Authors

• Eduard Margetić — Working Group for Invasive and Interventional Cardiology, Croatian Cardiac Society, Croatia — ORCID: 0000-0001-9224-363X
• Željko Baričević — Working Group for Invasive and Interventional Cardiology, Croatian Cardiac Society, Croatia — ORCID: 0000-0002-5420-2324

Abstract

Summary: Cardiovascular diseases are, despite positive trends and recent treatment advances, still the most common cause of death in the Republic of Croatia, mostly due to coronary artery disease. Croatia has every right to pride itself on the fact that patients with coronary disease are provided with modern, up to date and high-quality care comparable to more developed countries and wealthier healthcare systems. At the same time, the cardiovascular care in certain regions of Croatia is not at this level due to geographical, financial, and personnel limitations. There are multiple prerequisites for improving patient care, including the need for systematic and continuous efforts in prevention, diagnostics, and treatment. Starting with educational measures for population at-risk (through public-health campaigns promoting a healthy lifestyle) and optimizing the education of healthcare providers at the primary level, the reorganization of the healthcare system should work towards achieving availability and proper use of non-invasive diagnostic methods, unlimited access to appropriate medications, better organization of primary percutaneous coronary intervention network with reduced delays in revascularization, fully equipped interventional laboratories with improved working conditions for intervention teams, reduction of the waiting lists for cardiac surgery revascularization, and high-quality epidemiologic monitoring.

Keywords

coronary artery disease, Croatia, acute coronary syndrome, percutaneous coronary intervention, registries, prevention, rehabilitation

