Ales Tomek

Effect of catheter-based patent foramen ovale closure on the occurrence of arterial bubbles in scuba divers.

OBJECTIVES This study sought to evaluate the effect of catheter-based patent foramen ovale (PFO) closure on the occurrence of arterial bubbles after simulated dives. BACKGROUND PFO is a risk factor of decompression sickness in divers due to paradoxical embolization of bubbles. To date, the effectiveness of catheter-based PFO closure in the reduction of arterial bubbles has not been demonstrated. METHODS A total of 47 divers (age 35.4 ± 8.6 years, 81% men) with a PFO (PFO group) or treated with a catheter-based PFO closure (closure group) were enrolled in this case-controlled observational trial. All divers were examined after a simulated dive in a hyperbaric chamber: 34 divers (19 in the PFO group, 15 in the closure group) performed a dive to 18 m for 80 min, and 13 divers (8 in the PFO group, 5 in the closure group) performed a dive to 50 m for 20 min. Within 60 min after surfacing, the presence of venous and arterial bubbles was assessed by transthoracic echocardiography and transcranial color-coded sonography, respectively. RESULTS After the 18-m dive, venous bubbles were detected in 74% of divers in the PFO group versus 80% in the closure group (p = 1.0), and arterial bubbles were detected in 32% versus 0%, respectively (p = 0.02). After the 50-m dive, venous bubbles were detected in 88% versus 100%, respectively (p = 1.0), and arterial bubbles were detected in 88% versus 0%, respectively (p < 0.01). CONCLUSIONS No difference was observed in the occurrence of venous bubbles between the PFO and closure groups, but the catheter-based PFO closure led to complete elimination of arterial bubbles after simulated dives. (Nitrogen Bubble Detection After Simulated Dives in Divers With PFO and After PFO Closure; NCT01854281).

The Bleeding Risk during Warfarin Therapy Is Associated with the Number of Variant Alleles of CYP2C9 and VKORC1 Genes

Background: Warfarin is commonly used for the treatment and prevention of arterial and venous thromboembolism but its use is hindered by the risk of bleeding. The main reason for this risk is a narrow therapeutic index and a wide response variability after warfarin treatment. These shortcomings affect clinical outcomes including bleeding complications and may be associated with variant polymorphisms in the CYP2C9 and VKORC1 genes. Aim: It was the aim of this study to assess the impact of the total variant allele count of CYP2C9 and VKORC1 genes on bleeding related to warfarin treatment. Methods: In a retrospective cohort-design study, patients were genotyped for polymorphisms in genes CYP2C9 (*1, *2, *3) and VKORC1 (haplotype A, B). Extensive clinical data were obtained. Adjusted hazard ratios (HR) for the occurrence of major bleeding events (MBE) were counted separately for the induction and maintenance phases of warfarin therapy. Results: Out of the 329 patients in our clinical database, 194 patients were eligible and included in the analysis. MBE occurred in 51 patients (26.3%) during a mean follow-up of 26 months: 6 patients (11.8%) experienced early MBE during warfarin initiation, and 45 MBE occurred during the maintenance phase. The adjusted HR for MBE risk for patients with any CYP2C9 variant allele was 1.962 [95% confidence interval (CI) 1.08-3.56, p = 0.027]; for the VKORC1 AA haplotype, HR was 1.841 (95% CI 0.97-3.48, p = 0.06), while for 3 variant allele carriers of both genes, HR was 4.34 (95% CI 1.95-9.65, p < 0.001). Despite the insignificant association of the VKORC1 genotype with bleeding in our study, we have noted a warfarin dose-dependent effect with risk significance ascending: CYP2C9 *1/*1 + VKORC1 B/B < CYP2C9 *1/*1 + VKORC1 A/B < CYP2C9 *1/*2 + VKORC1 B/B. Conclusion: Patients who are carriers of 3 variant alleles of the genes CYP2C9 and VKORC1 exhibited a significantly higher risk of MBE during the initiation and maintenance phases of warfarin therapy. Vigilant and careful management of patients with a higher variant allele count, including switching to newer anticoagulants, could be considered in this high-risk cohort.

Utility of Transcranial Ultrasound in Predicting Alzheimer's Disease Risk

Alzheimers disease (AD) is a progressive, neurodegenerative disease characterized by an increasing incidence. One of the pathologic processes that underlie this disorder is impairment of brain microvasculature. Transcranial ultrasound is a non-invasive examination of cerebral blood flow that can be employed as a simple and useful screening tool for assessing the vascular status of brain circulation in preclinical and clinical stages of AD. The objective of this review is to explore the utility of using a transcranial ultrasound to diagnose AD. With transcranial ultrasound, the most frequently studied parameters are cerebral blood flow velocities and pulsatility indices, cerebrovascular reserve capacity, and cerebral microembolization. On the basis of current knowledge, we recommend using as a transcranial Doppler sonography screening method of choice the assessment of cerebrovascular reserve capacity with breath-holding test.

