Oral anticoagulation and VKORC1 polymorphism in patients with a mechanical heart prosthesis: a 6-year follow-up.

Therapy with Vitamin K antagonists (VKA) effectively reduces the thrombosis risk in many clinical conditions. Genetic variants of vitamin K epoxide reductase (VKORC-1) are associated with increased VKA effect and bleeding risk. It is unknown whether these variants could also affect the long-term outcome in patients with high-dosage oral anticoagulation and/or more difficult adherence to the therapeutic INR range. Hundred and twenty-four patients with mechanical heart valve replacement assuming VKA were genotyped for VKORC-1 -1639G>A (Rs9923231) polymorphism. Hemorrhage, venous thrombosis and atherothrombotic events were retrospectively assessed for a 6-year period. Furthermore, stability of their INR in relationship with the VKORC-1 genotype was investigated day-by-day for 3 months. No differences were observed in hemorrhage and venous thrombosis events according to rs 9923231. GG genotype carriers (n = 41) had no atherothrombotic events, while 4 strokes, 4 TIA and 3 AMI were diagnosed in A carriers (n = 83; P = 0.0008). During the daily observation period, A allele carriers had lower VKA requirements (4.7, 3.7, 2.2 mg/day for GG/GA/AA genotype respectively; P = 0.00001), higher mean INR (2.7, 2.8, 2.9; P = 0.05) and a higher number of examinations above the therapeutic range than GG carriers (17 % vs. 0 % in GG genotype, P = 0.036). Conversely, patients with GG genotype had a more stable dosage of VKA (P = 0.006) and a higher percentage of examinations under the therapeutic range (51, 43 and 36 % in GG, GA and AA genotype, respectively, P = 0.040). In patients with high dosage VKA, VKORC-1 polymorphism is associated to a different warfarin dosage, anticoagulation level, time spent outside the therapeutic range and, in the long-term, a different incidence of atherothrombotic events.

[Nurse involvement in primary care: it is the key to improve the outcomes in primary and secondary prevention?]. / II coinvolgimento degli infermieri nelle cure primarie: un elemento chiave per la profilassi primaria e secondaria della cardiopatia ischemica? Un'ipotesi aperta alla discussione.

Difficulties in management of risk factors, lifestyle and medications adherence to achieve secondary prevention of ischemic heart disease were described. Many studies indicate that the benefit of cardiac rehabilitation therapy after acute coronary events is only partially maintained during the following year. Thereafter, new strategies of medical care are needed to improve the long-term outcomes in coronary patients. Nurse co-ordinated, multidisciplinary cardiac rehabilitative programme could help patients to improve their lifestyle, to control their risk factors and to achieve their therapeutic goals for secondary prevention of ischemic heart disease.

[The challenge of improving evidence-based therapy adherence in the secondary prevention of coronary artery disease: the next frontier of cardiac rehabilitation]. / Migliorare l'aderenza all'assunzione dei farmaci per la prevenzione secondaria della cardiopatia ischemica: la prossima frontiera della riabilitazione cardiovascolare.

Non-adherence to prescribed drug regimens is an increasing medical problem affecting physicians and patients and contribute to negative outcomes, such as the increased risk of subsequent cardiovascular events. Analysis of various patient populations shows that the choice of drug, its tolerability and the duration of treatment influence the non-adherence. Intervention is required toward patients and health-care providers to improve medication adherence. This review deals about the prevalence of non-adherence to therapy after medical and surgical cardiac event, the risk factors affecting non-adherence and the strategies to implement it. Interventions that may successfully improve adherence should include improved physician compliance with guidelines, patient education and patient reminders, frequent visits or telephone calls from staff, simplification of the patient's drug regimen by reducing the number of pills and daily doses. Since single interventions do not appear efficaceous, it is necessary to establish multiple interventions simultaneously addressing a number of barriers to adherence.

[Lower is better: ENHANCE affair]. / Lower is better: la lezione del trial ENHANCE.

