Fuster, Valentı́n

Abstract Aims The aim of this article was to compare rates of all-cause death at 10 years following coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) in patients with or without diabetes. Methods and results The SYNTAXES study evaluated up to 10-year survival of 1800 patients with three-vessel disease (3VD) and/or left main coronary artery disease (LMCAD) randomized to receive either PCI or CABG in the SYNTAX trial. Ten-year all-cause death according to diabetic status and revascularization strategy was examined. In diabetics (n = 452), the risk of mortality was numerically higher with PCI compared with CABG at 5 years [19.6% vs. 13.3%, hazard ratio (HR): 1.53, 95% confidence interval (CI): 0.96, 2.43, P = 0.075], with the opposite seen between 5 and 10 years (PCI vs. CABG: 20.8% vs. 24.4%, HR: 0.82, 95% CI: 0.52, 1.27, P = 0.366). Irrespective of diabetic status, there was no significant difference in all-cause death at 10 years between patients receiving PCI or CABG, the absolute treatment difference was 1.9% in diabetics (PCI vs. CABG: 36.4% vs. 34.5%, difference: 1.9%, 95% CI: −7.6%, 11.1%, P = 0.551). Among insulin-treated patients (n = 182), all-cause death at 10 years was numerically higher with PCI (47.9% vs. 39.6%, difference: 8.2%, 95% CI: −6.5%, 22.5%, P = 0.227). Conclusions The treatment effects of PCI vs. CABG on all-cause death at 10 years in patients with 3VD and/or LMCAD were similar irrespective of the presence of diabetes. There may, however, be a survival benefit with CABG in patients with insulin-treated diabetes. The association between revascularization strategy and very long-term ischaemic and safety outcomes for patients with diabetes needs further investigation in dedicated trials. Trial registration SYNTAX: ClinicalTrials.gov reference: NCT00114972 and SYNTAX Extended Survival: ClinicalTrials.gov reference: NCT03417050.

Introduction: The benefits of optimal medical therapy (OMT) with or without percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery have been evaluated in patients with Type 2 Diabetes Mellitus (T2DM) and stable coronary artery disease (CAD) but analyses have not been stratified by detailed angiographic CAD burden or left ventricular ejection fraction (LVEF). Methods: A patient-level meta-analysis was undertaken among T2DM patients enrolled in COURAGE, BARI 2D and FREEDOM to assess the impact of randomization to OMT, PCI + OMT, or CABG + OMT on a composite end-point of Death/MI/Stroke and stratified by LVEF (≥ 50%, < 50%), 1, 2 or 3 vessel disease (VD) (% diameter stenosis ≥ 50%) and presence or absence of proximal left anterior descending (pLAD) disease. Hazard ratios (HR) for treatment groups were calculated from Cox regression models including all patients adjusting for trial and revascularization stratum in BARI 2D. Multivariable adjustment for risk factors was performed as a sensitivity analysis. Results: There were 5,034 patients included in the analysis (BARI 2D: n=2,368, COURAGE: n=766, FREEDOM: n=1,900) of whom 17% had LVEF < 50%, 29% had pLAD, and 77% had 2 or 3 VD. A total of 1,591 patients were randomized to OMT alone, 2,118 to PCI + OMT, and 1,325 to CABG + OMT. There were 1,116 events during a median 4.5 year follow-up. There was no significant effect on outcomes with OMT vs PCI + OMT irrespective of LVEF, presence/absence of pLAD and number of VD. By contrast, CABG + OMT significantly reduced the risk of Death/MI/Stroke in patients with 2 or 3 VD, irrespective of LVEF and presence/absence of pLAD (see Table). Results were similar with multivariable adjustment. Conclusions: In patients with T2DM and stable CAD, OMT alone appears to be as effective as PCI + OMT while CABG + OMT significantly reduces cardiovascular events in those with multivessel CAD, irrespective of LVEF or presence of pLAD.

