Impact on long-term mortality of access and non-access site bleeding after primary percutaneous coronary intervention.

OBJECTIVES: The influence of the bleeding site on long-term survival after the primary percutaneous coronary intervention (PCI) is poorly understood. This study sought to investigate the relationship between in-hospital access site versus non-access site bleeding and very late mortality in unselected patients treated with primary PCI. METHODS: Data of the 2715 consecutive patients with ST-segment elevation myocardial infarction treated with primary PCI, enrolled in a prospective registry of a high volume tertiary centre, were analysed. Bleeding events were assessed according to the Bleeding Academic Research Consortium (BARC) criteria. The primary outcome was 4-year mortality. RESULTS: The BARC type ≥2 bleeding occurred in 171 patients (6.3%). Access site bleeding occurred in 3.8%, and non-access site bleeding in 2.5% of patients. Four-year mortality was significantly higher for patients with bleeding (BARC type ≥2) than in patients without bleeding (BARC type 0+1), (36.3% vs 16.2%, p<0.001). Patients with non-access site bleeding had higher 4 year mortality (50.7% vs 26.5%, p=0.001). After multivariable adjustment, BARC type ≥2 bleeding was the independent predictor of 4 year mortality (HR 2.01; 95% CI 1.49 to 2.71, p<0.001). Patients with a non-access site bleeding were at 2-fold higher risk of very late mortality than patients with an access site bleeding (HR 2.62; 1.78 to 3.86, p<0.001 vs HR 1.57; 1.03 to 2.38, p=0.034). CONCLUSIONS: Both access and non-access site BARC type ≥2 bleeding is independently associated with a high risk of 4-year mortality after primary PCI. Patients with non-access site bleeding were at higher risk of late mortality than patients with access site bleeding.

Dabigatran - Metabolism, Pharmacologic Properties and Drug Interactions.

BACKGROUND: The superiority of dabigatran has been well proven in the standard dosing regimen in prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and extended venous thromboembolism (VTE) treatment. Dabigatran, an anticoagulant with a good safety profile, reduces intracranial bleeding in patients with atrial fibrillation and decreases major and clinically relevant non-major bleeding in acute VTE treatment. However, several important clinical issues are not fully covered by currently available directions with regard to dabigatran administration. The prominent one is reflected in the fact that dynamic impairment in renal function due to dehydratation may lead to haemorragic complications on the one hand, while on the other hand glomerular hyperfiltration may be a possible cause of dabigatran subdosing, hence reducing the drug's efficacy. Furthermore, limitations of the Cockcroft-Gault formula, considered a standard equation for assessing the renal function, may imply that other calculations are likely to obtain more accurate estimates of the kidney function in specific patient populations. Method and Conclusions: Although not routinely recommended, a possibility of monitoring dabigatran in special clinical settings adds to optimization of its dosage regimens, timely perioperative care and administration of urgently demanded thrombolytic therapy, therefore significantly improving this drug's safety profile. Despite the fact that dabigatran has fewer reported interactions with drugs, food constituents, and dietary supplements, certain interactions still remain, requiring considerable caution, notably in elderly, high bleeding risk patients, patients with decreased renal function and those on complex drug regimens. Additionally, upon approval of idarucizumab, an antidote to dabigatran solution, hitherto being a major safety concern, has been finally reached, which plays a vital role in life-threatening bleeding and emergency interventions and surgery.

Economic analysis of pharmacogenomic-guided clopidogrel treatment in Serbian patients with myocardial infarction undergoing primary percutaneous coronary intervention.

