Cardiologia Croatica. 2016;11(8)

Zdravko Babić, Marin Pavlov

In the field of acute coronary syndrome management by the methods of interventional cardiology (percutaneous coronary intervention, PCI), Croatian medicine has closely followed international results in spite of the relatively low investments in the Croatian healthcare system as compared with industrialized countries. Since the establishment of the Croatian Primary Percutaneous Coronary Intervention Network, i.e. in the last decade, more than 15,000 patients with acute myocardial infarction with ST-segment elevation (STEMI) were treated with PCI; the same treatment protocol has also been applied in other patients with unstable acute coronary syndrome. In recent years, the network has managed 540-550 patients with acute STEMI per million inhabitants, with each of the eleven PCI centers providing care for more than 384,000 catchment population through 24/7 work schedule. The trends observed in the past decade show the risk profile of these patients to increase, while maintaining the results of treatment at the levels comparable to those reported from similar PCI networks (postprocedural TIMI III flow up to 91% and in-hospital mortality ranging from 4.4% to 6.3%). Future plans include development of a continuous prospective electronic Registry of Invasive and Interventional Cardiology and Acute Coronary Syndrome, further reduction of reperfusion time, increasing introduction of optimal medication and materials in the treatment of these patients, and optimization of treatment of acute myocardial infarction without ST-segment elevation all over Croatia.

Vjeran Nikolić, Heitzler

Issuing driving license to a person requires previous successful results on testing the person’s familiarity with traffic regulations, demonstrating practical driving skills, and the last but not the least, meeting the necessary health related criteria. Cardiovascular disorders can lead to sudden cerebral functional events, thus posing a risk for traffic safety. These disorders and diseases can be direct reasons for proclaiming temporary or permanent driving inability. The article describes the most common cardiovascular diseases that can influence driving ability in both private and commercial drivers.

