Patrick Ohlmann

Registry of transcatheter aortic-valve implantation in high-risk patients

BACKGROUND Transcatheter aortic-valve implantation (TAVI) is an emerging intervention for the treatment of high-risk patients with severe aortic stenosis and coexisting illnesses. We report the results of a prospective multicenter study of the French national transcatheter aortic-valve implantation registry, FRANCE 2. METHODS All TAVIs performed in France, as listed in the FRANCE 2 registry, were prospectively included in the study. The primary end point was death from any cause. RESULTS A total of 3195 patients were enrolled between January 2010 and October 2011 at 34 centers. The mean (±SD) age was 82.7±7.2 years; 49% of the patients were women. All patients were highly symptomatic and were at high surgical risk for aortic-valve replacement. Edwards SAPIEN and Medtronic CoreValve devices were implanted in 66.9% and 33.1% of patients, respectively. Approaches were either transarterial (transfemoral, 74.6%; subclavian, 5.8%; and other, 1.8%) or transapical (17.8%). The procedural success rate was 96.9%. Rates of death at 30 days and 1 year were 9.7% and 24.0%, respectively. At 1 year, the incidence of stroke was 4.1%, and the incidence of periprosthetic aortic regurgitation was 64.5%. In a multivariate model, a higher logistic risk score on the European System for Cardiac Operative Risk Evaluation (EuroSCORE), New York Heart Association functional class III or IV symptoms, the use of a transapical TAVI approach, and a higher amount of periprosthetic regurgitation were significantly associated with reduced survival. CONCLUSIONS This prospective registry study reflected real-life TAVI experience in high-risk elderly patients with aortic stenosis, in whom TAVI appeared to be a reasonable option. (Funded by Edwards Lifesciences and Medtronic.).

Low-Gradient Aortic Stenosis Operative Risk Stratification and Predictors for Long-Term Outcome: A Multicenter Study Using Dobutamine Stress Hemodynamics

Background The prognostic value of dobutamine stress hemodynamic data in the setting of low‐gradient aortic stenosis has been addressed in small, single‐center studies. Larger studies are needed to define the criteria for selecting the patients who will benefit from valve replacement. Methods and Results Six centers prospectively enrolled 136 patients with aortic stenosis (96 men; median age, 72 years [range, 65 to 77 years]; median aortic valve area, 0.7 cm2 [range, 0.6 to 0.8]; mean transaortic gradient, 29 mm Hg [range, 23 to 34 mm Hg]; cardiac index, 2.11 L min‐1 m‐2 [range, 1.75 to 2.55 L min‐1 m‐2]). Left ventricular contractile reserve on the dobutamine stress Doppler study was present in 92 patients (group I) and absent in 44 patients (group II). Operative mortality was 5% (3 of 64 patients) in group I compared with 32% (10 of 31 patients) in group II (P=0.0002). Predictors for operative mortality were the lack of contractile reserve (odds ratio, 10.9; 95% confidence interval [CI], 2.6 to 43.4; P=0.001) and a mean transaortic gradient ≤20 mm Hg (odds ratio, 4.7; 95% CI, 1.1 to 21.0; P=0.04). Predictors for long‐term survival were valve replacement (hazard ratio, 0.30; 95% CI, 0.17 to 0.53; P=0.001) and left ventricular contractile reserve (hazard ratio, 0.40; 95% CI, 0.23 to 0.69; P=0.001). Conclusions In the setting of low‐gradient aortic stenosis, surgery seems beneficial for most of the patients with left ventricular contractile reserve. In contrast, the postoperative outcome of patients without reserve is compromised by a high operative mortality. Thus, dobutamine stress Doppler hemodynamics may be factored into the risk‐benefit analysis for each patient. (Circulation. 2003;108:319‐324.)

