Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial.

BACKGROUND: Rivaroxaban is an oral direct factor Xa inhibitor that has been effective in prevention of venous thromboembolism in patients undergoing elective orthopaedic surgery. However, its use after acute coronary syndromes has not been investigated. In this setting, we assessed the safety and efficacy of rivaroxaban and aimed to select the most favourable dose and dosing regimen. METHODS: In this double-blind, dose-escalation, phase II study, undertaken at 297 sites in 27 countries, 3491 patients stabilised after an acute coronary syndrome were stratified on the basis of investigator decision to use aspirin only (stratum 1, n=761) or aspirin plus a thienopyridine (stratum 2, n=2730). Participants were randomised within each strata and dose tier with a block randomisation method at 1:1:1 to receive either placebo or rivaroxaban (at doses 5-20 mg) given once daily or the same total daily dose given twice daily. The primary safety endpoint was clinically significant bleeding (TIMI major, TIMI minor, or requiring medical attention); the primary efficacy endpoint was death, myocardial infarction, stroke, or severe recurrent ischaemia requiring revascularisation during 6 months. Safety analyses included all participants who received at least one dose of study drug; efficacy analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00402597. FINDINGS: Three patients in stratum 1 and 26 in stratum 2 never received the study drug. The risk of clinically significant bleeding with rivaroxaban versus placebo increased in a dose-dependent manner (hazard ratios [HRs] 2.21 [95% CI 1.25-3.91] for 5 mg, 3.35 [2.31-4.87] for 10 mg, 3.60 [2.32-5.58] for 15 mg, and 5.06 [3.45-7.42] for 20 mg doses; p<0.0001). Rates of the primary efficacy endpoint were 5.6% (126/2331) for rivaroxaban versus 7.0% (79/1160) for placebo (HR 0.79 [0.60-1.05], p=0.10). Rivaroxaban reduced the main secondary efficacy endpoint of death, myocardial infarction, or stroke compared with placebo (87/2331 [3.9%] vs 62/1160 [5.5%]; HR 0.69, [95% CI 0.50-0.96], p=0.0270). The most common adverse event in both groups was chest pain (248/2309 [10.7%] vs 118/1153 [10.2%]). INTERPRETATION: The use of an oral factor Xa inhibitor in patients stabilised after an acute coronary syndrome increases bleeding in a dose-dependent manner and might reduce major ischaemic outcomes. On the basis of these observations, a phase III study of low-dose rivaroxaban as adjunctive therapy in these patients is underway. FUNDING: Johnson & Johnson Pharmaceutical Research & Development and Bayer Healthcare AG.

Infectious embolisation to the central nervous system from endocarditis: analyses of 99 cases.

Within a cohort of 606 cases of infective endocarditis, 263 were complicated and 99 embolizing, of them 32 to the central nervous system (CNS). Significant predictors of CNS embolisation were inappropriate therapy (p<0.01) and enterococcal etiology (p<0.01). Mortality in patients with CNS emboli was 65% what was significantly higher than in cases without embolisation - 15% (p<0.01).

Trends in risk factors and etiology of 606 cases of infective endocarditis over 23 years (1984-2006) in slovakia.

The aim of this study was to assess trends in risk factors, etiology, outcome and treatment strategies for endocarditis over 23 years in Slovakia. A prospective survey of 606 cases of infective endocarditis (IE) was conducted from 1984-2006. Rheumatic fever as well as previous dental surgery showed decreasing trends within the last 23 years. Also embolic complications of IE declined along with increasing rates of surgically treated patients. No significant changes in etiology were detected apart from the fact that culture-negative endocarditis increased from 10.7% to 55.4% between 1998-2001. Surgically treated patients increased from 22.7% (1984-1990) to 50.1% (2002-2006) and mortality dramatically decreased from 26.7% (1984-1990) to 5.3% (2002-2006). Staphylococcus aureus and coagulase-negative staphylococci were the leading causes (22.4% - 48%) followed by viridans streptococci (12.2%-18.2%) were a relatively stable trend over 23 years of IE in Slovakia.

[Effect of chronic Chlamydia infection with non-specific inflammation on cardiovascular complications in acute myocardial infarct]. / Vplyv chronickej chlamydiálnej infekcie s nespecifickým zápalom na kardiovaskulárne komplikácie pri akútnom infarkte myokardu.