Ljiljana Banfić

## Introduction At the initiative of the Croatian Cardiac Society (CCS), the Working Group on Angiology and Peripheral Vascular Diseases decided to address the state of Croatian angiology during 2015, based on the example of the Working Group on Peripheral Circulation of the European Society of Cardiology that was published in the European Heart Journal. The goal was to provide an overview of the positions and goals that CCS holds, based on the current knowledge and events in the European cardiologic community that marked the year 2015. (1) This editorial will briefly address the prevention of cardiovascular diseases and the importance of new markers in cardiovascular identification, diagnosis and treatment of peripheral artery disease, and finally the current issues related to venous thromboembolism treatment. ## Prevention of cardiovascular diseases Prevention of cardiovascular diseases is still very topical, and has in recent years increasingly included the expanded “vascular territories”, primarily carotid and peripheral circulation, in the assessment of cardiovascular risk. **Table 1** includes some of the recommendations published in current guidelines for the prevention of cardiovascular diseases (2) by the European Society of Cardiology (ESC) in May 2016. ### Table 1: Methods of cardiovascular risk assessment – using insight into the state of peripheral blood vessels (modified from reference 2 ). | **Recommendations** | **Class / Level** | | --- | --- | | Atherosclerotic plaque detection by carotid artery scanning may be considered as a risk modifier in cardiovascular risk assessment. | IIb / B | | Ankle-brachial index may be considered as a risk modifier in cardiovascular risk assessment. | IIb / B | | Carotid ultrasound intima-media thickness screening for cardiovascular risk assessment is not recommended. | III / A | Carotid intima-media thickness (CIMT) has become interesting clinical evidence and a marker in the focus of cardiovascular research as a potential challenge in the reclassification of cardiovascular risk, although current guidelines do not recommend it for routine application. A prospective multi-center study found that CIMT measurement was associated with cardiovascular events in participants under 45 years of age. (3) CIMT increase did not provide further information beyond that from the standard risk factors, but the study supported its use as a biomarker for persons that are still not qualified for screening for standard cardiovascular risk factors, given that these are usually used in persons above 40 years of age. (1) The position of CCS on this issue is fully in line with the ESC guidelines published in 2012 and 2016 (2, 4) (**Table 2**), although CIMT is still in the category of professional and scientific interest regarding cardiovascular risk assessment in our relatively small cardiovascular community and has no wider clinical application in routine risk assessment. CCS shares the positions and adheres to the rules of ESC, which states that CIMT measurement could cause inadequate concern and treatment in cases of false-positive results, but even a negative result could lead to unnecessary laxity and a false sense of safety regarding the proper relationship to a healthy lifestyle. Thus, the systematic assessment of cardiovascular risk in men younger than 40 years of age and women younger than 50 remains advocated by the newest guidelines on cardiovascular prevention published in 2016. ### Table 2: From the current cardiovascular disease prevention guidelines of the European Society of Cardiology (modified from reference 2 ). | **Recommendations** | **Class / Level** | | --- | --- | | Systematic cardiovascular risk assessment is recommended in individuals at increased cardiovascular risk, i.e. with family history of premature cardiovascular disease, familial hyperlipidaemia, major cardiovascular risk factors (such as smoking, high blood pressure, diabetes or raised lipid levels) or comorbidities increasing cardiovascular risk. | I / C | | It is recommended to repeat cardiovascular risk assessment every 5 years, and more often for individuals with risks close to thresholds mandating treatment. | I / C | | Systematic cardiovascular risk assessment may be considered in men >40 years of age and in women >50 years of age or post-menopausal with no known cardiovascular risk factors. | IIb / C | | Systematic cardiovascular risk assessment in men th CCS congress in October 2014. The results of the poll, in which 88 physicians took part (62 cardiologists, 14 internists, and 12 other physicians with other specialties) bear witness to the neglect for this method in the overall cardiologic practice. Approximately 20% of the participants responded to the poll. Active participation in the diagnostic process and assessment of peripheral artery disease did not include any method in the diagnosis of peripheral arterial disease for 56% of those polled, and only 7% used ABI as a screening method and as the initial, key method in the severity assessment in peripheral artery disease. A total of 55% respondents believed that ABI measurement would contribute to total cardiovascular status assessment in patients during routine assessment of arterial disease. All this indicates the need to once again ensure adherence to recommendations in the ESC guidelines for the diagnosis and treatment of peripheral artery disease that were presented as early as 2011 and were translated as summarized guidelines in the Republic of Croatia in 2013. (9, 10) We believe it would be worthwhile to alert the cardiologic public to the importance of the application of vascular biomarkers in primary and secondary cardiovascular prevention, so in **Table 4** we showed only the most important biomarkers with A-level evidence that have been accepted so far. ### Table 4: The applicability of vascular biomarkers in primary and secondary cardiovascular prevention (modified from reference 1 ). | Vascular biomarker | Class / Level | Risk stratification value / Simplicity of method | | --- | --- | --- | | **Ankle-brachial index** | IIa / A | +++ / ++++ | | Arterial stiffness | | | | Pulse wave velocity (carotid, femoral artery) | IIa / A | ++++ / +++ | | Carotid ultrasound | IIa / A | +++ / ++ | ## Peripheral artery disease The diagnostic process and disease assessment for peripheral artery diseases, despite the published guidelines, still relies only on clinical signs, arterial circulation duplex ultrasound, and angiography. Only a negligible number of centers use plethysmography, segmental blood pressure, and ABI in the diagnostic process, despite the fact that this method is an indispensable part of peripheral artery disease assessment. Based on data from the Information Health System of the Republic of Croatia (CEZIH) of the Croatian Health Insurance Fund (HZZO), a total of 644 angiointerventions on peripheral arteries were performed in 2015 in the Republic of Croatia (527 with the implantation of 1 stent and 117 with the implantation of 2 or more stents). This number also includes carotid artery interventions. Carotid endarterectomy, based on the same data, was performed in 1213 carotid arteries, which is in line with the recommendations and evidence from the publication we are referring to, suggesting that endarterectomy is a method that is still preferred over endovascular treatment for carotid stenosis. ## Vein thrombosis Public awareness is low regarding venous thromboembolism (VTE) and deep vein thrombosis (DVT) as well as pulmonary embolism (PE) and is estimated at 44% to 59%, which is lower than awareness of myocardial infarction (88%) and stroke (90%) as well as arterial hypertension (90%). (11) Additional public or media engagement is necessary in order to increase public awareness of the significance of VTE and thus reduce the disease burden of this widespread but preventable disease. We do not have clear objective data on the prevalence of venous thrombosis for the Republic of Croatia, since a registry for venous thrombosis does not exist. Knowing the true prevalence of the disease is only partially possible, since data only applies to the hospitalized part of the population. According to data from the CEZIH/HZZO database for 2015, it is estimated that approximately 1925 patients were treated for venous thrombosis in hospital conditions. It is not possible to determine the data on the true incidence of the disease based on this number of patients that had venous thrombosis as their initial diagnosis. If we accept that the incidence of venous thrombosis in Croatia is similar to the incidence reported in European and US publications, we can expect that the annual incidence in the general population is between 6000 and 7000 cases. It is important to once again point out the abovementioned results of the poll on the way VTE is being treated. The data show that 68% of physicians believe that the application of vitamin K antagonists (VKA) in the treatment of DVT and thromboembolism prophylaxis is a cause for concern, since only 30% that patients treated with VKA achieve target international normalized ratios (INR). Approximately 88% hold that the application of new oral anticoagulants would contribute to better compliance, comfort, and safety for venous thrombosis treatment. Approximately 70% of the respondents believed this would also reduce treatment costs for patients with DVT due to the increase in effectiveness, especially due to lower incidence of side effects. The initiative of the Working Group on Angiology and Peripheral Vascular Diseases of the CCS to improve interest and awareness of venous thrombosis is related to the preparation of the National Guidelines for the Diagnosis and Treatment of Venous Thrombosis and Venous Thromboembolism, which will soon be presented to the public and which, given the lack of ESC guidelines on the diagnosis and treatment of venous thrombosis, mostly rely on the recommendations published in the Chest Journal during 2016 and treatment guidelines for acute pulmonary embolism. (12, 13) ## Conclusion We believe it is not irrelevant that as many as 78% of cardiologists thought that further education in angiology should be ensured for the treatment and diagnostics of venous diseases and peripheral artery diseases. To satisfy these needs, which would lead to better clinical practice and compliance with current guidelines, it is necessary to achieve synergy between the possibilities determined by the Croatian Health Insurance Fund, but also strengthen the initiative of the CCS, encourage and develop registries in the field of angiology, and encourage professionals to be sensitive to the issues related to angiology in the Republic of Croatia. We also believe it is important to emphasize that in addition to the CCS, the scientific and professional activities of the Croatian Academy of Sciences and Arts in 2015 also contributed to public and professional awareness of the academic community regarding the current topics in peripheral artery diseases and biomarkers in cardiovascular risk assessment.

