and sudden cardiac death (SCD). METHODS AND RESULTS: The Finnish Cardiovascular Study (FINCAVAS) enrolled consecutive patients (n = 2,119; 1,342 men and 777 women) with a clinically indicated exercise test with bicycle ergometer. TWA (time domain-modified moving average method) was analyzed from precordial leads, and the results were grouped in increments of 10 microV. Hazard ratios (HR) for total and cardiovascular mortality and SCD were estimated for preexercise, routine exercise, and postexercise stages. Cox regression analysis was performed. During follow-up of 47.1 +/- 12.9 months (mean +/- standard deviation [SD]), 126 patients died: 62 were cardiovascular deaths, and 33 of these deaths were sudden. During preexercise, TWA >or= 20 microV predicted the risk for total and cardiovascular mortality (maximum HR >4.4 at 60 microV, P < 0.02 for both). During exercise, HRs of total and cardiovascular mortality were significant when TWA measured >or=50 microV, with 90 microV TWA yielding maximum HRs for total and cardiovascular death of 3.1 (P = 0.03) and 6.4 (P = 0.002), respectively. During postexercise, TWA >or=60 microV indicated risk for total and cardiovascular mortality, with maximum HR of 3.4 at 70 microV (P = 0.01) for cardiovascular mortality. SCD was strongly predicted by TWA levels >or=60 microV during exercise, with maximum HR of 4.6 at 60 microV (P = 0.002), but was not predicted during pre- or postexercise. CONCLUSION: Quantification of TWA enhances its capacity for determination of the risk for total and cardiovascular mortality and SCD in low-risk populations. Its prognostic power is superior during exercise compared to preexercise or postexercise.

Prognostic capacity of a clinically indicated exercise test for cardiovascular mortality is enhanced by combined analysis of exercise capacity, heart rate recovery and T-wave alternans.

BACKGROUND: Exercise capacity, heart rate recovery and T-wave alternans are independent predictors of cardiovascular mortality. We tested whether these parameters contain supplementary prognostic information. METHODS: A total of 3609 consecutive patients (2157 men) referred for a routine, clinically indicated bicycle exercise test were enrolled in the Finnish Cardiovascular Study (FINCAVAS). Exercise capacity was measured in metabolic equivalents, heart rate recovery as the decrease in heart rate from maximum to one minute post-exercise, and T-wave alternans by time-domain Modified Moving Average method. RESULTS: During 57-month median follow-up (interquartile range 35-78 months), 96 patients died of cardiovascular causes (primary endpoint) and 233 from any cause. All three parameters were independent predictors of cardiovascular mortality when analysed as continuous variables. Adding metabolic equivalents (p < 0.001), heart rate recovery (p = 0.002) or T-wave alternans (p = 0.01) to the linear model improved its predictive power for cardiovascular mortality. The combination of low exercise capacity (<6 metabolic equivalents), reduced heart rate recovery (≤12 beats/min) and elevated T-wave alternans (≥60 µV) yielded the highest hazard ratio for cardiovascular mortality of 16.5 (95% confidence interval 4.0-67.7, p < 0.001). Harrell's C index was 0.719 (confidence interval 0.665-0.772) for cardiovascular mortality with previously defined cutpoints (<8 units for metabolic equivalents, ≤18 beats/min for heart rate recovery and ≥60 µV for T-wave alternans). CONCLUSION: The prognostic capacity of the clinical exercise test is enhanced by combined analysis of exercise capacity, heart rate recovery and T-wave alternans.

Importance of regional specificity of T-wave alternans in assessing risk for cardiovascular mortality and sudden cardiac death during routine exercise testing.

BACKGROUND: T-wave alternans (TWA) indicates increased risk for life-threatening arrhythmias. However, the regional distribution and predictivity of TWA among precordial leads remain unknown. OBJECTIVE: We analyzed the magnitude and prognostic power of TWA in precordial leads separately and in combination during routine exercise stress testing in the largest TWA study conducted to date. METHODS: The Finnish Cardiovascular Study (FINCAVAS) enrolled consecutive patients (n = 3,598, 56 ± 13 [mean ± standard deviation] years old, 2,164 men, 1,434 women) with a clinically indicated exercise test with bicycle ergometer. TWA was analyzed with the time-domain modified moving average method. RESULTS: During a follow-up of 55 months (interquartile range of 35-78 months), 231 patients died; 97 deaths were cardiovascular, and 46 were classified as sudden cardiac deaths (SCDs). In Cox analysis after adjustment for common coronary risk factors, each 20-µV increase in TWA in leads V1-V6 multiplied the hazard ratio for cardiovascular mortality by 1.486-fold (95% confidence interval [CI] 1.127-1.952; P = .005). Each 20-µV increase in TWA in lead V5 amplified the hazard ratio for cardiovascular mortality by 1.545 (95% CI 1.150-2.108; P = .004) and for SCD by 1.576 (95% CI 1.041-2.412; P = .033). CONCLUSIONS: Maximum TWA monitored from anterolateral precordial lead V5 is the strongest predictor of cardiovascular mortality and SCD during routine exercise testing in our analysis. Higher TWA values indicate greater cardiovascular mortality and SCD risk, supporting the concept that quantification of TWA should receive more attention.