It is known that local and systemic inflammatory processes play an important role in the genesis and development of atheroclerotic lesions and in the pathophysiology of acute coronary syndromes. This hypothesis is supported by findings of elevated parameters of the "inflammatory" reaction in the affected blood vessels but also in the blood of atherosclerotic patients. Known risk factors do not explain quite satisfactorily epidemiological cardiovascular phenomena and different manifestations of coronary heart disease. It is very probable that also Chlamydia pneumoniae is a risk factor. This assumption is based on evaluation of seroepidemiological data, examination of atherosclerotic plaques not only in humans but also in animal models with chlamydial infection. Based on retrospective and prospective evaluation of case-records the authors analyzed the incidence of cardiovascular complications in 83 patients with acute myocardial infarction (AIM), incl. 51 patients (31 men and 20 women, mean age 64.4 +/- 3.4 years who had a non-specific inflammation and chlamydial infection, and 32 patients (24 men and 8 women, mean age 64.7 +/- 3.6 years) who had chlamydial infections but no non-specific inflammation (in the blood). These patients were selected from all patients hospitalized during 1998-2001. When diagnosing acute myocardial infarction we applied WHO criteria, and the presence of at least two of three criteria was necessary: a history of prolonged (more than 20 min). stenocardia, electrocardiographic changes typical for ischaemia and/or necrosis and elevation of myocardial enzymes in serum, Non-specific inflammatory activity was present in patients (i.e. positive) if the following laboratory parameters were recorded: C-reactive protein > 5 mg/l assessed by the radial immunodiffusion method; fibrinogen > 4 mg/l assessed by the coagulation method according to Claus; leukocytes > 9.6 x 10(3)/microliter, leukocytes were counted automatically in a Coulter chamber; lymphocytes > 3.4 x 10(3)/microliter. Red cell sedimentation rate > 20 mm/hour. The activity was evaluated as positive when all parameters were elevated. The presence of chronic infection with Chlamydia pneumoniae was assessed qualitatively by antibody positivity (IgG) in serum using the microimmunoflurescent method (using a set from Labsystems Co.). The incidence of associated risk factors (obesity, smoking, diabetes, hyperlipidaemia and hypertension) is higher in the sub-group of patients with Chlamydia infections without inflammation, however, the difference is not statistically significant. The incidence of cardiovascular attacks was higher in the sub-group of patients with chlamydial infection and concurrent inflammation as compared with the sub-group of patients with chlamydial infection without inflammation. In case of re-infarction of the myocardium, a sudden cerebrovascular attack, death and arrhythmia the difference was statistically significant, while in case of cardiac failure and cardiogenic shock the difference was not significant. Patients with acute myocardial infarction with chlamydial infection and a concurrent non-specific inflammation had to be treated more often by combined (i.e. more intense) treatment, thrombolytic treatment, PTCA and surgery (bypass) of the coronary vessels as compared with patients with Chlamydia infections but without inflammation. The authors assume therefore that not only different risk factors but also the effect of non-specific inflammation and Chlamydia infection contribute towards the increased number of cardiovascular postinfarction complications. Therefore a therapeutic approach involving eradication of infection and suppression of the inflammatory reaction should be considered.

Etiology and risk factors of 339 cases of infective endocarditis: report from a 10-year national prospective survey in the Slovak Republic.

The authors studied the etiology, outcome and risk factors of 339 cases of infective endocarditis (IE) in Slovakia over the last 10 years. Aortic valve was infected in 59.9%, mitral in 38.1% and tricuspidal/pulmonary in 5.0% of cases. The majority of IE were caused by staphylococci (29.2%), 15.0% were due to viridans streptococci, 7.4% due to Enterococcus faecalis, 3.9% due to the HACEK group (Haemophilus spp., Actinobacillus spp., Corynebacterium spp., Eikenella spp., Kingella spp.) and 39.2% were culture negative. The following risk factors were the most frequently identified: rheumatic fever in 24.2%, dental surgery in 13.3%, previous cardiosurgery in 7.1% and neoplasia in 7.1%. All patients were treated with antimicrobials and 42.5% of patients also with surgery (valvular prosthesis replacement): 61 (18.0%) died, and 278 (82.0%) survived at day 60 after the diagnosis of endocarditis was made. Univariate analysis did not show significant differences in most of the recorded risk factors between patients who died and those who survived: apart from staphylococcal etiology (44.3% vs. 26.6%, P < 0.01), persistent bacteremia (with three or more positive blood cultures 24.6% vs. 9.7% P < 0.002) which were significantly associated with higher attributable mortality, as was absence of surgery (55.7% vs. 6.1% P < 0.001), whereas antibiotic therapy in combination with surgery significantly predicted better outcome (P < 0.001). We compared risk factors, etiology, therapeutic strategies and outcome of IE in two periods: from 1991-1997 (180 cases) and from 1998-2001 (159 cases). Rheumatic fever was less commonly observed in second period (1998-2001) P < 0.01 since its prevalence in Slovakia is rapidly decreasing. Dental surgery was less frequent as well (20.5% vs. 5.0% P < 0.001). There was a significant shift in etiology within the second study period: negative-culture endocarditis (despite better bacteriological techniques) (P < 0.001) was more frequently observed in the 1st period and represented 53.3% of all cases in 1998-2001 in comparison to 26.7% in 1991-1997. Enterococci (P < 0.0002) were also more frequent in the 2nd period. Persistent bacteremia (3 or more positive blood cultures 20.5% vs. 3.1%, P < 0.001 was less commonly observed within the 2nd period (1998-2001) in comparison to 1991-1997. More patients in the second period (1998-2001) had complications of IE (P < 0.001) than in the 1st period. However mortality was lower (22.2% vs. 13.2%, P < 0.044) because of more surgical intervention in the 2nd period (52.8% vs. 33.3%, P < 0.001).