Sanja Matijević, Rončević, David Gobić, Teodora Zaninović, Jurjević, Željka Rubeša, Miculinić, Luka Zaputović

LDL cholesterol (LDL-C) is a strong independent cardiovascular (CV) risk factor that can be easily influenced. Today, statins are the therapy of choice for the achievement of target LDL-C values. Although controlled clinical trials have demonstrated their effectiveness and safety, in practice we are often met with statin intolerance as well as a failure to achieve target LDL-C values in a significant portion of the patients despite maximal doses. In patients with high and very high CV risk, other antilipemic pharmacotherapy is often also insufficient. PCSK9 inhibitors (PCSK9-I) are new revolutionary drugs with a potent effect on LDL-C. The rapid development of PCSK9-I began in 2003 with the discovery of a PCSK9 gene mutation in patients with familial hypercholesterolemia. The product of this gene, proprotein convertase subtilisin/kexin type 9 (PCSK9), has an important role in the expression of LDL receptors and cholesterol metabolism. Animal models demonstrated that inactivation of the PCSK9 gene lowers LDL-C with regression of atherosclerotic changes in the aorta. Heterozygotes and homozygotes with the inactivation mutation of PCSK9 have lower LDL-C values and lower incidence of atherosclerosis. Among the various groups of PCSK9-I, monoclonal antibodies saw strong development (alirocumab, evolocumab, bococizumab). Phase 3 clinical trials on familial and primary hypercholesterolemia with statin intolerance or resistance have demonstrated a strong positive effect of alirocumab and evolocumab on LDL-C values (a reduction of 60%), with high safety and good tolerability. The OSLER study on evolocumab also demonstrated positive effects on CV outcomes. Multiple clinical trials on PCSK9-I are currently monitoring their effect on CV morbidity and mortality. Positive results from these studies would confirm the great potential of PCSK9-I for better prevention and treatment of CV diseases.