INTRODUCTION: Clopidogrel, which is activated by the CYP2C19 enzyme, is among the drugs for which all major regulatory agencies recommend genetic testing to be performed to identify a patient's CYP2C19 genotype in order to determine the optimal antiplatelet therapeutic scheme. The CYP2C19*2 and CYP2C19*3 variants are loss-of-function alleles, leading to abolished CYP2C19 function and thus have the risk of thrombotic events for carriers of these alleles on standard dosages, while the CYP2C19*17 allele results in CYP2C19 hyperactivity. AIMS: Here, we report our findings from a retrospective study to assess whether genotyping for the CYP2C19*2 allele was cost effective for myocardial infarction patients receiving clopidogrel treatment in the Serbian population compared with the nongenotype-guided treatment. RESULTS: We found that 59.3% of the CYP2C19*1/*1 patients had a minor or major bleeding event versus 42.85% of the CYP2C19*1/*2 and *2/*2, while a reinfarction event occurred only in 2.3% of the CYP21C9*1/*1 patients, compared with 11.2% of the CYP2C19*1/*2 and CYP2C19*2/*2 patients. There were subtle differences between the two patient groups, as far as the duration of hospitalization and rehabilitation is concerned, in favor of the CYP2C19*1/*1 group. The mean cost for the CYP2C19*1/*1 patients was estimated at €2547 versus €2799 in the CYP2C19*1/*2 and CYP2C19*2/*2 patients. Furthermore, based on the overall CYP2C19*1/*2 genotype frequencies in the Serbian population, a break-even point analysis indicated that performing the genetic test prior to drug prescription represents a cost-saving option, saving €13 per person on average. CONCLUSION: Overall, our data demonstrate that pharmacogenomics-guided clopidogrel treatment may represent a cost-saving approach for the management of myocardial infarction patients undergoing primary percutaneous coronary intervention in Serbia.

Incidence, predictors and prognostic implications of bleeding complicating primary percutaneous coronary intervention.

BACKGROUND/AIM: Data about bleeding complicating primary percutaneous coronary intervention (PCI) are more frequently obtained from randomized clinical trials on patients with acute coronary syndromes (ACS), but less frequently from surveys or registries on patients with ST-elevation myocardial infarction (STEMI). The aim of this study was to investigate the incidence, predictors and prognostic impact of in-hospital major bleeding in the population of unselected real-world patients with acute STEMI undergoing primary PCI. METHODS: All consecutive patients presenting with STEMI who underwent primary PCI at a single large tertiary healthcare center between January 2005 and July 2009, were studied. Major bleeding was defined according to the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) study criteria. We examined the association between in-hospital major bleeding and death or major adverse cardiac events (MACE) in patients treated with PCI. The primary outcomes were in-hospital and 6-month mortality and MACE. RESULTS: Of the 770 STEMI patients treated with primary PCI, in-hospital major bleeding occurred in 32 (4.2%) patients. Independent pre-dictors of major bleeding were advanced age (≥ 65 years), female gender, baseline anemia and elevated white blood cell (WBC) count and signs of congestive heart failure at admission (Killip class II-IV). In-hospital and 6 month mortality and MACE, rates were more than 2.5-fold-higher in patients who developed major bleeding compared with those who did not. Major bleeding was predictor of 6-month MACE, independent of a few risk factors (previous MI, previous PCI, diabetes mellitus and hypertension); (OR = 3.02; 95% CI for OR 1.20-7.61; p = 0.019) but was not a true independent predictor of MACE and mortality in the fully adjusted models. CONCLUSION: Patients of advanced age, female gender, with baseline anemia and elevated WBC count and those with Killip class II-IV at presentation are at particularly high risk of bleeding after primary PCI. Bleeding is associated with adverse outcome and may be an important marker of patient frailty, but it is not a true independent predictor of mortality/MACE.

Amlodipine as an antiischemic drug is superior to long acting nitrates.

European Society of Cardiology Guidelines cite results of meta-analysis that the use of calcium channel blockers results in fewer angina episodes per week vs. long-acting nitrates. Moreover, we listed 12 reasons more to prefer amlodipine over long-acting nitrates, especially in stable angina pectoris patients with arterial hypertension. It may be the way to decrease polypharmacy without loosing efficacy. Some important advantages of amlodipine versus long-acting nitrate(s) are: amlodipine also treats hypertension, it helps reducing hypertensive target organ damages (e.g. left ventricular hypertrophy) and prevents morning blood pressure surge. Moreover, amlodipine can be given once daily (which improves adherence), it produces neither tolerance nor rebound, it has less side effects.

[Contemporary approach to primary prophylaxis of venous thromboembolism regarding the impact of risk factors on anticoagulation therapy duration].