Influence of Preoperative Left Ventricular Contractile Reserve on Postoperative Ejection Fraction in Low-Gradient Aortic Stenosis

Background— Dobutamine stress hemodynamics (DSH) has the potential to stratify operative risk in low-gradient aortic stenosis (AS), but little is known about the relation between left ventricle contractile reserve and postoperative left ventricular ejection fraction (LVEF). We sought to assess the value of DSH to predict postoperative improvement in LVEF. Methods and Results— Sixty-six consecutive patients with symptomatic severe AS (aortic valve area ≤1 cm2), LVEF ≤40%, and mean pressure gradient ≤40 mm Hg prospectively enrolled in the French multicenter study on low-gradient AS and who survived to aortic valvular replacement (AVR) were included. Preoperative contractile reserve was present in 46 patients (group I; 70%) and absent in 20 patients (group II; 30%). In the overall sample, 58% of patients improved by 2 New York Heart Association (NYHA) classes after AVR. Mean LVEF improved from 29±6% to 47±11% (P<0.0001). LVEF improved by ≥10 EF units in 38 patients (83%) in group I and in 13 patients (65%) in group II. Mean LVEF improvement was similar in the 2 groups (19±10% versus 17±11%; P=0.54). On multivariable analysis, multivessel coronary artery disease (P=0.05) and baseline mean transaortic pressure gradient (P=0.01) were related to LVEF improvement, whereas contractile reserve was not. Conclusions— LVEF increases in the majority of patients with low-gradient AS who survive after AVR. Although the absence of contractile reserve on DSH is related to high operative mortality, it does not predict the absence of LVEF recovery in patients surviving to AVR. These data further support the concept that surgery should not be contraindicated on the basis of absence of contractile reserve alone.

Dual-antiplatelet treatment beyond 1 year after drug-eluting stent implantation (ARCTIC-Interruption): a randomised trial.

BACKGROUND Optimum duration of dual antiplatelet treatment (DAPT) after coronary stenting remains uncertain, with an unknown efficacy to safety ratio of extended treatment leading to discrepancies between international guidelines and clinical practice. We assessed whether DAPT continuation beyond 1 year after coronary stenting is beneficial. METHODS This analysis was a planned extension of the previously published ARCTIC-Monitoring trial, in which we randomly allocated 2440 patients to a strategy of platelet function testing with antiplatelet treatment adjustment or a conventional strategy after coronary stenting with drug-eluting stent (DES). We recruited patients (aged 18 years or older) scheduled for planned DES implantation at 38 centres in France. After 1 year of follow-up, patients without contraindication to interruption of DAPT were eligible for a second randomisation to this second phase of the study (ARCTIC-Interruption). Using a computer-generated randomisation sequence (1:1; stratified by centre), we allocated patients to a strategy of interruption of DAPT where the thienopyridine was interrupted and single aspirin antiplatelet treatment was maintained (interruption group) or a strategy of DAPT continuation for 6-18 months (continuation group). The primary endpoint was the composite of death, myocardial infarction, stent thrombosis, stroke, or urgent revascularisation, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00827411. FINDINGS Between Jan 4, 2011, and March 3, 2012, 1259 eligible patients were randomly allocated to treatment in ARCTIC-Interruption: 624 to the interruption group and 635 to the continuation group. After a median follow-up of 17 months (IQR 15-18), the primary endpoint occurred in 27 (4%) patients in the interruption group and 24 (4%) patients in the continuation group (hazard ratio [HR] 1·17 [95% CI 0·68-2·03]; p=0·58). STEEPLE major bleeding events occurred more often in the continuation group (seven [1%] patients) compared with the interruption group (one [<0·5%] patient; HR 0·15 [0·02-1·20]; p=0·073). Major or minor bleedings were also more common in the continuation group compared with the interruption group (12 [2%] patients vs three [1%] patients; HR 0·26 [0·07-0·91]; p=0·04). INTERPRETATION Our finding suggests no apparent benefit but instead harm with extension of DAPT beyond 1 year after stenting with DES when no event has occurred within the first year after stenting. No conclusion can be drawn for high-risk patients who could not be randomised. The consistency between findings from all trials of such interruption suggests the need for a reappraisal of guidelines for DAPT after coronary stenting towards shorter duration of treatment. FUNDING Allies in Cardiovascular Trials Initiatives and Organized Networks (ACTION Study Group), Fondation de France, Sanofi-Aventis, Cordis, Medtronic, Boston Scientific, Fondation SGAM.