Ezetimibe lowers the intestinal absorption of cholesterol, being complementary to the effects of statin. To check its efficacy in lowering the carotid intima-media thickness, in 2002 a multicenter international trial called ENHANCE was started, in order to assess by ultrasound the regression of atherosclerotic plaques. The protocol tested the use of simvastatin 80 mg + placebo versus simvastatin 80 mg + ezetimibe 10 mg in 720 randomized patients. Both drugs were well tolerated. Combination therapy was associated with a larger reduction in LDL cholesterol, but there were no differences in the intima-media thickness measured at three sites in the carotid arteries, nor differences in cardiovascular events between the two groups in the trial. These results provoked disappointment of sponsors (Merck, Schering Plough) who, although the results of the trial were available since march 2007, delayed official communication of about 18 months. This led to speculations and rumors among media, American Government, cardiologic scientific associations, and consequences in the Ezetimibe market and at Wall Street. In particular, the American College of Cardiology didn't accept the communication of ENHANCE results to the Late Breaking Trial Session of the Chicago congress, diverting it to another secondary forum. In conclusion, the experience of the ENHANCE trial suggests to pharmaceutical companies, researchers, clinicians, scientific companies and media a deep meditation in order to avoid in the future similar problems in the management of results of medical research.

Thirty-nine-year survival with the Starr-edwards mitral valve prosthesis.

We report a case of a 57 year-old woman with Starr-Edwards model 6120 mitral valve replacement and Kay-Shiley bioprosthetic tricuspid valve replacement in 1968 at Niguarda Hospital in Milan. The mitral caged-ball has proved its excellent durability and its good hemodynamic performance in many patients, even if subject to high tendency to thrombosis. In literature there is no evidence of durability of this prosthesis longer than 35 years. Our patient after 39 years from mitral valve replacement lives a happy and fulfilling life (NYHA II), with no evidence of hemolysis, ball variance, symptomatic embolization or major bleeding.

[Sexual activity in women with cardiovascular disease: a literature review]. / Le problematiche sessuali nelle donne con malattie cardiovascolari: una revisione della letteratura.

Female sexual dysfunction (FSD) is a complex condition that involves both psychological and organic domains, including the cardiovascular system, and has an impact on quality of life in more than one third of women. However, only few papers are available in the medical literature regarding FSD and its relation with cardiac diseases. In this review, we discuss the physiology of sexual intercourse in women, the pathophysiology of FSD, the sexual counseling to provide, and the therapeutic choices to minimize the negative impact of cardiovascular diseases on female sexual activity.

[Why do cardiologists disregard sexual health of their patients? A critical review]. / Perché i cardiologi trascurano la salute sessuale dei loro pazienti? Una revisione critica.

Sexual activity is an essential aspect of normal human function, well-being and quality of life. Sexual dysfunction is a common problem of increasing incidence in patients with cardiovascular disease, particularly younger and male, and continues over time in life, but these issues are not often discussed in daily practice both for a limited patient-physician relationship and clinicians' poor knowledge. Many studies suggest that the majority of patients and their partners have questions or concerns about their sexual health. Healthcare providers can help their patients if they are aware of the problem. Cardiologists need more knowledge and specific practical training in providing information on sexual concerns and sexual counseling to cardiac patients. This review aims at providing clinicians with most recent evidence about sexual dysfunction, and its management in patients with cardiac disease. Sexual couseling of cardiac patients is an important role for healthcare providers.

[Remarks on angina pectoris]. / Considerazioni sull'angina pectoris.

In the first volume of the New England Journal of Medicine of 1812, J. Warren published a paper on the subject of angina pectoris, in which clearly emerge the difficulties facing the physicians of that time in trying to formulate a correct diagnosis and prescribe the right therapy. We thought it would be certainly of interest to offer our readers an Italian translation of this article, obviously with some stylistic modifications and supplemented with information coming from other historical scientific works. William Heberden in his report on " breast pain" was the first physician to use the term "angina" and the description of symptoms that he gave in 1772 is still today valid and correct.

