Efficacy and safety of alirocumab in insulin-treated patients with type 1 or type 2 diabetes and high cardiovascular risk: Rationale and design of the ODYSSEY DM-INSULIN trial.

AIMS: The coadministration of alirocumab, a PCSK9 inhibitor for treatment of hypercholesterolaemia, and insulin in diabetes mellitus (DM) requires further study. Described here is the rationale behind a phase-IIIb study designed to characterize the efficacy and safety of alirocumab in insulin-treated patients with type 1 (T1) or type 2 (T2) DM with hypercholesterolaemia and high cardiovascular (CV) risk. METHODS: ODYSSEY DM-INSULIN (NCT02585778) is a randomized, double-blind, placebo-controlled, multicentre study that planned to enrol around 400 T2 and up to 100 T1 insulin-treated DM patients. Participants had low-density lipoprotein cholesterol (LDL-C) levels at screening≥70mg/dL (1.81mmol/L) with stable maximum tolerated statin therapy or were statin-intolerant, and taking (or not) other lipid-lowering therapy; they also had established CV disease or at least one additional CV risk factor. Eligible patients were randomized 2:1 to 24weeks of alirocumab 75mg every 2weeks (Q2W) or a placebo. Alirocumab-treated patients with LDL-C≥70mg/dL at week 8 underwent a blinded dose increase to 150mg Q2W at week 12. Primary endpoints were the difference between treatment arms in percentage change of calculated LDL-C from baseline to week 24, and alirocumab safety. RESULTS: This is an ongoing clinical trial, with 76 T1 and 441 T2 DM patients enrolled; results are expected in mid-2017. CONCLUSION: The ODYSSEY DM-INSULIN study will provide information on the efficacy and safety of alirocumab in insulin-treated individuals with T1 or T2 DM who are at high CV risk and have hypercholesterolaemia not adequately controlled by the maximum tolerated statin therapy.

[Operative risk of heart valve surgery after 80 years]. / Le risque opératoire de la chirurgie valvulaire après 80 ans.

The continuous prolongation of life expectancy in developed nations and the progress made in the surgical treatment of valvulopathy have substantially increased the number of octogenarians undergoing heart valve surgery with extracorporeal circulation. Most of them have calcified aortic stenosis and the valve is replaced with a bioprosthesis. At these ages, mitral valve disease--usually insufficiency--is predominantly treated by repair rather than valve replacement. In both cases, the etiology is primarily degenerative. In addition, an ever-increasing percentage of these patients require replacement of deteriorated bioprostheses. These octogenarians are exposed to surgical risk estimated to be about 9-10%, i.e. 2-3 times higher than that of patients under 70 years of age, and even higher when surgery is a reintervention. Furthermore, morbidity affecting approximately an additional third of those undergoing surgery must be added to this mortality. Therefore, only half of the patients have uncomplicated surgical outcomes. Age is not the only factor enhancing the risk, which is also linked to comorbidities, preoperative functional class, stage of the evolving valvulopathy, and association of coronary artery disease. Predictive scores (Parsonnet, EuroScore) have been devised to evaluate the surgical risk to which these patients are subjected. Rigorous selection of patients with severe valvulopathy should enable potential candidates, willing to undergo an intervention, to be provided with indications for surgery sufficiently early so as to not enhance the risk by intervening too late.

[Can bioprostheses be implanted at younger ages?]. / Peut-on abaisser l'âge d'implantation des bioprothèses?

The choice between mechanical prosthesis (MP) and bioprosthesis (BP) depends on the respective advantages and disadvantages of the two types of valves. MP theoretically have an indefinite life span but carry the risk of thromboembolic events that requires anticoagulant therapy, which itself is responsible for hemorrhages. BP bear a theoretically lower thromboembolic risk but have a limited life span that requires reintervention at a subsequent date, latter when the patient is older at implantation and operated on for aortic replacement. Actually MP is preferred before 60 years and BP after 70 years. Between 60 and 70 years there is not consensus. The limit recommended is around 65 years for aortic replacement and 70 years for mitral replacement. This limit can change either for upper or lower limit depending on patient's life expectancy, technological improvements of MP as well as BP, improvements of medical follow up of anticoagulant therapy (either self testing or use of anti thrombin). In the future the age limit of implantation of BP can be lowered but MP didn't have their last word.