Diagnostic and prognostic value of circulating D-Dimers in patients with acute aortic dissection.

Objective:We sought to determine whether assessing D-Dimer might be helpful for the management of acute aortic dissection (AAD). Design:Single-center retrospective case-control study. Setting:University Hospital of Strasbourg France. Patients:Patients were 94 consecutive patients admitted to our institution with confirmed AAD and in whom D-Dimer test had been performed at presentation. These patients were matched with 94 controls presenting with clinical suspicion of dissection, which was later ruled out. Interventions:Patient characteristics and clinical course were analyzed. Measurements and Main Results:Ninety-three (99%) patients with AAD had elevated D-Dimer (>400 ng/mL) with a median D-Dimer value of 8610 ng/mL (interquartile range, 2982–20,000 ng/mL). Receiver operating characteristic curves analysis showed that D-Dimer, but not C-reactive protein, troponin, lactate dehydrogenase, or leukocyte count, was predictive of a diagnosis of AAD, with a sensitivity and specificity of 99% and 34%, respectively. D-Dimer concentration positively correlated with the anatomical extension of the dissection to the different segments of the aorta (R = .47, p < .0001). A positive relationship was observed between D-Dimer and in-hospital mortality rate among patients with AAD (p = .037). On multivariate analysis, the independent predictors of in-hospital mortality were the presence of pericardial effusion (odds ratio, 6.80; confidence interval, 1.87–27.60), D-Dimer >5200 ng/mL (odds ratio, 5.38; confidence interval, 1.27–30.87), and female gender (odds ratio, 4.96; confidence interval, 1.39–19.95). Conclusions:D-Dimers are elevated in patients with AAD and provide valuable diagnostic and prognostic information. In patients with acute chest pain and elevated D-Dimer, a diagnosis of AAD should also be considered. D-Dimer might be a useful complementary tool to the current diagnostic work-up of patients with suspected AAD.

Cardiovascular Mortality in Chronic Kidney Disease Patients Undergoing Percutaneous Coronary Intervention Is Mainly Related to Impaired P2Y12 Inhibition by Clopidogrel

OBJECTIVES We sought to determine whether low platelet response to the P2Y(12) receptor antagonist clopidogrel as assessed by vasodilator-stimulated phosphoprotein flow cytometry test (VASP-FCT) differentially affects outcomes in patients with or without chronic kidney disease (CKD) undergoing percutaneous coronary intervention (PCI). BACKGROUND Although both CKD and impaired platelet responsiveness to clopidogrel are strong predictors of unfavorable outcome after PCI, the impact of their association is unknown. The platelet VASP-FCT assay is specific for the P2Y(12) ADP receptor pathway. In this test, platelet activation is expressed as the platelet reactivity index (PRI). METHODS Four-hundred forty unselected patients (CKD: 126, estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m(2)), no-CKD: 314 eGFR >60 ml/min/1.73 m(2)) undergoing urgent (n = 336) or planned (n = 104) PCI were prospectively enrolled. In each subgroup, patients were classified as low-responders (LR: PRI ≥ 61%) or responders (R: PRI <61%) to clopidogrel. RESULTS At a mean follow-up of 9 ± 2 months, all-cause mortality, cardiac death, and possible stent thrombosis were higher in CKD than in no-CKD patients. Within the CKD group, the LR status was associated with higher rates of all-cause mortality (25.5% vs. 2.8%, p < 0.001), cardiac death (23.5% vs. 2.8%, p < 0.001), all stent thrombosis (19.6% vs. 2.7%, p = 0.003), and MACE (33.3% vs. 12.3%, p = 0.007). Conversely, in no-CKD patients, the LR status did not affect outcomes. Multivariate analysis identified Killip class ≥ 3, drug-eluting stent implantation, and the interaction between LR and CKD (hazard ratio: 11.96, 95% confidence interval: 1.22 to 116.82; p = 0.033) as independent predictors of cardiac death. CONCLUSIONS In CKD patients, the presence of low platelet response to clopidogrel is associated with worse outcomes after PCI.