The study comprised 170 consecutive patients (pts) seen at Mayo Clinic between 1962 and 1970 who underwent mitral valve replacement with Starr-Edwards prosthesis (model 6000 in 35% of pts, model 6120 in 65% of pts) because of significant chronic mitral incompetence (functional Class III-IV). All patients were on oral anticoagulants and were followed until January 1980 with a followup of 10 to 19 years (yrs) (median 15 yrs). We analyzed (1) the cumulative incidence of systemic emboli, their location and whether or not they left residual deficit; and (2) possible risk factors that might have been predictive, including in the analysis: age, sex, functional class, presence or absence of atrial fibrillation, degree of cardiomegaly, type of prosthesis and degree of anticoagulation.At 12 yrs of followup, 48% of pts had at least one episode of emboli (among these pts, 12% had two episodes); the rate of emboli was maximal within 1 yr postoperatively but persisted over the total followup at a rate of about 3% per yr. Of all emboli, 94% occurred in the cerebral circulation and 66% left neurological deficit. Regarding predictive factors, the incidence of emboli was slightly higher in pts with the prosthesis model 6000 (p<0.05) and in pts considered to be poorly anticoagulated (p<0.05).This unique long-term followup study on pts with mitral Starr-Edwards prosthesis reveals that systemic emboli is a persistent and significant problem. Preliminary data indicates that the addition of a platelet inhibitor to the oral anticoagulant may be beneficial.

BG 0 patients (pts) have lower risk for cardiovascular-thromboembolic disease than A-AB-B pts, particularly males. This might be related to blood hypocoagulability (lower Factor VIII). We report BG frequencies in our Caucasian renal transplant population divided in two groups, ES reflux nephropathy (RN) and ESRD of other etiologies excluding diabetes mellitus.BG 0 male pts are protected, especially for ESRN. To determine whether this sex dependency could be related to different VIII: RWF levels or PS, VIII:RWF levels (n=82) and 51Cr-labelled PS (n=74) were analyzed in controls according to sex and BG.VIII: RWF is sex independent and lower in BG 0. PS is BG independent and shortened in males. A hypercoagulable State reflected by high VIII: RWF and short PS might explain the increased risk of non-BG 0 males to develop ESRD. Non-BG 0 male pts with RN may be more susceptible to develop progressive RD.

In right-sided extracardiac conduits inserted for surgical correction of certain congenital heart defects, obstruction is a significant late complication requiring conduit replacement in about 5% of the patients. Our histopathologic study indicates a significant role of platelets in the pathogenesis. This study was designed to evaluate the feasibility of imaging procedure with 111-Indium-labeled platelets to localize and later quantify platelet accumulation in the conduits. Four patients with pulmonary atresia and 1 with truncus arteriosus underwent conduit placement, 2 with and 3 without porcine valve. Autologous platelets collected.from 43 ml of blood drawn prior to surgery were labeled with 111-Indium-oxine in ACD-saline medium (labeling efficiency 50-60%). 400-500 μCi of autologous 111-Indium-labeled platelets were administered intravenously immediately after surgery in 4, and five days after surgery in 1 patient. Imaging was performed at 6 hours and daily for 1-4 days using a portable gamma camera interfaced with a computer and fitted with medium-energy parallel hole collimator. Platelet deposition was noted at the site of the conduit in all 5 patients. Maximum accumulation (0.1-0.3% of dose) of platelets was seen within the first 24 hours. Activity over blood pool and lungs declined and over liver and spleen increased in a predictable manner over the imaging period. This technique has potential use as a noninvasive quantitative tool to study the effect of platelet inhibitor drugs in preventing conduit obstruction.

Platelet-arterial wall interaction appears to be important in the genesis of atherosclerosis. Pigs with homozygous von Willebrand’s disease (vWd) appear resistant to atherosclerosis. We investigated whether there is impairment in platelet-arterial wall interaction in porcine vWd. Superficial endothelial injury was produced in a 4 cm segment of carotid artery by drying for 3 minutes in a stream of air which entered one end (100 ml/min) and exited through a small hole in the other end. This procedure was performed in 9 normal and 6 vWd pigs 24 hours after the I.V. infusion of III-Indium-labeled platelets. Carotid blood flow was re-established and the pigs were sacrificed 24 hours later and the carotids fixed in glutaraldehyde.The ratio of radioactivity (cpm/g) of injured/noninjured carotid arteries was markedly decreased in the vWd pigs. In addition, transmission and scanning electron microscopy confirmed superficial endothelial damage in all injured segments, but only significant platelet deposition in the normal pig injured segments.After a mild endothelial injury, this “in vivo” evidence of impaired platelet-arterial wall interaction in vWd may be related to the resistance to atherosclerosis in these animals.