[The best of valvular heart disease in 2002]. / L'essentiel de 2002 des valvulopathies.

For AS, besides a very thorough update by Carabello on their management, new experimental work confirms that the pathophysiology of the condition is closer to atherosclerotic and inflammatory processes than pure degeneration. Moreover this year brings a batch of long term post-operative results, one of which is an important series relating to 2194 bioprostheses followed up for 15 years. The choice of valvular substitute between 60 and 70 years old is the subject for several studies. A series of 259 re-operations for bioprosthesis deterioration allows quantification of the operative risk to which those with this substitute are subjected in case of degeneration. Finally, the strategy to adopt in a patient with an indication for aortocoronary bypass but also with a not-tight AS is discussed (abstention, decalcification, or "preventive" valvular replacement?). For aortic insufficiency (AI) some new results for the Ross operation have been published and the first publications reporting on the attempts of experimental positioning of bioprostheses via the percutaneous route in animals are appearing. As for mitral valvulopathies, MI has carved a privileged place. Much work this year relates amongst other things to functional MI in dilated cardiomyopathies with dilatation of the ring, to the natural history of mitral valvular prolapse detailed in an important series of 833 patients, and to the evolutive risk of atrial fibrillation (AF) with MI and its treatment during plasty or mitral valvular replacement procedures. Anticoagulant treatment for mechanical prostheses is the subject of much work drawn from a large German prospective study (GELIA) confirming the general tendency for alleviation of intensity in aortic especially but also mitral valvulopathies, stressing the advantages of autocontrol. Finally, the Valvulopathy Working Group of the European Society of Cardiology publishes its recommendations for asymptomatic valvulopathies, recalling the echographic criteria of dilatation and left ventricular function to be retained for operative indications, emphasising furthermore the significance of the stress test in the follow up of asymptomatic AS.

[Anticoagulation of valvular prostheses]. / L'anticoagulation des prothèses valvulaires.

Prosthetic valve replacement has transformed the outcome of patients with severe or poorly tolerated valvular heart disease. Between the two main families of prostheses, only mechanical prostheses require indefinite anticoagulant therapy to lower the thromboembolic risk. National and international guidelines have been published within the past decade. They have outlined how anticoagulation, essentially oral anticoagulant therapy and transient heparin, should be used. The intensity of anticoagulation depends on the type of prosthesis, its position, the presence of atrial fibrillation and the individual's risk of thromboembolism. Monitoring is based on the INR. Temporary recourse to heparin therapy is necessary for all situations in which the risk of major hemorrhage requires more flexible treatment (postoperative period, extracardiac surgery, stroke, severe hemorrhage) or when warfarin is contraindicated because of its risk of inducing malformation (pregnancy). Low molecular weight heparins are not yet authorized for use in prosthesis bearers. Nonetheless, they are being prescribed by more-and-more teams, seduced by the facility of their use, their more stable action and, usually, no need for biological monitoring. And their use is supported by the most recent guidelines, several favorable publications, and the excellent results obtained with them in treating other thromboembolic pathologies. Indispensable to lower the rate of thromboembolic events, anticoagulant therapy bears a hemorrhagic risk that is higher for prolonged and marked anticoagulation. On the other hand, despite effective anticoagulation, the occurrence of thromboemboli can lead to considering the adjunction, in certain cases, of anti-platelet aggregating agents, particularly favored in North America, and recommended in Europe for patients with a predilection for atheromas.

[The best of 2001. Valve diseases]. / L'essentiel de 2001 en valvulopathies.