Increased levels of procoagulant tissue factor-bearing microparticles within the occluded coronary artery of patients with ST-segment elevation myocardial infarction: role of endothelial damage and leukocyte activation.

OBJECTIVE During myocardial infarction, platelet activation and endothelial apoptosis are responsible for the release of procoagulant membrane-derived microparticles (MPs) in the bloodstream. Few data are available on the potential role played by MPs in coronary atherothrombosis. In the present study, we investigated the levels and cellular origins of MPs within the occluded coronary artery of patients with ST-segment elevation myocardial infarction (STEMI) treated by primary angioplasty (PCI). METHODS A total of 12 patients with STEMI treated by primary PCI within 24h of symptom onset were included in this study. MPs procoagulant activity and cellular origin were characterized within the occluded coronary artery before PCI (C(0)), after restoration of the epicardial blood flow (C(1)), and in blood collected from the femoral artery (F). RESULTS Levels of leukocyte-derived CD11a(+) MPs, endothelial-derived CD105(+) MPs, and tissue factor (TF)-bearing MPs were significantly higher within the occluded coronary artery than in peripheral blood samples. Restoration of the epicardial blood flow led to a significant reduction of procoagulant CD11a(+) and CD105(+) MPs by 30% and 42%, respectively (p<0.05). CONCLUSIONS Elevation of procoagulant MPs within the occluded coronary artery of patients with STEMI suggests their pathophysiological role in coronary atherothrombosis.

Induction of Nitric Oxide Synthase and Dual Effects of Nitric Oxide and Cyclooxygenase Products in Regulation of Arterial Contraction in Human Septic Shock

BACKGROUND The role of endogenous nitric oxide (NO) and cyclooxygenase metabolites was investigated in contractile responses of small omental arteries from patients with hyperdynamic septic shock. METHODS AND RESULTS Expression of inducible NO synthase (immunostaining) and a high but variable level of NO production (NO spin trapping) was detected in arteries from patients with septic shock. In these vessels, ex vivo contractile responses to the thromboxane A2 analogue U46619 and to low concentrations of norepinephrine (NE) (up to 10 micromol/L) were not significantly different from controls. However, higher concentrations of NE caused pronounced fading of contraction in septic but not in nonseptic arteries. Exposure to either the NO synthase inhibitor NG-nitro-L-arginine methyl ester or the cyclooxygenase inhibitor indomethacin had no effect in control vessels. However, both inhibitors increased the response to the contractile effects of the 2 agonists only in patients with septic shock. In contrast to NG-nitro-L-arginine methyl ester, which decreased the threshold concentration of the fading effect of NE, indomethacin abolished this effect in arteries from septic patients. CONCLUSIONS These results provide direct evidence for the induction of NO synthase in small arteries from patients with septic shock. They suggest that in these arteries, increased production of NO, in conjunction with vasodilatory cyclooxygenase metabolites, contributes to counteract hyperreactivity to agonists and decreases the cyclooxygenase product-mediated pronounced fading of contraction caused by a high concentration of NE.

Characterization of endothelium‐derived relaxing factors released by bradykinin in human resistance arteries