Neurosonological Examination: A Non-Invasive Approach for the Detection of Cerebrovascular Impairment in AD

There has been a growing interest in vascular impairment associated with Alzheimer’s disease (AD). This interest was stimulated by the findings of higher incidence of vascular risk factors in AD. Signs of vascular impairment were investigated notably in the field of imaging methods. Our aim was to explore ultrasonographic studies of extra- and intracranial vessels in patients with AD and mild cognitive impairment (MCI) and define implications for diagnosis, treatment, and prevention of the disease. The most frequently studied parameters with extracranial ultrasound are intima-media thickness in common carotid artery, carotid atherosclerosis, and total cerebral blood flow. The transcranial ultrasound concentrates mostly on flow velocities, pulsatility indices, cerebrovascular reserve capacity, and cerebral microembolization. Studies suggest that there is morphological and functional impairment of cerebral circulation in AD compared to healthy subjects. Ultrasound as a non-invasive method could be potentially useful in identifying individuals in a higher risk of progression of cognitive decline.

Among antithrombotic agents, prasugrel, but not ticagrelor, is associated with reduced 30 day mortality in patients with ST-elevated myocardial infarction

BACKGROUND ST-elevated myocardial infarction (STEMI) holds the highest early mortality among patients with acute coronary syndromes. Despite numerous claims of clinical benefits and superiority over clopidogrel, there are no head-to-head outcome randomized clinical trials (RCTs) directly comparing novel antithrombotic agents in STEMI. Moreover, since most regulatory approvals are based on a single RCTs results, their meta-analyses are rare to compare death rates. We analyzed the 30-day mortality in STEMI patients who underwent percutaneous coronary intervention (PCI) and were treated with antithrombotic agents compared to clopidogrel as a reference. METHODS AND RESULTS Altogether, 10 RCTs and 1 retrospective study with a total number of 26,658 STEMI patients were included. Random-effects model with Mantel-Heanszel weighting was used to pool outcomes into a meta-analysis. Therapy with clopidogrel was associated with 2.76% 30-day STEMI mortality which was similar to that of ticagrelor (2.6%; OR=0.9395 [CI=0.76 to 1.17; p=0.58]), and for bivalirudin (2.8%; OR=1.02 [CI=0.82 to 1.27; p=0.86]), but was slightly higher for heparin (3.0%; OR=1.08 [CI=0.86 to 1.35; p=0.52]). There was a trend towards lower mortality after tirofiban (2.1%; OR=0.77 [CI=0.52 to 1.13; p=0.20]), and cangrelor (1.7%; OR=0.59 [CI=0.29 to 1.20; p=0.19]), although the sample size for both agents was woefully small. The only agent which offers a significant 30-day mortality benefit in STEMI was prasugrel with significant lowest 1.75% death rate (OR=0.63 [CI=0.46 to 0.86; p=0.03]). CONCLUSIONS Among antithrombotic agents, prasugrel, but not ticagrelor, offers significant 30-day mortality benefit over clopidogrel in PCI-treated STEMI patients justifying short-term use in such a high-risk population.

Refuting the Ticagrelor-Aspirin Black Box Warning: And Proposing a Ticagrelor Early-PCI Black Box Warning

CONTEXT Ticagrelor, a novel reversible antiplatelet agent, has a black box warning to avoid maintenance doses of aspirin>100mg. However, a significant ticagrelor-early percutaneous coronary intervention (PCI) interaction exists. OBJECTIVE To discuss the inappropriateness of the black box warning for aspirin doses>100mg with ticagrelor and the appropriateness (and need) for a black box warning for ticagrelor patients needing early (within 24 hours of randomization) PCI. RESULTS The FDA Complete Response Review for ticagrelor indicates that aspirin doses ≥ 300 mg/daily was not a significant interaction. In the ticagrelor-aspirin ≥ 300 mg cohort, all-cause mortality (through study end) and cardiovascular (CV) mortality (through study end) were not significantly increased (HR=1.27; 95% CI, 0.84-1.93, p=0.262 and HR=1.39; 95% CI:0.87-2.2, p=0.170), respectively. However, in patients treated with early (within 24 hours) PCI, ticagrelor significantly increased all-cause mortality (30 day: HR=1.89; 95% CI: 1.26-2.81, p=0.002, and through study end, HR=1.41; 95% CI,1.08-1.84, p=0.012) and increased CV mortality (30 day: HR=1.31; 95% CI: 0.97-1.77, p=0.075, and through study end, HR=1.35; 95% CI, 0.995-1.82, p=0.054) compared to clopidogrel. CONCLUSIONS Early-PCI was more prevalent in the US versus outside-US regions (61% versus 49%). The black box warning for the use of maintenance aspirin doses over 100mg/daily with ticagrelor is inappropriate and ignores the more important, credible, and highly significant ticagrelor-early PCI adverse interaction in PLATO.