The publications in 2001 regarding valvulopathies have concerned all sectors of this pathology. Aortic valvulopathies are the object of new work supporting the relationship between aortic sclerosis or stenosis and cardiovascular risk factors. They confirm the analogy between lesions of inflammatory origin observed on calcified valves and atherosclerotic plaques (Mohlner). They find higher rates of serum lipids in the case of valvular replacement for stenosis than for aortic insufficiency albeit in an older population (Novaro). Monin shows the possibility of a better pre-operative prognostic approach for advanced aortic stenoses at low transvalvular gradient with left ventricular dysfunction, for which the post-operative results are better when low dose stress echocardiography has shown the existence of a contractile reserve. For the results of aortic surgery with biological prostheses it is widely reported that they behave as homografts (O'Brien), stented heterografts (Puvimanasinghe) or stent-less (Hubaut). A controversy exists on the subject of the degenerative mechanism of bioprostheses between the supporters of the immunological hypothesis (Human) and those of the purely degenerative hypothesis (Mitchell). This controversy is far from being insignificant because the infectious or other risks run by patients with bioprostheses are conceivable with the addition of an immuno-suppressant treatment. Among the mitral valvulopathies, insufficiencies with an ischaemic origin have a harmful effect on the long term prognosis even for medium leaks (Grignoni). As for the method of repairing these ischaemic leaks, consensus has not been reached between the proponents of exclusive revascularisation, plasty or replacement (Mickleborough, Otsuji). The quality of the very long term results for mitral plasty by Carpentier's technique for rheumatic mitral insufficiency (Chauvaud) or non-rheumatic (Braunberger, Mohty) is confirmed, especially for the latter. Its feasibility by a minimally invasive approach is reported (Schroeyers). Anticoagulation for prostheses remains one of the challenges for valvular surgery. The addition of a platelet anti-aggregant is not accepted by all, due to the increased haemorrhagic risk. A meta-analysis of 2,199 operations seems in favour of this addition if the dose is weak (Massel). It's a question of an attitude having become normal practice across the Atlantic, but not in Europe (Englberger).

[Aortic stenosis with left ventricular dysfunction: evaluation and management]. / Le rétrécissement aortique avec dysfonction ventriculaire gauche: évaluation--indications thérapeutiques.

Aortic stenosis is the most frequent valvulopathy in France today. Valve replacement has transformed the prognosis, when indications are present before the appearance of irreversible left ventricular dysfunction. However, some patients are still not seen before this time or their surgery was deferred. Thus, the postoperative prognosis depends on the reversibility of this dysfunction which can occur even when the stenosis is severe and essentially reflects the elevated afterload. The prognosis is less favorable once myocardial fibrosis has developed in response to left ventricular hypertrophy or when ischemic cardiopathy contributes to this dysfunction. The diagnosis and prognosis are based on the confirmation of the presence of a severe stenosis and that the removal of this obstacle will lead to regression of the dysfunction. For this, Doppler echocardiography is determinant, as combined with a dobutamine test, it is able to evaluate the tightness of the stenosis, the severity of the left ventricular dysfunction and its reversibility. When the stenosis is severe with contractile reserve, indicating a better postoperative prognosis, dobutamine does not induce an appreciable change of the aortic area, but the mean pressure gradient, often low prior to dobutamine administration, rises. Although the surgical risk remains higher in the presence of left ventricular dysfunction, the ultimate prognosis is more favorable when the test suggests regression is possible.

[The best in 2000 on valve diseases]. / L'essentiel de 2000 dans les valvulopathies.

During the year 2000, publications on valvular heart disease have concerned all aspects of this field of cardiology at a time when old and dated therapeutic procedures are being reassessed. The ageing population of the developed world has led to aortic stenosis playing a large part, and the study of its natural history has provided two keynote publications. Aortic valve replacement, increasingly involving older patients, led to the evaluation of this surgery in this age group in which bioprostheses are often associated with coronary bypass surgery. Conversely, in younger patients, there is a regain in interest in autograft (Ross' procedure) or homograft valve replacement which requires a rigorous infrastructure of supply. In mitral valve disease, the indications of conservative surgery of mitral incompetence, ideal in degenerative forms of the posterior leaflet, have been progressively extended to include bacterial endocarditis in many cases and ischaemic mitral regurgitation according to some authors. Rheumatic lesions are not commonly treated by this technique although some encouraging results have been reported. Percutaneous mitral commissurotomy has attained maturity in the treatment of mitral stenosis, even in the less favourable forms such as restenosis after an initial percutaneous procedure or even after surgical commissurotomy. Valve replacement surgery by prosthetic valves is forty year old and many long-term retrospective and prospective evaluations of the results on large patient population either with one type of prosthesis or comparing different bioprostheses or bioprostheses with mechanical valves have been performed. The ideal age for implanting bioprostheses remains uncertain, between 60 and 70, depending on the authors. Finally, problems of anticoagulation in patients with prosthetic valves were the object of three interesting publications about the use of low molecular weight heparin, aspirin and the risks during pregnancy. 2000 was a year of steady and regular progress in the study of valvular heart disease without any major revolutionary contributions.