[Can we prevent the progression of aortic valve sclerosis and stenosis? The need for a prospective, randomized trial]. / E possibile prevenire la progressione della sclerosi e della stenosi valvolare aortica? Necessità di uno studio prospettico randomizzato.

Cardiologists long assumed that aortic valve sclerosis/stenosis is a wear-and-tear, degenerative process; recent studies suggested that lipoproteins can play a key role in the development of both sclerosis/stenosis in the aortic valve. Thus, sclerosis/stenosis cannot be considered as a simple degenerative process, but on the contrary it is complex and involves multiple pathogenetic mechanisms. Experimental, clinical and epidemiological data support the link between aortic valvulopathy and atherosclerosis: both are caused by inflammation, lipid deposition, and accumulation of extracellular bone matrix protein. In non-randomized clinical studies, hydroxy-methylglutaryl-coenzyme A reductase inhibitors minimized the progression of aortic valvulopathy. The major pharmacological effect, supposed to underlie the inferred (but still unproven) impact of statins on aortic sclerosis/stenosis is plasma cholesterol reduction. Lately, retrospective clinical studies supported this hypothesis and suggested a key role for statins in delaying the progression of aortic valvulopathy. However, the potential favorable effects of statins require confirmation. Prospective trials in Canada and Europe are now ongoing (ASTRONOMER--Aortic Stenosis Progression Observation Measuring Effects of Rosuvastatin; SEAS--Simvastatin and the Ezetimibe in Aortic Stenosis) and will address the use of cholesterol-lowering drugs in reducing the progression of aortic valve stenosis and in improving clinical outcomes.

[Nonvalvular atrial fibrillation: data from the Observatory of Cardiovascular Diseases in the province of Trieste (Italy)]. / La fibrillazione atriale non valvolare: dati dall'Osservatorio delle Malattie Cardiovascolari della provincia di Trieste.

BACKGROUND: Nonvalvular atrial fibrillation (NVAF) is the most common arrhythmia in outpatients and is associated with increased mortality, thromboembolic and hemorrhagic events. Although several international studies have evaluated its prognostic impact in the real world, Italian data are still lacking. Our aim was to define the prevalence, comorbidity, treatment and outcome in a population of "real-life" outpatients with NVAF. METHODS: From 2009 to 2013, 21 282 consecutive patients referred to the Cardiovascular Center of Trieste were enrolled in the study. NVAF was defined in the absence of moderate-to-severe valvular disease, valvular interventions, rheumatic heart disease. Events evaluated in the follow-up included mortality, hospitalizations, thromboembolism and hemorrhage. Clinical data and events were derived from the cardiac regional electronic patient records and the ICD-9 hospital discharge records. RESULTS: 3379 patients (15.8%) had NVAF (35.6% paroxysmal, 34.5% persistent, 29.9% permanent); compared to the general population these patients were older, predominantly male, with hypertension, diabetes and history of stroke/transient ischemic attack and heart failure. Oral anticoagulant therapy was prescribed in 54% of cases, above all in persistent or permanent forms, in patients with higher CHA2DS2-VASc score and younger age. The rate of all-cause mortality, cardiovascular hospitalization, thromboembolic and hemorrhagic events during follow-up was higher in patients with NVAF than in the general population. The use of oral anticoagulant therapy reduced the incidence of thromboembolic events. CHA2DS2-VASc score emerged as an independent predictor of thromboembolic events in patients with paroxysmal (35% higher risk), persistent (40% higher risk) and permanent atrial fibrillation (34% higher risk than patients without atrial fibrillation). CONCLUSIONS: In "real-life" outpatients NVAF is associated with older age, more comorbidities and increased cardiovascular events. CHA2DS2-VASc and HAS-BLED scores predict accurately the risk for thromboembolic and hemorrhagic events. Oral anticoagulation reduces thromboembolic events, but its use is limited to just half of the patients.