Clopidogrel, prasugrel, ticagrelor or vorapaxar in patients with renal impairment: do we have a winner?

The optimal utilization of antiplatelet therapy in patients with renal impairment (RI) following acute coronary syndromes (ACS) represents an urgent, unmet and yet unsolved need with regards to the choice of agents, duration of treatment and potential dose/regimen adjustment. The lack of any large randomized trials designed and powered specifically in such high-risk patients, absence of the uniformed efficacy and safety data reporting policy to the FDA and endless overoptimistic publications based on post hoc analyses of primary trials sometimes exaggerating benefits and hiding risks, clouds reality. In addition, triaging RI patients is problematic due to ongoing kidney deterioration and the fact that such patients are prone to both vascular occlusions and bleeding. The authors summarize available FDA-confirmed evidence from the latest trials with approved antiplatelet agents, namely clopidogrel (CAPRIE, CURE, CREDO, CLARITY, CHARISMA); prasugrel (TRITON, TRILOGY); ticagrelor (PLATO, and PEGASUS); and vorapaxar (TRACER and TRA2P) in RI patient cohorts on top of aspirin as part of dual antiplatelet therapy (DAPT). We deliberately avoided any results unless they were verified by the FDA, with the exception of the recent PEGASUS, since Agency reviews are not yet available. Despite differences among the trials and DAPT choices, RI patients universally experience much higher (HR = 1.3–3.1) rates of primary endpoint events, and bleeding risks (HR = 1.7–3.6). However, only ticagrelor increases creatinine and uric acid levels above that of clopidogrel; has the worst incidence of serious adverse events, more adverse events, and inferior outcomes in patients with severe (eGFR <30 ml/min), especially in the lowest (eGFR <15 ml/min) RI subsets. Clopidogrel, prasugrel and vorapaxar appear safer. Moreover, less aggressive half dose (5 mg/daily) prasugrel and strict DAPT, are well justified in RI, but not predominantly triple strategies with vorapaxar as tested in TRA2P and especially in TRACER. In conclusion, data from clinical trials, their sub-studies and affiliated FDA reviews indicate that RI cause more vascular occlusions and bleeding in ACS patients treated with DAPT. Among the novel antiplatelet agents, prasugrel and vorapaxar, but probably not ticagrelor, offer advantage in RI patients.

Effect of conservative dive profiles on the occurrence of venous and arterial bubbles in divers with a patent foramen ovale: A pilot study

Patent foramen ovale (PFO) is a risk factor for decompression sick-ness(DCS)indiversduetoparadoxicalembolizationofnitrogenbubblesformed in peripheral blood during decrease of ambient pressure [1].Inour previous study we have demonstrated that catheter-based PFO clo-sure prevented right-to-left shunting of bubbles and might preventDCS recurrence [2]. However, the question of PFO closure is still debat-able [3].Also,randomizedclinicaldataarelackinginthis field.Therefore,the majority of divers are currently not referred for PFO closure, andvarious conservative dive profiles (CDP) are recommended to preventunprovoked DCS (i.e., without violation of decompression regimen) [4].Unfortunately, to date, the safety of these CDP has not been tested in di-verswithPFO.Theaimofthisstudywastotesttheeffectofdivetimeandascent rate restrictions on the occurrence of venous and arterial bubblesin diverswith PFO after simulated dives.We compareda standardly rec-ommended no-decompression dive [5] and a stricter regimen withslower ascent to the same control dive, which was previously used totest the efficacy of catheter-based PFO closure [2].Wescreenedatotalof 532 consecuti vediversforPFOusingtranscra-nialcolorcodedsonography(TCCS).ThediagnosisofPFOwascon firmedbytransesophagealechocardiography.Forty-sixdivers(36.4±10 years;72% men) with a significant PFO (grade 3 according to the internationalconsensus criteria [6]) who had previously not undergone PFO closurewere enrolled in this pilot study. All divers performed a simulated diveto 18 m in a hyperbaric chamber. Divers were randomized into threegroups: group A (n = 13; 36.5 ± 9 years; 77% men) performed a stan-dard Buhlmann regimen no-decompression dive (dive time 51 min,ascent rate 10 m/min), group B (n = 14, 40.9 ± 12 years; 64% men)performed the same regimen with a slower ascent (51 min, 5 m/min),and a control group (n = 19; 33.0 ± 8 years; 74% men) performed astaged-decompression dive according to the US Navy decompressionregimen (80 min, 9 m/min, decompression stop 7 min at 3 m). Within60 min of surfacing, the presence of venous and arterial bubbles wasassessed. Venous bubbles were assessed by pulse wave Doppler in therightventricularout flowtract (RVOT),andarterialbubbles byTCCS dur-ing native breathing and after Valsalva maneuvers, as described previ-ously [2]. The study was approved by the local ethics committee and allpatients signed an informed consent.In all divers, visualization of RVOT and the middle cerebral artery waspossible. The occurrence of arterial and venous bubbles is summarized inFig. 1. There was significantly lower occurrence of venous bubbles ingroups A and B compared to controls (for group A, 31% vs. 74%, p =0.03; for group B, 14% vs. 74%, p b 0.01). The reduction in arterial bubbleoccurrencewasnotsigni ficantingroupAcomparedtocontrols,buttherewas elimination of arterial bubbles in group B (for group A, 8% vs. 32%,p = 0.42;forgroupB,0%vs.32%,p= 0.03).Therewasnosigni ficantdif-ference in venous or arterial bubble occurrence between groups A and B(venous, 31% vs. 14%, p = 0.38; arterial, 8% vs. 0%, p = 0.48). All diverswere observed for any DCS symptoms 24 h after the simulated dive. Inthe control group transient neurological symptoms (headache, unusualfatigue, and transitory visual disturbances) were present in 21% of divers,no DCS symptoms were observed in group A (p = 0.13) or B (p = 0.12).Generally, the aim of our research is to stratify the risk of DCS indiverswithPFOandtofindtheoptimalmanagementstrategyforsymp-tomatic divers, including potential catheter-based PFO closure. In our