Maximum cardiac output during incremental exercise by first-pass radionuclide ventriculography.

STUDY OBJECTIVE: To validate a noninvasive first-pass radionuclide ventriculographic (FPRV) measurement of maximum cardiac output (Qv) during exercise. DESIGN: Comparison of Qv to that measured by the Fick principle (Qf) at peak exercise. SETTING: Academic cardiopulmonary exercise laboratory. PATIENTS: Seventy-eight consecutive patients without a history of septal defect undergoing clinically indicated maximum incremental cardiopulmonary exercise testing with pulmonary arterial catheterization and FPRV. MEASUREMENTS AND RESULTS: Ventilation and gas exchange were measured breath-by-breath or by a mixing chamber/mass spectrometer system. Arterial and mixed venous O2 content were measured each minute during exercise. When patients without left-to-right ventricular stroke count ratio evidence for left-sided regurgitation were isolated, peak Qv was linearly related to Qf (r=0.75, p=0.0001). To account for a small systematic overestimation (bias) of Qf by Qv, the linear equation for the Qv/Qf relation was derived for patients studied between 1990 and 1993 and applied to those studied subsequently. The resulting corrected peak Qv was tightly related to peak Qf (r=0.90, p<0.001) with confidence intervals for slope and intercept overlapping identity. CONCLUSION: FPRV can reasonably estimate maximum cardiac output during incremental exercise in patients for whom the technique has ruled out left-sided cardiac regurgitant lesions.

[Indications of coronary angioplasty after thrombolysis]. / Indications de l'angioplastie coronaire après thrombolyse.

Thrombolysis is the most widely used method of coronary reperfusion in the acute phase of myocardial infarction. The indications of angioplasty after thrombolysis have been subject of considerable controversy over the last few years. Three randomised trials (TIMI 2, TAMI, ECSG) have shown that it is not desirable to perform systematic immediate angioplasty after intravenous thrombolysis with rt-PA. Angioplasty may be carried out as a "salvage" procedure in cases of failure of thrombolysis. The validity of this approach was confirmed recently by the "RESCUE" trial in anterior myocardial infarction. The practical application of its results is confronted by logistical problems inherent to the practice of angioplasty in the acute phase of myocardial infarction and to the inadequacy of non-invasive methods for the detection of coronary reperfusion after thrombolysis. Angioplasty may also be necessary in cases of left ventricular failure or cardiogenic shock. The efficacy of a rapid angioplasty in cases of recurrence of ischaemia after thrombolysis has been proved in reducing mortality and preserving left ventricular function. The results of TIMI IIB and SWIFT trials show that secondary angioplasty, several days after thrombolysis, is only usually indicated in patients with residual clinical ischaemia or positive stress tests. This attitude should however be modulated in the light of the "open artery" theory and the limitations of methods of evaluating myocardial viability. The present strategies will no doubt be modified with the introduction of new thrombolytic and/or antithrombotic agents and the use of coronary stents.

[Complex cardiac lesion diagnosed more than 20 years after the causal injury]. / Lésion cardique complexe diagnostiquée plus de 20 ans après. Le traumatisme causal.

Penetrating wounds of the heart, when not immediately fatal, may give rise to complex lesions associating valvular regurgitations and fistulous connections. The authors report the case of a patient with mitral and aortic regurgitation associated with an aorto-left atrial fistula of traumatic origin and causing invalidating cardiac failure. The interest of this particular case lies in the duration of the interval between the causal trauma and the appearance of symptoms (over 20 years). Complete surgical repair of the lesions provided a good functional result. The authors discuss the different types of lesions which may be caused by wounds of the heart and their modes of presentation.