DOI

Full Text

## EPIDEMIOLOGY Cardiovascular diseases (CVD) are the leading global cause of mortality and morbidity. According to data from the 2013 Global Burden of Disease Study, it is estimated that approximately 30% of all deaths are caused by cardiovascular disease (1). At the European level, CVD makes for 47% of total mortality, and 40% in the European Union alone. Although advances in the treatment of CVD over the last few years have caused a significant reduction in mortality in the most economically developed countries, inaugurating the malignant diseases as the leading cause of death, cardiovascular diseases are still a dominant public-health problem in most countries. Especially upsetting is the fact that between 4% to as much as 42% of mortality from CVD, depending on economic strength and the level of development of the healthcare system of a given country, happens in the economically most productive population under the age of 60, which sheds additional light on importance of this burning issue with clear unfavorable social and economic effects. Nor can we ignore the fact that many cardiovascular events result in disability – expressed by use of the so-called DALY (disability-adjusted life year) score that includes the lost years of life due to premature death and the years of disability due to disease, the burden of CVD is 10-18% of all diseases (2). The healthcare systems in most countries, especially in developing countries, are overtaxed by the growing need to care for a population of patients with heart disease, stroke, malignant diseases, diabetes, chronic respiratory diseases, etc. The concept of organizing a healthcare system is based on making curative medicine the focus of the system through well-equipped and well-staffed hospital institutions that provide high-quality care for a small number of patients, with high expenses from a limited health budget, while at the same time more-or-less ignoring the fact that these are diseases that can and should be systematically prevented. As a consequence we are left with a large proportion of people with high cardiovascular risk who remain unidentified, and even individuals with diagnosed issues do not have adequate access to primary-level care. The importance of the situation and the need to resolve these issues has also been recognized, at the global level, by the World Health Organization in their Global Action Plan for the Prevention and Control of Noncommunicable Diseases for 2013-2020, as a continuation of the first version of the Plan for 2008-2013. The new Plan has stressed four key risk factors – tobacco consumption, lack of physical activity, unhealthy diet, and alcohol abuse (3). Coronary heart disease (CHD) is responsible for the majority of deaths from CVD. In 2008, of the 17.3 million deaths cause by CVD globally (which is expected to increase to 23.6 million by 2030), as much as 7.3 million were a result of CHD (4). According to data from the Croatian Institute of Public Health, death caused by CVD made up 48.3% of total deaths in 2012 and was the leading cause of death, of which somewhat less than half was caused by CHD. Epidemiologically speaking, there has been a continuous positive trend in the reduction of mortality rate from CVD in Croatia, but with a standardized mortality rate of 342.1/100,000, Croatia is among the European countries with moderately high mortality rates (5). There is still a noticeable negative difference when compared with neighboring Mediterranean countries, which clearly indicates insufficiencies in the implementation of measures based on strategic documents (National Programs for the Prevention of CVD, Action Plan 2015 – 2020 for Croatia). Based on all of the above, the Republic of Croatia faces a period of challenges to find a solution for prevention and better-quality treatment of CVD, including CHD as the most prominent representative of CVD. The key to success lies in recognizing the current weaknesses of the system and adopting a more active approach in elucidating problems, of which many could be resolved, despite financial limitations, through smarter redistribution of funds from the health budget and by taking into account long-term costs and benefits. Prevention is a key factor and a problem that should be addressed through a systematic healthcare policy insisting on strengthening the personal responsibilities of the individual in making lifestyle choices. In the next few sections we shall give a brief overview of a selection of specific problems faced by a typical patient in Croatia with the suspicion and/or diagnosis of CHD, in the context of stable coronary disease and acute coronary events. ## STABLE CORONARY HEART DISEASE ## Diagnostics ## Non-invasive diagnostics The basis of diagnosing stable CHD is in the proper interpretation of the clinical picture – depending on the patient’s age, sex, and history of chest pain (typical or atypical angina, nonanginal pain), it is possible to assess pre-test probabilities and, on one hand, establish the diagnosis of stable angina pectoris in a certain percentage of patients (e.g. an older man with typical symptoms), or, on the other hand, eliminate CHD as an option with a high probability of being correct (a young woman with nonanginal pain), with no further diagnostic processing being required (6). This achieves savings in human, temporal, and financial resources at the very first step of the process. Calculating pre-test probabilities, coupled with knowledge of the specificities and sensitivities of different diagnostic methods (exercise stress test, stress echocardiography, myocardial scintigraphy, MSCT coronary angiography, magnetic resonance imaging, positron emission tomography) and their comparative strengths and weaknesses, determines which method will provide the greatest clinical benefit, i.e. the lowest number of false positive or negative results – this, other than in the diagnostic sense, is also extremely important for prognosis, since the percentage of myocardial ischemia calculated or assessed with these methods also determines the type of treatment, i.e. the need for invasive procedures (coronary angiography) and revascularization. Such rational application of diagnostic tools creates savings at the second step as well (7). Unfortunately, the application of these guidelines is significantly limited by the poor availability of key diagnostic methods. Stress echocardiography is only performed in a small number of specialized echocardiographic laboratories, predominantly using dobutamine to create drug-based exertion, in far smaller relative numbers than the standards of developed countries and with further limitations due to basic technical inadequacies (e.g. the unavailability of the supine bicycle ergometer to perform exertion through physical