Neutralizing the Adverse Prognosis of Coronary Artery Calcium

OBJECTIVES To report and compare the outcomes and survival of patients with abnormal computed tomography-derived coronary artery calcium (CT-CAC) scores undergoing aggressive medical treatment at a cardiac prevention clinic. PATIENTS AND METHODS We conducted a retrospective analysis of 849 patients with intermediate risk based on the Framingham risk score and an abnormal CT-CAC score who were aggressively treated in a preventive cardiology risk factor modification program from June 23, 2000, to September 1, 2012. The primary outcome was a composite end point of myocardial infarction, resuscitated cardiac arrest, revascularization, and cardiovascular death. The effect of the CT-CAC subgroup on major adverse coronary heart disease events (MACEs) was evaluated by calculating hazard ratios with Cox proportional hazards regression modeling. The Centers for Disease Control and Prevention Wonder database was used to identify age- and sex-matched controls from the general population of Kansas and Missouri. RESULTS The mean age of the study patients was 65.4 years (58.4% men [496]). The median follow-up was 58 months, and the mean CT-CAC score was 336 Agatston units. Thirty-four patients (4.0%) reached the primary end point, including 4 deaths. The adjusted 10-year mortality rates were similar in the study group and control group (9.3 vs 10.6; P=.80). After adjustment, a CT-CAC score greater than 400 Agatston units correlated with a higher risk of MACEs (hazard ratio, 3.55; P=.01). CONCLUSION These results suggest that intermediate-risk patients with abnormal CT-CAC scores when treated with intensive risk factor reduction have lower rates of MACEs than predicted by the Framingham risk score and the presence of coronary artery calcium.

Optimization of anticoagulation with warfarin for stroke prevention: pharmacogenetic considerations.

Warfarin is a cornerstone of oral anticoagulation for stroke prevention. Anticoagulation with warfarin in patients with atrial fibrillation is over twice as effective in secondary prevention of stroke as any other tested alternatives, including all other antithrombotic drugs or surgical interventions. General belief is that warfarin is capable of preventing 20 ischemic strokes for every hemorrhagic one it causes. However, warfarin is one of the most feared agents as a result of its woeful safety profile and difficulties in maintaining the proper daily dose. Recent research in pharmacogenetics predominantly focused on elucidating the influence of individual genetic predispositions to administered warfarin. Although the incorporation of genotype information improves the accuracy of adequate dose prediction, an improvement in anticoagulation control or a reduction in hemorrhagic complications has not been yet convincingly demonstrated. It is clear that identifying an individual patients risk for hemorrhage on warfarin will require more broad clinical and genetic studies. Future research focused on patients with stroke should concentrate on defining the possible differences, especially focusing on predicting bleeding events in general and intracranial hemorrhages in particular. The purpose of this review is to summarize the existing evidence about pharmacogenetics of warfarin in general, especially focusing on stroke prevention.