[Prosthetic valve endocarditis: current problems]. / L'endocardite infectieuse sur prothèse valvulaire: problèmes actuels.

Prosthetic valve endocarditis is a rare complication of valve replacement surgery but carries a grim prognosis. The physiopathology of this condition allows identification of two clinically distinct forms based on their bacteriological profiles and outcome: early endocarditis, diagnosed in the first year following valve replacement is observed in 0.7 to 3% of cases: staphylococci are the predominant organism as contamination usually occurs at operation. The prognosis is poor due to the high incidence of complications and the mortality rate is about 60 to 70%; late endocarditis: diagnosed after the second year, it is observed in 0.5 to 1% of cases per year. Contamination is due to bacteraemia and the commonest organisms are the streptococci. The mortality rate is over 20%. The diagnosis is particularly difficult in chronic forms and those with negative blood cultures. Cardiac imaging in prosthetic valve endocarditis is mainly dependent on Doppler echocardiography especially using the transoesophageal approach which allows evaluation of lesion such as abscesses, vegetations and perivalvular leaks, and enables planning of treatment. Management is medico-surgical. Apart from symptomatic treatment of complications, antibiotic therapy using synergistic drugs at bactericidal dosages intravenously is essential as soon as bacteriological specimens have been sent for culture. Surgery is essential in early forms but may be avoided in uncomplicated late forms. The timing of surgery (the objectives of which are to excise the infected material, to repair destructive lesions and to implant a new valve) is a decisive factor in reducing the morbidity and mortality of this condition. Prophylactic measures have a particularly important role to play: they are based on pre- per- and postoperative guide lines.

[Contribution of antimyosin antibody myocardial scintigraphy in the diagnosis of acute myocarditis]. / Apports de la scintigraphie myocardique aux anticorps anti-myosine dans le diagnostic des myocardites aiguës.

The authors report three cases of acute myocarditis: the first patient was a 23 year old woman treated for tuberculosis who presented with rapidly progressive congestive cardiac failure. The second patient was a 52 year old man with atypical chest pain and the third was a 55 year old woman presenting as an acute myocardial infarction. In all three cases, a positive antimyosin antibody myocardial scintigraphy supported the presumptive diagnosis. The authors review the principles of the method and its potential indications, antimyosin antibody scintigraphy being able to demonstrate recent myocardial necrosis but not to identify the cause. The sensitivity of the technique is high (83 to 100% according to the series) but the specificity is much lower (about 55%) compared with endomyocardial biopsy, an investigation which is specific but not very sensitive. Modifications of the antibody and the radioactive tracer used at present should improve the diagnostic value of the technique in the near future.

[Other indications of thrombolysis: thrombolysis in the elderly, late thrombolysis]. / Les autres indications de la thrombolyse: thrombolyse chez le sujet âgé, thrombolyse tardive.

Thrombolytic therapy has been shown to preserve left ventricular function and reduce mortality in the acute phase of myocardial infarction. When the usual inclusion criteria are respected, only about 30% of patients can benefit from this form of treatment. The "excluded" cases are more numerous and have a worse prognosis. This has led to a review or the indications, especially with respect to age and the maximum time delay before instituting treatment. The data currently available comes mainly from large from retrospective analyses of subgroups taken from large scale thrombolytic trials, and must be confirmed by randomized studies specifically designed to analyse these problems. In elderly patients, the benefits in terms of mortality are important but the haemorrhagic risk is also greater and has to be accurately evaluated. Age by itself should not be considered to be an absolute contraindication to thrombolytic therapy which may be undertaken in elderly patients with large infarcts after having carefully excluded the other contraindications frequently observed in this age group. Late thrombolysis probably acts by mechanisms other than limitation of infarct size. The results are less impressive than when thrombolysis is instituted early require confirmation by the randomised studies currently under way. However, at present, is seems justified to prescribe thrombolytic therapy after the 6th hour in patients with large infarcts who continue to have chest pain. The limitations of thrombolytic therapy with regards to age and delay of administration should, therefore, be reconsidered taking into account the individual risk benefit ratio.