activity) and a small circle of educated staff. SPECT myocardial perfusion scintigraphy is also used less than expected – the availability and performance of this method would be improved by more intensive cooperation between cardiologists and nuclear medicine specialists (or introducing subspecialty in cardiovascular imaging) and by replacement of outdated equipment. The use of exercise stress test is overemphasized (and often uncritically applied) and is the most common method employed. MSCT coronary angiography, due to its high negative predictive value, has its place in eliminating obstructive CHD in patients with moderately increased pre-test probabilities (8), as well as in imaging of coronary artery anomalies and aortocoronary bypass grafts, but is also limited by lack of availability to most of the population, particularly in the public health system. PET and MR currently have no place in routine clinical practice in Croatia. ## Invasive diagnostics ## Coronary angiography It is well known that coronary angiography is the gold standard in diagnosing CHD, whether for classical atherosclerotic, obstructive CHD, functional disorders in the form of vasospastic angina, or other, less common causes (anomalies, inflammatory events, etc.). The invasive nature of the method carries a risk of serious complications with a low incidence (0.93 are discarded as insignificant, and measurements 2 being an indication for revascularization. IVUS can also be potentially useful for morphological analysis of atherosclerotic plaque. OCT is similarly indicated in the preparation and guidance of PCI and plaque analysis. It can also have an especially important role in the use of bioabsorbable scaffolds and assessing the severity of transplant vasculopathy (17). ## Treatment ## Medication Medication treatment for CHD largely consists of pharmacological treatment of risk factors. A significant part of the overall problem is due to inadequate treatment of arterial hypertension with all-too-common acceptance of suboptimal arterial pressure values. Part of the problem is also in poor patient compliance – the role of the physician is extraordinarily important here in educating the patient and choosing the most appropriate treatment and in avoiding polymedication and polypragmasia. It is doubtful whether this can be fully achieved with the current organization and overburdening of the healthcare system, where not even minimal temporal norms can be achieved that would allow for good communication between the physician and patient. Everyday experience also shows that there is an overly large portion of patients with CHD who have not been prescribed statins or with inadequate dosage in view of the treatment goal of LDL-cholesterol levels based on ESC guidelines (LDL-C 50% reduction if target levels are not achievable) (18). In light of this, there is a place for additional treatment with non-statin drugs (ezetimibe), which is especially important in patients with previous acute coronary syndrome – the IMPROVE-IT study showed a reduction in the number of ischemic coronary and cerebrovascular events due to combination therapy with ezetimibe/simvastatin in comparison with simvastatin, with low incidence of side effects (19). A specifically Croatian problem is also the unavailability of efficient modern antianginal drugs (trimetazidine, ranolazine, ivabradine) to the wider patient population due to expensive co-payment requirements. ## Interventional revascularization Outcomes for patients treated with PCI depend on the technical performance of the procedure, prevention of early complications, patient compliance in necessary therapy (with emphasis on antiaggregation therapy), and largely also on the availability and choice of material. Drug-eluting stents (DES) are the gold standard in modern interventional cardiology, as opposed to bare-metal stents (BMS) (20). In comparison with BMS, DES have significantly lower stent restenosis rates, with the newer DES generation almost completely eliminating differences in stent thrombosis rates in comparison with BMS, which clearly and unambiguously provides clinical justification for the use of DES in most patients (an exception may be patients with increased risk of bleeding or other contraindications for long-term application of dual antiaggregation therapy, e.g. an impending surgical procedure) (21). In 2015, penetration of DES in Croatia was approximately 40%. It is to be expected that there could be a drop in price consequent to the increase in the number of implanted DES (in comparison with BMS), which is currently the only barrier to their more widespread usage. Drug coated balloons (DCB) are available in Croatia if specially indicated, as are bioabsorbable vascular scaffolds (BVS). ## Surgical revascularization Aortocoronary bypass surgery is a revascularization method that, according to current guidelines, has an advantage over PCI in a certain patient population (e.g. patients with triple-vessel CHD, for SYNTAX scores >22, diseases of left main coronary artery, etc.) (22). It should however be noted that the research that became the basis of clinical practice and which the guidelines refer to has to some extent fallen behind the times and the current situation. Advances in the development of stents and PCI techniques with regard to surgical revascularization (which very rarely involves more than one arterial bypass graft) shed a different light on the issue. The glaring weakness of cardiac surgery revascularization in Croatia is the long waiting list for the procedure. A way out of this situation is good cooperation between cardiologists and cardiac surgeons as a team of physicians forming decisions on the best options for a particular patient, taking into account the local circumstances. ## ACUTE CORONARY SYNDROME ## ST elevation acute myocardial infarction Primary percutaneous coronary intervention is a superior way of achieving reperfusion in comparison with fibrinolytic therapy if it can be performed within 120 minutes from the first medical contact (FMC). Delaying reperfusion therapy is deleterious since its potential benefit drops with time (“time is muscle”) and the chance of complications increases. Delays in the application of reperfusion therapy is the best indicator of the (lack of) quality of this vital part of care for patients with acute myocardial infarction and should be permanently monitored with the goal of optimizing the system (23). Possible causes for delays in application of reperfusion therapy include: - Patient delay– the loss of time between symptom onset and FMC. To improve the situation in this area it is necessary to continuously educate the population on the symptoms of acute myocardial infarction, which is still not being done in Croatia at a systemic and intensive level, although