Relaxing factors released by the endothelium and their relative contribution to the endothelium‐dependent relaxation produced by bradykinin (BK) in comparison with different vasodilator agents were investigated in human omental resistance arteries. BK produced an endothelium‐dependent relaxation of arteries pre‐contracted with the thromboxane A2 agonist, U46619. The B2 receptor antagonist, Hoe 140 (0.1, 1 and 10 μM), produced a parallel shift to the right of the concentration‐response curve to BK with a pA2 of 7.75. Neither the cyclo‐oxygenase inhibitor, indomethacin (10 μM) alone, the nitric oxide synthase inhibitor, Nω‐nitro‐L‐arginine methyl ester (L‐NAME, 300 μM) alone, the nitric oxide scavenger, oxyhaemoglobin (Hb, 10 μM) alone, nor the combination of L‐NAME plus Hb affected the concentration‐response curve to BK. Conversely, the combination of indomethacin with either L‐NAME or Hb attenuated but did not abolish the BK‐induced relaxation. By contrast, the relaxations produced by the Ca2+ ionophore, calcimycin (A23187), and by the inhibitor of sarcoplasmic reticulum Ca2+‐ATPase, thapsigargin (THAPS), were abolished in the presence of indomethacin plus L‐NAME. Also, the presence of indomethacin plus L‐NAME produced contraction of arteries with functional endothelium. The indomethacin plus L‐NAME resistant component of BK relaxation was abolished in physiological solution (PSS) containing 40 mM KCl and vice versa. However, in the presence of KCl 40 mM, indomethacin plus L‐NAME did not affect the nitric oxide donor, S‐N‐acetylpenicillamine‐induced relaxation. The indomethacin plus L‐NAME resistant component of the relaxation to BK was significantly attenuated by the K+ channel blocker tetrabutylammonium (TBA, 1 mM). However, it was not affected by other K+ channel blockers such as apamin (10 μM), 4‐aminopyridine (100 μM), glibenclamide (10 μM), tetraethylammonium (10 mM) and charybdotoxin (50 nM). In the presence of indomethacin plus L‐NAME, the relaxation produced by BK was not affected by the phospholipase A2 inhibitor, quinacrine (10 μM) or by the inhibitor of cytochrome P450, SKF 525a (10 μM). Another cytochrome P450 inhibitor, clotrimazole (10 μM) which also inhibits K+ channels, inhibited the relaxation to BK. These results show that BK induces endothelium‐dependent relaxation in human small omental arteries via multiple mechanisms involving nitric oxide, cyclo‐oxygenase derived prostanoid(s) and another factor (probably an endothelium‐derived hyperpolarizing factor). They indicate that nitric oxide and cyclo‐oxygenase derivative(s) can substitute for each other in producing relaxation and that the third component is not a metabolite of arachidonic acid, formed through the cytochrome P‐450 pathway, in these arteries.

Optical Coherence Tomography to Optimize Results of Percutaneous Coronary Intervention in Patients with Non-ST-Elevation Acute Coronary Syndrome: Results of the Multicenter, Randomized DOCTORS Study (Does Optical Coherence Tomography Optimize Results of Stenting).

Background: No randomized study has investigated the value of optical coherence tomography (OCT) in optimizing the results of percutaneous coronary intervention (PCI) for non–ST-segment elevation acute coronary syndromes. Methods: We conducted a multicenter, randomized study involving 240 patients with non–ST-segment elevation acute coronary syndromes to compare OCT-guided PCI (use of OCT pre- and post-PCI; OCT-guided group) to fluoroscopy-guided PCI (angiography-guided group). The primary end point was the functional result of PCI assessed by the measure of post PCI fractional flow reserve. Secondary end points included procedural complications and type 4a periprocedural myocardial infarction. Safety was assessed by the rate of acute kidney injury. Results: OCT use led to a change in procedural strategy in 50% of the patients in the OCT-guided group. The primary end point was improved in the OCT-guided group, with a significantly higher fractional flow reserve value (0.94±0.04 versus 0.92±0.05, P=0.005) compared with the angiography-guided group. There was no significant difference in the rate of type 4a myocardial infarction (33% in the OCT-group versus 40% in the angiography-guided group, P=0.28). The rates of procedural complications (5.8%) and acute kidney injury (1.6%) were identical in each group despite longer procedure time and use of more contrast medium in the OCT-guided group. Post-PCI OCT revealed stent underexpansion in 42% of patients, stent malapposition in 32%, incomplete lesion coverage in 20%, and edge dissection in 37.5%. This led to the more frequent use of poststent overdilation in the OCT-guided group versus the angiography-guided group (43% versus 12.5%, P<0.0001) with lower residual stenosis (7.0±4.3% versus 8.7±6.3%, P=0.01). Conclusions: In patients with non–ST-segment elevation acute coronary syndromes, OCT-guided PCI is associated with higher postprocedure fractional flow reserve than PCI guided by angiography alone. OCT did not increase periprocedural complications, type 4a myocardial infarction, or acute kidney injury. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01743274.