Morbidity and mortality in 229 elderly patients with nonrheumatic atrial fibrillation. A five-year follow-up.

BACKGROUND: In the elderly the impact of atrial fibrillation on mortality and morbidity is substantial. Oral anticoagulant therapy reduces the risk of stroke by 70%; nevertheless, it remains largely underused. We evaluated, in a community prospective study, the factors associated with embolic events and death and the feasibility of oral anticoagulant therapy managed by general practitioners. METHODS: We enrolled at the Trieste Cardiovascular Center 229 patients aged > or = 65 years with non-rheumatic atrial fibrillation. At baseline, each patient underwent a transesophageal echocardiography and received instructions about oral anticoagulation. Patients were regularly followed by their general practitioner and finally evaluated at the Center. RESULTS: At baseline, the mean age was 73 years, 14% of patients were free of heart disease, 27% had had a previous embolic event, and 33% had an atrial thrombus. After a 5-year follow-up, 85% of the patients had been admitted to hospital, 17% had suffered an embolic event, and 35% were dead. Diabetes and the presence of a low flow in the left atrial appendage were predictive of embolic events. Heart failure, spontaneous echocontrast and aortic plaques were predictive of death. Anticoagulant therapy increased from 14 to 34% but the incidence of major bleeding did not change. The patients on anticoagulant therapy at follow-up constituted the group with the worst cardiovascular profile and embolic rate, but had a lower death rate (19%) compared with those on antiplatelet therapy (32%) and with those without antithrombotic therapy (67%). The hospitalization rates were respectively 78, 83 and 100%. CONCLUSIONS: In a group of elderly patients followed by their general practitioner with the support of a specialized cardiologic unit, oral anticoagulant therapy was well tolerated and associated with a significant decrease in mortality and hospitalization.

[Ximelagatran: a promising new drug for oral anticoagulation]. / Ximelagatran: nuova prospettiva per l'anticoagulazione orale.

Ximelagatran is the first orally available direct thrombin inhibitor. Ximelagatran is a pro-drug with an antithrombotic effect comparable to that of warfarin. Clinical studies have demonstrated that ximelagatran is as effective as warfarin in the prevention of deep-vein thrombosis, of stroke in patients with nonvalvular atrial fibrillation, and of the adverse cardiovascular events in patients with recent myocardial infarction. Ximelagatran can be administered without any need of laboratory test.

[Cardiac rehabilitation: a plus value for secondary prevention?]. / Riabilitazione cardiovascolare: un valore aggiunto per la prevenzione secondaria?

In patients with a history of myocardial infarction, cardiovascular mortality in the absence of treatment is high (5% per year after a first myocardial infarction and 10% per year after a subsequent myocardial infarction). There is a convincing evidence that secondary prevention reduces the risk of new ischemic events and mortality. Specifically, the modification of cardiovascular risk factors and the use of prophylactic treatments have shown that the risk of a further major ischemic event abruptly decreases. There are a number of effective therapies to consider for these patients after myocardial infarction. Careful patient assessment and individualized treatments are required for the maximum benefit. Patients with coronary artery disease can benefit from both medical and life-style secondary prevention measures. Nevertheless half of these patients in general practice does not have the opportunity for an effective medical intervention. Thus, there appears to be a considerable gap between the ideal management and the actual management in practice of these patients. Several types of strategies to improve disease management may be ineffective. Rehabilitation Centers can assure a continuum in the standard care for patients with coronary artery disease and thus they represent a plus value in secondary prevention.

[Amiodarone and thyroid dysfunction: a pending problem]. / Amiodarone e distiroidismi: un problema ancora aperto.