Brain embolism, left atrial thrombi and cardiosurgery.

Patients with embolization into the brain and mobile thrombus in the left atrium (LA) are in the danger of recurrent embolization. A patient with the history of recent cerebral vascular accident (CVA) would be at higher risk of cerebral complications due to cardiopulmonary bypass and this risk may be as high as that of re-embolization. We present a case of a 41-year old man with an acute ischemic focus (3 x 3 cm) in the temporoparietal lobe verified by computer tomography (CT). Transthoracic echocardiography showed severe aortic insufficiency, low ejection fraction of dilatated left ventricle (LV). Transesophageal echocardiography showed a mobile thrombus (2.2 x 1.1 cm) in LA. The cardiovascular surgeon consultant did not recommend urgent operation. Instead, the patient was treated by low molecular heparin. CT of the brain after 10 days of treatment was normal. Patient underwent a successful aortic valve replacement. At the time of surgery there was no thrombus in the LA. Subsequently, the patient recovered normally with no neurologic sequelae. This case illustrates the difficulty arising from the consideration of the relative risks of acute surgery vs conservative management in patient with recent CVA and a large mobile thrombus in LA.

Aetiology and outcome in 53 cases of native valve staphylococcal endocarditis.

Within the last 30 years the profile of infective endocarditis has altered considerably with regard to microbiological causation, clinical features, and natural history. A contributory factor has undoubtedly been the development of potent antibiotics and their sometimes indiscriminate use. The increase in intravenous drug abuse in urban centres, the use of immunosuppressive agents, and the use of prosthetic heart valves have also all contributed. Although cardiac surgery in the uninfected heart provides a perfect environment for infective endocarditis, the improved design of prosthetic valves and the enhanced long-term survival and decreased immediate operative risk, means that surgery is viewed as the best option in many cases. In a series of 53 cases of staphylococcal endocarditis from a national endocarditis survey, those risk factors which influenced outcome were analysed. Thirty out of 53 patients had predisposing heart disease. Mortality was 39.6%. Statistical analysis revealed that attributable mortality was significantly associated with skin infection, systemic embolisation, and inappropriate therapy. Interestingly, surgical treatment was associated with better outcome.

Native valve staphylococcal endocarditis: etiology, risk factors and outcome in 53 cases.

Fifty-three cases of staphylococcal endocarditis from a national endocarditis survey were analyzed for risk factors and outcome. Thirty of 53 patients had predisposing heart disease (39.6% rheumatic fever) but only 3 were on dialysis, only 2 had central venous catheter, only 2 intravenous drug abuse but 7 had prior cardiosurgery. Mortality was 39.6%. In analyzing risk factors for death, attributable mortality was significantly associated with skin infections (P < 0.05), embolization (P < 0.02), inappropriate therapy (P < 0.005) either because of too short therapy (P < 0.003) or wrong antibiotic combination (P < 0.01). Surgical therapy was associated with better outcome (4.8% deaths vs. 31.2% survivors, P < 0.04).

Invazivna diagnostika, transkatetrova a chirurgicka liecba akutnych koronarnych syndromov.

On the basis of long-term personal experiences and critical evaluation of the present literatury sources authors described the role of invasive diagnostic methodes and transcathetral and cardiosurgical possibilities in the recognition and therapy of acute coronary syndromes. These techniques are, and in the forthcoming year shall be available only in specialized institutions. The paper describes the indication for these aggressive techniques as well as their limitations and complications. The goal of the presented article is to inform both the cardiological and frequently broad physician s societies about the possibilities of diaventional cardiology and cardiosurgery which will be gradually more applied in the care of the patients with acute coronary syndromes. (Ref. 39, Tab. 2, Fig.3.).