Cerebral blood flow in the anaesthetized immature sheep fetus and the response to hypercapnia.

Regional cerebral blood flow (CBF) has been measured in eight anaesthetized, exteriorized, fetal sheep between 58 and 62 days gestation; four were controls, four were hypercapnic (PaCO2 = 78 +/- 5 mmHg, mean +/- S.E.M.). Blood flow values were calculated from quantitative autoradiography following the infusion of [14C]iodoantipyrine into a cannulated fetal placental vein, for the cerebellum, medulla, and five layers of the developing neocortex: cortical plate (CP), subplate zone (SP), intermediate zone (IZ), subventricular zone (SV), and the ventricular zone (VZ). The highest control CBF rates were recorded in the cortical plate (49.3 +/- 7.4 ml min-1 (100 g)-1, mean +/- S.E.M., posterior cortex) and in the ventricular zone (40.5 +/- 4.8, posterior cortex), which at this stage of development are the regions of greatest cell density. The lowest CBF rates were recorded in the subplate zone (23.8 +/- 6.8, anterior cortex) and in the intermediate zone (23.4 +/- 7.6, anterior cortex), which are the regions of lowest cell density. Experimentally induced hypercapnia increased CBF in all brain regions and enhanced the regional pattern of flow. The results provide evidence that CBF in the immature fetal sheep brain (at 58-62 days gestation) is heterogeneous under both control and hypercapnic conditions (especially in the neocortex). Blood vessels of the fetal sheep brain at this early stage of development are clearly responsive to CO2.

Immediate and mid-term results of percutaneous mitral commissurotomy.

The results of percutaneous mitral commissurotomy (PMC) were assessed in a series of 600 patients (pts) with mitral stenosis. Their mean age was 43 +/- 15 years (13-86). One hundred and eight had had a previous surgical commissurotomy; 464 were in NYHA class III or IV; atrial fibrillation was present in 188. One hundred and fifty-nine had valvular calcification and angiography disclosed a mild regurgitation (MR) (1/4) in 255. Technical failure occurred in 19 pts. In the remainder, PMC improved valve function: valve area (VA) increased from 1.1 +/- 0.3 cm2 to 2.2 +/- 0.5 cm2 (P less than 0.0001) as assessed by haemodynamics, and from 1 +/- 0.2 to 2 +/- 0.4 cm2 (P less than 0.0001) as assessed by two-dimensional echocardiography. Complications were as follows: death (0.5%), haemopericardium (0.8%), severe MR (3.8%), embolism (3.3%), atrial shunt (14%). Secondary surgery for complications following PMC was necessary in 4.8% of cases. There were poor results (VA less than 1.5 cm2 and/or MR greater than 2/4) in 13%; their predictors being valve anatomy (P less than 0.001), initial valve area (P less than 0.01) and previous surgical commissurotomy (P less than 0.05). Among the 437 pts resident in France, 98% were followed-up 15 +/- 11 months after PMC (range 1-48). After 42 months, the actuarial rates of survival, freedom from need for reoperation and good functional results were respectively: 87 +/- 6%, 81 +/- 3% and 72 +/- 6%.(ABSTRACT TRUNCATED AT 250 WORDS)

[Delays in hospital admissions of myocardial infarction]. / Délais d'hospitalisation dans l'infarctus du myocarde.

Analysis of the delays in hospital admission to the coronary care unit of 100 patients with recent myocardial infarctions showed an average delay time of 9 hr 50 with early hospital admission within 4 hours in 38% of cases. The number of early hospital admissions increased to: 51% when the infarct was preceded by unstable angina (35 cases, p less than 0.05); 65% when the patient himself diagnosed a coronary thrombosis (34 cases, p less than 0.001); 72% when the intermediary was a specialised emergency medical service called directly by the patient (11 cases, p less than 0.01). These results confirm the necessity of improving public education and of increasing direct access to emergency cardiovascular ambulance services.