Adequate thromboprophylaxis primarily requires timely detection of reversible and irreversible risk factors of venous thromboembolism (VTE) and their categorization. It is important to note that the highest percentage ofVTE episodes occur in non-surgical (medical) patients and that VTE develops in a large number of surgical patients upon hospital discharge; this emphasizes the need for adequate VTE prevention in inflammatory diseases, acute medical illness and other medical diseases as well as for prolonging and optimizing the anticoagulant regimen after surgical intervention in the primary VTE prophylaxis. As almost completely unrecognized and neglected major risk factors of VTE in clinical practice, we particularly point out the chronic obstructive pulmonary disease (COPD) and heart failure, especially in NYHA functional class III and IV patients with significantly reduced left heart ventricle. It is necessary to raise clinicians' awareness of a potential danger from wrongly and one-sidedly interpreted dyspnea and coughing signs in patients with COPD as typical symptoms of basic respiratory disease as well as from ascribing the signs of disease aggravation in heart failure patients exclusively to cardial status worsening, neglecting the possibility of having unrecognized and untreated pulmonary embolism at issue. Contemporary way of life enhances the development of new VTE risk factors such as traveler's thrombosis, in particular during long-haul flights as well as in individuals sitting at a computer for prolonged periods (e-thrombosis). Determining and recognizing VTE risk factors, especially those formerly neglected nonsurgical ones and simultaneous presence of multiple risk factors within a given period is required for defining an adequate anticoagulant regimen in primary VTE prophylaxis for surgical and non-surgical (medical) patients.

Prognostic implications of bleeding measured by Bleeding Academic Research Consortium (BARC) categorisation in patients undergoing primary percutaneous coronary intervention.

OBJECTIVE: To investigate the relationship between inhospital bleeding as defined by Bleeding Academic Research Consortium (BARC) consensus classification and short-term and long-term mortality in unselected patients admitted for primary percutaneous coronary intervention (PCI). METHODS: We analysed data of all consecutive patients with ST segment elevation myocardial infarction (STEMI) admitted for primary PCI, enrolled in a prospective registry of a high volume centre. The BARC-defined bleeding events were reconstructed from the detailed, prospectively collected clinical data. The primary outcome was mortality at 1 year. RESULTS: Of the 1808 patients with STEMI admitted for primary PCI, 115 (6.4%) experienced a BARC type ≥2 bleeding. As the BARC bleeding severity worsened, there was a gradient of increasing rates of 1-year death. The 1-year mortality rate increased from 11.5% with BARC 0+1 type to 43.5% with BARC type 3b bleeding. After multivariable adjustment for demographic and clinical characteristics of patients, the independent predictors of 1-year death were BARC type 3a (HR 1.99; 95% CI 1.16 to 3.40, p=0.012) and BARC type 3b bleeding (HR 3.22; 95% CI 1.67 to 6.20, p<0.0001). CONCLUSIONS: The present study demonstrated that bleeding events defined according to the BARC classification hierarchically correlate with 1-year mortality after admission for primary PCI. The strongest predictor of 1-year mortality is the BARC type 3b bleeding.

Diagnostic relevance of ADAMTS13 activity: evaluation of 28 patients with thrombotic thrombocytopenic purpura - hemolytic uremic syndrome clinical diagnosis.

INTRODUCTION: The significance of ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motif-13) activity for diagnosis and therapy of thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) is still a controversial issue. OBJECTIVE: The aim of this report was to analyze the value of ADAMTS13 measurements in the diagnosis of TTP and HUS. METHODS: At presentation, we analyzed patients with idiopathic TTP (n = 18), secondary TTP (n = 4), diarrhea positive HUS (n = 3) and diarrhea negative HUS (n = 3) treated in Belgrade, Serbia from 2004 to 2010. ADAMTS13 activity from acute phase samples was measured using the residual collagen binding activity assay at the Haemophilia and Thrombosis Centre, Milan, Italy. RESULTS: There was a significant correlation between reduced ADAMTS13 activity and idiopathic TTP diagnosis (p = 0.000) as well as between lower ADAMTS13 activities and higher reticulocytes (p = 0.017) and lactate dehydrogenase levels (p = 0.027). Significant correlation was also found between higher protease activity and diagnosis of HUS (p = 0.000). There was a statistically significant correlation between higher ADAMTS13 activities and higher platelets count (p = 0.002), blood urea nitrogen (p = 0.000), and creatinine level (p = 0.000). CONCLUSION: Severe ADAMTS13 deficiency points at the diagnosis of idiopathic TTP and it is present in the secondary TTP but not in HUS.

Clinical experience in treatment of thrombotic thrombocytopenic purpura--hemolytic uremic syndrome with 28 patients.