[Invasive diagnosis, transcatheter and surgical treatment of acute coronary syndromes]. / Invazívna diagnostika, transkatétrová a chirurgická liecba akútnych koronárnych syndrómov.

On the basis of long-term personal experiences and critical evaluation of the present literatury sources authors described the role of invasive diagnostic methods and transcathetral and cardiosurgical possibilities in the recognition and therapy of acute coronary syndromes. These techniques are, and in the forthcoming year shall be available only in specialized institutions. The paper describes the indication for these aggressive techniques as well as their limitations and complications. The goal of the presented article is to inform both the cardiological and frequently broad physicians' societies about the possibilities of diaventional cardiology and cardiosurgery which will be gradually more applied in the care of the patients with acute coronary syndromes. (Ref. 39, Tab. 2, Fig. 3.)

Etiology and risk factors of 180 cases of native valve endocarditis. Report from a 5-year national prospective survey in Slovak Republic.

Risk factors, etiology, and outcome of 180 cases of infective endocarditis (IE) in the Slovak Republic for 5 years were prospectively studied in a national survey. According to the Duke Endocarditis Service Criteria (1994), 169 cases were considered definitive and 21 possible/probable. The aortic valve was infected in 46.7%, mitral in 47.2%, and tricuspidal/pulmonary in 6.1% of cases. The majority of endocarditis cases was caused by Staphylococcus aureus and coagulase-negative staphylococci (CNS) (33.3%); only 12.2% were due to viridans streptococci; 11.7% were due to Enterococcus faecalis; 6.1% due to Haemophilus spp.; 10.1% due to other organisms; and 26.7% were culture negative. Single positive cultures of CNS were not considered clinically significant. More than 25% of 180 patients were older than 60 years. Rheumatic fever was a risk factor in 35.5%, dental surgery in 20.5%, prior cardiosurgery in 7.8%, and neoplasia in 6.7%. All patients were treated with antimicrobials (average length of therapy was 29.5 days) and 33.3% of patients also had surgery (valvular prosthesis replacement). Forty (22.2%) died, and 140 (77.8%) survived at day 60 after the diagnosis of endocarditis was made. All 40 deaths were attributable to infection. Univariate analysis comparing deaths and survivors did not show significant differences in most of the recorded risk factors between both groups, except age > 60 (40.0% versus 21.4%, p < 0.05), staphylococcal etiology (55.0% versus 27.1%, p < 0.04), and antibiotic therapy < 21 days (without surgery) (65.0% versus 3.6%, p < 0.01). These risk factors were significantly more frequently associated with deaths. Viridans streptococcal IE and surgical therapy in addition to antibiotics were associated with lower mortality in comparison to staphylococcal endocarditis (p < 0.045) or to cases treated with antibiotics only (p < 0.05). In comparison to other nationally based surveys in Europe (Greece, Croatia, France), the percentage of culture-negative endocarditis and spectrum of pathogens differed significantly.

[Analysis of risk factors for perioperative myocardial infarct in aortocoronary bypass]. / Analýza niektorých perioperacného infarktu myokardu pri aortokoronárnom bypasse.

BACKGROUND: Perioperative myocardial infarction (PMI) belongs to the main complications of revascularization surgery of the heart. Perioperative analysis of PIM risk factors can aid the cardiosurgeons, anestesiologists and cardiologists to stratify the group exposed to the risk of PIM origin and to prepare the most appropriate complex peroperative procedure for this group of patients. AIM: The particular aim is to evaluate and analyze some PIM risk factors prior to and during surgery. METHODS: The paper represents a retrospective study which analyzes two period (1984-1986 and 1992). The total number of patients in the investigated group is 277. The group afflicted with PIM is constituted of 29 patients. The following clinical, hemodynamic, angiographic risk factors are analyzed prior to surgery: age, sex, precedence of infarction of myocardium, arterial hypertension, instabile angina pectoris, end-diastolic pressure and left ventricular ejection fraction, affliction of the main trunk of the left coronary artery and some peroperattive factors (number of grafts, sequence bypass, endarterectomy, completion of revascularization, a. mammaria interna graft, duration of the artificial vascular circuit and clamping of the aorta). RESULTS: Significant relation for the pIM origin was found in arterial hypertension (p<0.05), affliction of the main trunk (p<0.05), prolonged period of clamping of the aorta (p<0.05 in 1984-86, p<0.01 in 1992) and artificial vascular circuit (p<0.001). CONCLUSION: The basic PIM risk factors include the following: arterial hypertension prior to surgery, affliction of the main trunk of the left coronary artery, prolonged duration of the artificial vascular circuit and clamping of the aorta. MEANING FOR PRACTICE: 1. The analyzed problem represents a positive feedback for cardiosurgeons, anestesiologists and cardiologists. 2. The analysis of the risk factors can be utilized also by future surgical workplaces in the Slovak Republic.