Atrioventricular conduction and cardiovascular mortality: assessment of recovery PR interval is superior to pre-exercise measurement.

BACKGROUND: A prolonged electrocardiographic PR interval at rest has been considered a benign phenomenon until recently. OBJECTIVE: We hypothesized that measurement of the PR interval during recovery from physical exertion could improve cardiovascular mortality risk stratification because it would track the dynamic influences of homeostatic mechanisms controlling atrioventricular (AV) conduction. METHODS: A total of 1,979 consecutive patients (1,244 men and 735 women) with clinically indicated bicycle ergometer tests enrolled in FINCAVAS (the Finnish Cardiovascular Study) were included in the study. The PR interval was measured at 1 min before and at 2 min after exercise. RESULTS: During the mean follow-up period of 47 months (interquartile range: 37 to 59 months), 50 cardiovascular deaths (end point) were registered. The unadjusted hazard ratios (HR) in Cox regression analyses were significant for both continuous PR interval and first-degree atrioventricular (AV) block for pre- and post-exercise phases. After adjustment for standard markers, the PR interval for 20-ms increments (HR: 1.17, P = .117) and first-degree AV block (HR: 1.85, P = .138) during the pre-exercise phase were not prognostic. However, during recovery from exercise, prolonged AV conduction achieved significance both in continuous (HR: 1.29, P = .006) and dichotomized analyses (HR: 2.41, P = .045). CONCLUSION: The PR interval before exercise is not a robust risk stratifier for cardiovascular death during 4-year follow-up. Post-exercise assessment of AV conduction may offer improved prediction because of functional abnormalities that become manifest only during this physiologic challenge to the heart.

Impaired exercise capacity predicts sudden cardiac death in a low-risk population: enhanced specificity with heightened T-wave alternans.

AIMS: Because sudden cardiac death (SCD) is due to cardiac electrical instability, we postulated that prediction of this mode of death by exercise capacity will be enhanced by combined assessment with T-wave alternans (TWA), an index of repolarization abnormality. MATERIAL AND METHODS: The Finnish Cardiovascular Study enrolled consecutive patients (n=2,044) with a routine clinically indicated exercise test. Exercise capacity was measured in metabolic equivalents (METs) and TWA by time-domain modified moving average method. RESULTS: During 47.2+/-12.8-month follow-up (mean+/-SD) 120 patients died; 58 were cardiovascular deaths, and 29 were SCD. In multivariate analysis after adjustment for sex, age, smoking, use of beta-blockers, as well as other common coronary risk factors, the relative risk of patients whose exercise capacity was depressed (MET < 8) was 8.8 (95% CI 2.0-38.9, P=0.004) for SCD. The combination of low exercise capacity (MET < 8) and elevated TWA (> or =65 microV) yielded relative risks for SCD of 36.1 (6.3-206.0, P<0.001), for cardiovascular mortality of 21.1 (6.7-66.2, P<0.001), and for all-cause mortality of 7.8 (3.5-17.4, P<0.001) over patients with neither factor. CONCLUSIONS: Reduced exercise capacity, particularly in combination with heightened TWA, indicating enhanced cardiac electrical instability, powerfully predicts risk for SCD in patients referred for exercise testing.

Combined assessment of heart rate recovery and T-wave alternans during routine exercise testing improves prediction of total and cardiovascular mortality: the Finnish Cardiovascular Study.

BACKGROUND: Identification of individuals who are at risk for cardiovascular death remains a pressing public health challenge. Derangements in autonomic function acting upon an electrically unstable substrate are thought to be critical elements in triggering cardiovascular events. OBJECTIVE: The purpose of this study was to analyze heart rate recovery (HRR) in combination with T-wave alternans (TWA) to improve risk assessment. METHODS: The Finnish Cardiovascular Study (FINCAVAS) enrolled consecutive patients (N = 1,972 [1,254 men and 718 women], age 57 +/- 13 years [mean +/- SD]) with a clinically indicated exercise test using bicycle ergometer. TWA was analyzed continuously with the time-domain modified moving average method. Maximum TWA at heart rates <125 bpm was derived. RESULTS: During 48 +/- 13 months of follow-up (mean +/- SD), 116 patients died; 55 deaths were cardiovascular. In multivariable Cox analysis after adjustment for common coronary risk factors, high exercise-based TWA (> or =60 microV) and low HRR (< or =18 bpm) yielded relative risks for all-cause mortality of 5.0 (95% confidence 2.1-12.1, P <.01) and for cardiovascular mortality of 12.3 (95% confidence interval 4.3-35.3, P <.01). High recovery-based TWA (> or =60 microV) and low HRR (< or =18 bpm) yielded relative risks for all-cause death of 6.1 (95% confidence interval 2.8-13.2, P <.01) and for cardiovascular mortality of 8.0 (95% confidence interval 2.9-22.0, P <.01). Prediction by HRR and TWA, both singly and in combination, exceeded that of standard cardiovascular risk factors. CONCLUSION: Reduced HRR and heightened TWA powerfully predict risk for cardiovascular and all-cause death in a low-risk population. This novel approach could aid in screening of general populations during routine exercise protocols as well as improve insights into pathophysiology.