BACKGROUND: Neither optimal treatment nor significance of ADAMTS13 (A Desintegrin And Metalloprotease with ThromboSpondin type 1 repeats) activity for diagnosis and therapy of thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) have not been defined yet. The aim of the report is to analyze response to different volumes of plasma exchange (PE), and relationship to ADAMTS13. DESIGN AND METHODS: 28 patients clinically diagnosed with idiopathic TTP (n = 18), secondary TTP (n = 4), atypical HUS (n = 3) and typical HUS (n = 3) manifested 31 acute episodes. Patients were treated with PE in 26, and with plasma transfusion in 5 episodes with additional different therapies. RESULTS: PE volumes were as follows: 1 in 7, 1.5 in 3, 2 in 14, and intensifying schedule (1 to 1.5) in 2 episodes. Procedure number was lower in patients treated with 2 and 1.5 (p = 0.019) than in those treated with 1 volume exchange and PE intensifying, respectively (p = 0.010). PE response rate was 25/26 (96.15%). Exacerbation frequency was higher in idiopathic TTP patients (3/19) treated with 1 compared with patients treated with > 1 volume exchange (p = 0.003). Survival rate was 25/28 (89.29%). ADAMTS13 activity was reduced in 22 with severe deficiency in 14 patients. CONCLUSION: Patients responded to different treatments regardless of ADAMTS13 activity, requiring less PEs with larger volume exchanges.

Obstacles in the diagnostics and therapy of heparin-induced thrombocytopenia.

An immune-mediated, severe, acquired prothrombotic disorder, heparin-induced thrombocytopenia type II (HIT II) occurs in 0.5-5% of patients exposed to unfractionated heparin longer than 5-7 days. Arterial and venous thromboses are induced by HIT II in about 35-50% of patients. Typical death rate for HIT is about 29%, while 21% of HIT patients result in amputation of a limb. The trend towards the occurrence of HIT due to the administration of low molecular weight heparins (LMWH) taking ever conspicuous place in the standard venous thromboembolism (VTE) prophylaxis has been more frequently observed recently. It is considered that LMWH may cause HIT II in about 0.25-1%. The need for further modification of HIPA assays with LMWH has been imposed in the HIT laboratory diagnostics, heretofore overburdened with complexity. There are several constantly opposing problems arising in HIT laboratory diagnostics, one of which is that in a certain number of patients immunologic assays detect nonpathogenic antibodies (mainly IgM or IgA heparin-PF4 antibodies) while, on the other hand, the occurrence of HIT pathogenetically mediated by minor antigens (neutrophil-activating peptide 2 or interleukin 8) may be neglected in certain cases. The following factors play an important role in the interpretation of each laboratory HIT assays performed: 1. correlation with HIT clinical probability test, the best known of which is 4T'score, 2. the interpretation of the laboratory findings dependent on the time of the thrombocytopenia onset, as well as 3. the sensitivity and specificity of each test respectively. The HIT diagnostics in the presence of other comorbid states which may also induce thrombocytopenia, more precisely known as pseudo HIT (cancer, sepsis, disseminated intravascular coagulation, pulmonary embolism, antiphospholipid syndrome, etc), represents a specific clinical problem.

Elevations in soluble CD40 ligand in patients with high platelet aggregability undergoing percutaneous coronary intervention.

High aggregatory responses despite antiplatelet treatment is associated with an increased risk of thrombotic complications following percutaneous coronary intervention (PCI). In the present study, we investigated the relationship between platelet aggregatory responses to ADP and the release of CD40L (sCD40L): an immunomodulatory compound involved in atherothrombosis - in patients undergoing PCI. ADP-induced platelet aggregation, sCD40L and soluble P-selectin (sP-selectin) were determined before and 24 h after PCI, in samples from 52 patients receiving aspirin and thienopyridines. Platelet aggregation to ADP above the median was defined as 'high aggregation', and aggregation below the median as 'low aggregation'. Data below are medians and interquartile ranges. Patients with 'high platelet aggregability' had a significantly higher increase in both sCD40L (Delta-values: 0.78 (-0.19-3.18) vs. -0.65 (-2.10-0.00) ng/ml, P = 0.002) and sP-selectin (Delta-values: 8.0 (-2.00-16.00) vs. 4.50 (-13.00-0.50) ng/ml, P = 0.001) compared with patients with 'low platelet aggregability'. In a multivariate linear regression analysis adjusted for clinical characteristics and type of preintervention therapy, the only independent predictors of sCD40L and sP-selectin were platelet aggregation to ADP before PCI (P < 0.001) and the combination of platelet aggregation to ADP before PCI and urgency of PCI (P < 0.001). Circulating CD40L is more markedly increased after PCI in patients with high ADP-induced platelet aggregation.