[Personal experience with determination of endogenous, digoxin-like substances in patients with myocardial infarct and other cardiopathies]. / Nase skúsenosti s vysetrením endogénnych, digoxínu podobných látok u chorých s infarktom myokardu a inými kardiopatiami.

A group of 65 patients with acute infarction of myocardium (IM) who were not treated with digitalis preparations were subdued to examination to the presence of digitalis-like substances in their urine by means of radioimmuno-analytic method with use of anti-digoxin antibodies. The control group was constituted of 69 healthy subjects. Patients afflicted with IM had significantly increased concentrations of DLS in serum in comparison with health subjects. No significant relations of DLS to the activity of creatinkinase, IM localisation, occurrence of dysrhythmias, heart insufficiency and IM mortality were discovered. An increase in DLS in the blood of patients with acute IM probably coincides with a decreased cardiac output, with the activation of the stress axis and retention of sodium and fluids. The second examined group of patients was constituted of 20 subjects with other severe cardiopathies (inborn and acquired heart defects, chronic ischemic heart disease, inflammatory and degenerative diseases of the heart, and hypertension), who were subdued to catheter examinations. The authors discovered no significant differences of DLS concentrations in the blood during catheterization of individual compartments of inferior vena cava, superior vena cava, and the right ventricle. They were not successful in defining the particular site of DLS secretion on the basis of this examination. The authors pay attention to interaction of DLS during the radioimmuno-analytic examination of the digoxin serum concentration.

[Perioperative myocardial infarct in association with surgical treatment of coronary heart disease]. / Perioperacný infarkt myokardu v súvislosti s chirurgickou liecbou koronárnej choroby srdca.

Perioperative myocardial infarction is a major complication of revascularization surgery of the heart which can negatively affect both the quality and duration of the patient's life. The aim of the paper is to contribute to the understanding of the problem which involves the definition, incidence, pathogenesis, diagnosis, complications, therapy and prognosis of perioperative myocardial infarction. One of the basic factors implicated in the development of perioperative derangement of the cardiac muscle is closely analyzed, namely insufficient protection of the myocardium with subsequent ischemia-reperfusion induced myocardial damage. Pitfalls of electrocardiographic diagnosis are pointed out and the rather complicated interpretation of increased enzyme levels following cardiac surgery is discussed. Complications, management, as well as early and late prognosis of patients with perioperative myocardial infarction are also dealt with.

[Acute myocardial infarct in a 15-year-old patient]. / Akútny infarkt myokardu u 15-rocného pacienta.

The authors present the case-history of a 15-year-old sportsman with acute "non Q" myocardial infarction. The disease is associated with excessive physical strain and subsequent protracted paroxysm of supraventricular tachycardia with severe hypotension. The paper is supplemented by ECG tracings and laboratory findings, echocardiographic, scintigraphic, coronarographic and other examinations. Pathological changes of the coronary arteries, or preexisting metabolic disease or myocardial disease, valvular defects or congenital anomalies were not confirmed. The authors draw attention to the possible occurrence of myocardial infarction also in very young subjects as a result of excessive physical strain along with other possible pathogenetic mechanisms.

[Thrombosis and thromboembolism in patients with a Björk-Shiley prosthesis]. / Trombóza a tromboembolizmus u chorých s Björkovou-Shileyovou protézou.

Thrombosis and thromboembolism are, in addition to left ventricular function, the basic factors which deteriorate the score and long-term prognosis in patients with valvular prostheses. The authors analyze the problem of thrombosis and thromboembolism in 261 patients with Björk-Shiley's prosthesis who were operated during the last five years. The authors consider as the main risk factors in the first place inadequate anticoagulation treatment, the position of the implant in the mitral orifice, the type of valvular implant and atrial fibrillation. The authors present a brief account of successful thrombolysis of a thrombotized Björk-Shiley prosthesis in the mitral orifice, the basic diagnostic procedure when thrombosis of an artificial valve is suspected and possible ways how to reduce the risk of thrombosis and thromboembolism.