Amiodarone is an antiarhytmic drug used in many clinical situations for its probed effect; it is also preferred in particular groups of patients (heart failure, post-ischemical) for its safe and its prognostic benefits. However, a substantial proportion of amiodarone treated patients develop either hypothyroidism or thyrotoxicosis. Both abnormalities may occur in apparently normal glands or in glandes with pre-existed abnormalities. It may be difficult to recognize the dysfunction because of the many changes in thyroid function test results that occur in euthyroid patients who are receiving amiodarone. Hypothyroidism is a well defined clinical situation managable thanks to common guidelines. The occurrence of hypothyroidism does not necessitate withdrawing amiodarone while instituting L-T4 replacement therapy, although many cases are transient and will spontaneously remit after amiodarone withdrawal. At the opposite, hyperthyroidism needs more attention to be diagnosed and to be treated, in fact there is a "personal" clinical-therapeutical behave towards it, caused by the lack of big trials made on this clinical situation. Effective strategies exist for the management of thyroid dysfunction, these should be tailored to the needs of the individual patient.

[Control of anticoagulant therapy with portable prothrombin time device in patients with mechanical heart valve prostheses: two-year follow-up]. / Il trattamento anticoagulante con coagulometro portatile nei pazienti portatori di protesi valvolari meccaniche: un follow-up di due anni.

BACKGROUND: Monitoring patients on oral anticoagulation is essential to prevent haemorrhage and recurrent thrombosis, but it is still difficult. We studied a group of 348 patients with mechanical heart valve prostheses to verify whether the use of a new portable prothrombin time device might improve the management of oral anticoagulant therapy. METHODS AND MATERIAL: We used a new portable prothrombin time device to check the anticoagulation therapy in a group of 348 patients with mechanical heart valve prostheses to validate its results by comparing to routine I.N.R. determinations (28 pts) and verify its user-friendliness by a face-to-face interview. Furthermore, the incidence of haemorrhagic and thromboembolic events has been studied by a two-year follow-up. RESULTS: Pearson correlation indicated an R2 = 0.9 between I.N.R. values determined by routine or by a new portable prothrombin time device. All patients agreed to replace the routine I.N.R. determinations with those by the new procedure, particularly female, young and those with usually difficult blood collections. During the two-year follow-up period, 21 haemorrhagic (2.6/100/patients/year) and 5 thromboembolic events (0.6/100/patients/year) occurred; but neither replaced valves' thrombi nor fatal events were found out. CONCLUSIONS: I.N.R.s determined using a new portable prothrombin time device are convincing as routine determinations. Such new procedure improves the quality of life, and the therapeutical range of anticoagulation is maintained safer and longer than by routine determinations. These results suggest that the control of anticoagulation in patients to a set I.N.R. therapeutic range is improved by using portable prothrombin time device in expert anticoagulation clinics, such improvement may result in reducing mortality as well as morbidity in patients treated with oral anticoagulants.

[New perspectives for anticoagulation in non-rheumatic atrial fibrillation: oral antithrombins]. / Nuove prospettive per l'anticoagulazione nella fibrillazione atriale non reumatica: gli inibitori orali diretti della trombina.

Non-rheumatic atrial fibrillation (NRAF) is one among the major public health problems, because it is associated with a high incidence of stroke or systemic thromboembolism. Warfarin significantly reduces cerebral/systemic events mainly in high-risk patients; unfortunately such drug is often as well under-used in eligible patients as under-dosed in treated patients. Traditional therapy with oral anticoagulants has several disadvatages: narrow therapeutic window, and often unpredictable dose-response so that frequent monitoring of the INR is required. It is therefore crucial that patients preferences and education be integrated into the decision-making process. Physicians often underprescribe oral anticoagulants since they perceive the risk of major bleeding as unacceptable because of some well known risk factors (e.g. previous bleedings, severe hypertension), and of qualms about drug interactions or alleged poor compliance. Therefore, the development of easy-to-use antithrombotic agents is still a challenge. New agents such as oral direct thrombin inhibitors are going to hold the promise for the next future. Ximelagatran is an orally active small molecule; being the first new oral anticoagulant used in large clinical trials. This molecule has many advantages in comparison to warfarin, such as the rapid onset/offset of action, the fixed oral dose, the no need of dose adjustment or of anticoagulation monitoring, as well the lack of food/alcohol intake interference as of drug interactions. The SPORTIF III and V trials have shown that ximelagatran is not inferior to warfarin in the prevention of strokes in patients with NRAF (both persistent and paroxysmal), but a side effect--consisting in the significant elevation of liver enzymes (> 3 times the upper limit of normal) in 6% of patients--was found. Further randomized trials are clearly needed, while current data suggest that ximelagatran will be able to represent a future viable therapeutic option for prevention of thromboembolism in patients with NRAF, offering huge advantages with respect to classic oral anticoagulants.