Eighteen dogs underwent aortocoronary femoral vein bypass graft surgery. All dogs were injected with 300 μCi of I-131-iodocholesterol and 100 μCi of C-14-cholesterol and sacrificed 24 hours postoperatively: group I dogs, 1 day; group II dogs, 3 days; group III dogs, 7 days; and group IV dogs, 1 year after surgery respectively. Radioactivity in blood, grafted femoral vein (GFV), control femoral vein (CFV), femoral artery, aorta and vena cava were determined with Beckman gamma and beta counters. Results indicate a sixfold increase in permeability as assessed by uptake of cholesterol in grafted vein with respect to control vein in the 1-day period postsurgery.The cholesterol uptake in GFV (p<.01) decreases to half of this value seven days after surgery. Scanning electron microscopy demonstrates patchy endothelial cell loss from GFV and slow re-endothelialization which decreases cholesterol uptake.Vein graft permeability as assessed by cholesterol uptake thus provides a sensitive marker of graft de- endothelialization. This information is now permitting us to better understand the platelet-arterial wall interaction and of the role of platelet inhibiting drugs at different stages after aortocoronary bypass surgery.

The incidence of reinfarction, death and systemic thromboembolism is greatest in the first 2 months after acute myocardial infarction and decreases with time after infarction. Reasons for this are unknown, but increased platelet vascular wall interaction may be a contributing factor. Thirteen patients, mean age 53 years, had a platelet survival determination (platelet half-life calculated by least square analysis) within 1 month (mo) after acute, uncomplicated myocardial infarction (10 transmural, 3 subendocardial); a platelet survival study was repeated 3-8 mo (average 4 mo) later. All patients were on oral anticoagulants and during the time of observation none of the patients had any clinical thromboembolic events.Ten of the 13 patients had a shortened (<92 hours) platelet survival half-life of 75 hours (avg) within 1 mo after myocardial infarction which increased significantly (P<.01) to 94 hours (avg) four mo (avg) later. Ten control patients with angiographically proven coronary artery disease, stable angina pectoris, and a shortened platelet survival of 85 hours (avg) had a repeat platelet survival 6 mo later that was not significantly changed (mean variability 5%).The shortened platelet survival that improves with time after myocardial infarction is compatible with the increased incidence of reinfarction, death and thromboembolism early after myocardial infarction. Whether the increased platelet consumption reflects platelet deposition in the coronary vessels or in the left ventricle (as a mural thrombus) is at present under investigation with imaging of III-Indium-labeled platelets.

Platelet calcium appears to be essential in platelet activation. Accordingly, Verapamil (a channel calcium blocker) was tested “in vivo” as a possible platelet inhibitor agent. Fifteen dogs underwent bilateral femoral artery grafting with one polytetrafluoroethylene (Gore-Tex) and one autologous vein graft. Peroperatively, five dogs were infused continuously with Verapamil (6 μgs/kg/min) and 9 dogs were left untreated and the arterial prostheses were surgically implanted. Using autologous Indium-111-labeled platelets injected 24 hours prior to surgery as a platelet marker, grafts were removed 1 hour following resumption of blood flow. Radioactivity per unit weight of Gore-Tex, vein and blood were determined with a gamma counter and the relative radioactivity with respect to the internal reference standard of blood is tabulated belowVerapamil-treated dogs showed a significant reduction in the “in vivo” platelet deposition on Gore-Tex and autologous venous grafts. Preliminary data indicates that “in vitro” platelet aggregation with soluble calf skin collagen (515 μg/ml) and ADP (2-100 μm) is not different between control and drug-treated dogs.Calcium channel blockers may be promising “in vivo” platelet inhibitor agents; in addition, they may provide further understanding of the different processes involved in “in vivo” and “in vitro” platelet activation.