Clinical challenge: heparin-induced thrombocytopenia type II (HIT II) or pseudo-HIT in a patient with antiphospholipid syndrome.

Treatment of patients with heparin-induced thrombocytopenia type II (HIT II) and thrombosis in some cases that represents a clinical challenge, which, if unrecognized, may lead to treatment delay or disease progression with potentially lethal outcome. We present a case of a 19-year-old patient with antiphospholipid syndrome, factor V (FV) Leiden mutation in heterozygous state, and venous thromboembolism. The patient was subjected to intravenous infusions of unfractionated heparin (UFH), and 16 days after the beginning of the treatment, his condition worsened, with thrombocytopenia and extension of thrombosis. Whereas the patient had a high clinical score for HIT II, functional and antigenic assays for the presence of HIT antibodies were negative. After repeated negative functional and antigenic assays, pseudo-HIT was suspected and nadroparin was introduced, which resulted in further worsening of the clinical presentation. Disease remission, along with complete normalization of platelet count, was finally accomplished with the introduction of lepirudin. The presence of multiple comorbid states, such as antiphospholipid syndrome, can potentially make laboratory confirmation of disease more difficult in patients with HIT II. In our opinion, it is of great importance that HIT II diagnosis be primarily clinical and that laboratory test results are carefully interpreted, especially when HIT is indicated by high clinical score values.

Carvedilol increases copper-zinc superoxide dismutase activity in patients with acute myocardial infarction.

Balanced and coordinated antioxidant defence enzyme activities are of utmost importance for correct physiological function and for shielding against unwelcome pathological conditions. We determined the activities of copper-zinc superoxide dismutase (CuZnSOD), catalase, glutathione peroxidase and glutathione reductase in erythrocytes isolated from patients receiving different therapy (streptokinase alone or in combination with metoprolol or with carvedilol) for up to 168 hr after starting treatment for acute myocardial infarction. We observed increased CuZnSOD activity in erythrocytes isolated from patients treated with streptokinase-carvedilol (after 6, 24 and 168 hr) and in erythrocytes isolated from patients treated with streptokinase-metoprolol (after 24 hr). In addition, positive correlation between CuZnSOD and catalase activities was found in erythrocytes isolated from patients that received streptokinase-carvedilol after 168 hr. As metoprolol does not react directly with hydrogen peroxide, it would appear that combined streptokinase-metoprolol therapy exerted its effects primarily via by beta-blockade whereas combined streptokinase-carvedilol therapy appeared to function via both beta-blockade and direct antioxidant mechanisms.

Salvage late plasmapheresis in a patient with pulmonary embolism caused by heparin-induced thrombocytopenia primarily resistant to danaparoid sodium and lepirudin.

We report the case of 64-year-old female patient with pulmonary embolism and bilateral femoropopliteal deep vein thrombosis caused by heparin-induced thrombocytopenia type II (HIT II) resistant to danaparoid sodium and subsequently administered lepirudin in whom a single late plasmapheresis performed on day 6 of the initiation of treatment of HIT reversed the course of the disease, preventing its highly potential fatal outcome. Primarily administered lepirudin was not only ineffective but even led to further aggravation of the patient's clinical state and platelet count drop in the first stage of the HIT treatment. The improvement of the patient's clinical state was not achieved before therapeutic plasma exchange (TPE) had removed the greatest part of pathogenetic circulating substrate. Only after TPE, lepirudin, introduced again, led to the platelet count recovery. In the subsequent course of the treatment, lepirudin was combined with an overlapping oral anticoagulant. Previously positive heparin aggregation test and fast particle gel heparin-platelet factor 4 immunoassay were normalized as well as the patient's clinical status. Early plasmapheresis, administered within 4 days of the onset of thrombocytopenia in HIT, as a beneficial therapeutic measure in certain individual cases, is indisputable. However, our results do not concur with previously reported findings of the so far most comprehensive study on plasmapheresis performed in the management of HIT with thrombosis, discrediting late plasmapheresis administered 4 days after the onset of the disease not only as ineffective, but even as an aggravating factor. Our results suggest the possible beneficial impact of late plasmapheresis as a method that may reverse a prothrombotic process and lead to a fast improvement in the patient's platelet count, especially in cases initially resistant to thrombin inhibitors.