[Family screening of patients with premature coronary artery disease: opportunities and challenges of cardiovascular health in the 21st century]. / Lo screening dei familiari dei pazienti con cardiopatia ischemica precoce: una sfida per promuovere la salute cardiovascolare nel terzo millennio.

A positive family history of premature coronary heart disease is a strong and independent risk factor for relatives and its effect is synergistic with other traditional and not traditional risk factors. It is well documented a familial aggregation of premature coronary heart disease particularly related to family clustering of several cardiovascular risk factors. The screening and the identification, by a comprehensive cardiovascular risk factor assessment, of high-risk relatives of patients with premature coronary artery disease by cardiologists and general practitioners is crucial. A family-centered approach to the prevention of coronary artery disease represents an opportunity and a challenge for promoting cardiovascular health in the 21st century.

[Antithrombotic prophylaxis in patients with ventricular dysfunction: critical review of the literature and new perspectives]. / Profilassi antitrombotica nei pazienti con disfunzione ventricolare: una revisione critica della letteratura e nuove prospettive.

Recent observational data suggest that mild or moderate heart failure is associated with an annual risk of stroke of approximately 1.2%. Indeed, it is possible that the major cause of sudden death in chronic heart failure is not related to arrhythmias, but to vascular occlusion. Anticoagulation may reduce the rate of embolic events, but there is controversy about the mandatory use of antithrombotic therapy for all patients with ventricular dysfunction in sinus rhythm. At present antithrombotic therapy is indicated only in "high risk" subgroups of patients: atrial fibrillation, mobile/protruding/irregular thrombi, acute post-myocardial infarction thrombi or a recent history of thromboembolism. Actually there is no evidence to recommend the use of aspirin to prevent thromboembolism in patients with ventricular dysfunction in sinus rhythm. Further trials of both antiplatelet agents and anticoagulation are sorely needed and we are waiting for the results of large trials such as the WATCH trial (Warfarin and Antiplatelet Therapy in Chronic Heart Failure) and the WARCEF trial (Warfarin Versus Aspirin in Reduced Ejection Fraction). The future appears promising due to the advent of a new oral direct thrombin inhibitor, ximelagatran, with good efficacy and safety profile for the treatment and prevention of thromboembolism.

[Atrial fibrillation and heart failure: cause or effect?]. / Fibrillazione atriale e scompenso cardiaco: causa o effetto?

The association between atrial fibrillation and heart failure is well documented. Heart failure is one of the established predisposing conditions for the development of atrial fibrillation; conversely, heart failure is a common condition in patients with atrial fibrillation. In patients with heart failure the atrial electrophysiologic properties might be modified by hemodynamic overloading and neurohumoral activation. Atrial fibrillation promotes heart failure with multiple mechanisms including uncontrolled heart rate, loss of atrioventricular synchrony, irregularity in the ventricular rhythm, valvular regurgitation and neurohormonal effects. Treatment includes correction of neurohumoral activation, prevention of thromboembolism, maintenance of sinus rhythm, and pharmacologic and interventional control of ventricular rate. The results of recent trials (PIAF-Pharmacological Intervention in Atrial Fibrillation, RACE-RAte Control versus Electrical cardioversion for persistent atrial fibrillation, AFFIRM-Atrial Fibrillation Follow-up Investigation of Rhythm Management) suggest that a rate control strategy can be better than rhythm control, particularly in patients at high risk of relapse, like those with left ventricular dysfunction.