there has been visible effort from expert societies associated with this issue. Special care should be given to the education of patients with already established CHD and their families. - Delay between FMC and establishing the diagnosis – in health institutions that take part in the care of patients with ST elevation myocardial infarction (STEMI), the time between FMC to an ECG should be <10 minutes. Croatian experience shows that excellent progress can be achieved in this basic area – the emphasis should be on cases where the diagnosis was delayed due to atypical symptoms (in as many as 30% of cases) and omissions in recording of the ECG of the posterior and right precordial leads (e.g. occlusion of LCx can result in “silent“ standard 12-channel ECG recording). In cases of clear clinical suspicion, one should insist on repeated ECG and urgent echocardiographic examination – there is no excuse for skipping these steps while waiting for the findings of elevated markers of myocardial necrosis. - Delay between FMC and reperfusion – this is a delay in the whole care system for patients with STEMI. The guidelines are clear. In case of primary PCI, the interval between FMC to passing a wire through the occluded coronary artery should be ≤90 minutes, or ≤60 minutes if the patient is in a center capable of administering PCI treatment. If fibrinolytic therapy is applied with the goal of reperfusion, the interval from FMC to infusion start should be ≤30 minutes. The Croatian primary PCI network, which is organized as a system of 12 centers for primary PCI with an accompanying “ring”, i.e. an area of cooperation with regional healthcare institutions that have no capabilities of emergency PCI reperfusion, has brought about a renaissance in the care for patients with STEMI and provides ever better results every year, comparable with much wealthier European countries. When FMC takes place in an institution with no primary PCI capabilities, the emergency transportation procedure is activated to transport the patient to a PCI-capable center that has an experienced and trained team on 24-hour standby, 7 days a week (in Croatia this is the case in 11/12 centers performing primary PCI). This leads to maximally effective acute care for patients with STEMI with a minimum of complications, especially in high-volume centers, which is clearly shown by data from scientific publications. Additional benefits to the patient are provided by the transradial vascular approach – one of the goals is to achieve its widespread application in all Croatian PCI centers. Based on information collected from databases from the Network centers, 2271 patients with STEMI were treated with primary PCI in Croatia in 2014 and 2015. With 539 interventions per million inhabitants, Croatia is in the second “strength” category in Europe, which is a laudable result. Intrahospital mortality for patients treated with primary PCI over the last 10 years has been holding in the range between 4.4 and 6.8%. The above results must be considered with caution, however, since the data in question are retrospective and thus somewhat imprecise, but positive trends coupled with a continuous drop in cardiovascular mortality indicate the favorable direction Croatia is heading in. On the other hand, there is certainly room to improve, and improvements can be achieved without major additional costs to the healthcare system. One of the more significant problems is connected with the inadequately long transportation of patients to PCI centers – a possible solution might include the reorganization of emergency medical services (EMS) in such a way that a patient with STEMI is immediately directed to a center with PCI capabilities, bypassing the regional hospital. If such a patient is still brought to a regional hospital, transport to a PCI center should be secured in the same EMS vehicle so as to save on time. Furthermore, if transport to a PCI center is not possible in the appropriate time frame and the patient presented shortly after myocardial infarction onset, the option of using fibrinolytic therapy should not be ignored. For patients who arrive directly to a PCI center as FMC outside regular working hours, the time to revascularization depends on the time for the interventional team to arrive to the hospital – a certain amount of time could be saved by adequate on-site organization, i.e. the continuous availability of the interventional team on location. This is a rational approach to the benefit of the patient, but the number of interventional cardiologists and other medical personnel is insufficient for such a system to be sustainable. It is worth noting that the concept of on-call assumes a high level of enthusiasm from staff with unsatisfactory financial compensation and an obligation to work regular hours the next day, regardless of the duration and number of interventions over the last 24 hours. To appropriately determine key points where the issues arise, it is very important to have insight into basic and reliable data needed to evaluate the system. With that goal in mind, the Working Group on Invasive and Interventional Cardiology of the Croatian Cardiac Society and the Working Group on Acute Coronary Syndrome, in cooperation with the Agency for the Quality and Accreditation in Health and Social Care, started an initiative to create the Registry of Invasive and Interventional Cardiology that will include a prospective registry for myocardial infarction at the national level. Regarding medical therapy, it is crucial to apply dual antiplatelet therapy (DAPT), i.e. a combination of aspirin and thrombocytic ADP-receptor blockers. According to current guidelines of the European Society of Cardiology (23), which are also the guidelines of the Croatian Cardiac Society, the first-line treatment among platelet ADP-receptor blockers are ticagrelor (180 mg per os once daily, maintenance dose 2×90 mg daily) and prasugrel (not registered in Croatia). The second line of treatment is the still most widespread drug clopidogrel (600 mg once daily, maintenance dose 75 mg daily), which has a weaker and slower starting effect on platelet aggregation in comparison with ticagrelor and prasugrel. Clopidogrel should be used in interventional STEMI treatment only when ticagrelor and prasugrel are not available or if there are contraindications for their use. Based on the above, the optimal drug choice should be facilitated by the fact that ticagrelor is on the list of the Croatian Health Insurance Fund, and is indicated in combination with aspirin for the prevention of atherothrombotic events in adult patients with acute coronary syndromes, including patients that have recently been conservatively treated and those that were treated with PCI or aortocoronary bypass. For interventional teams on 24/7 standby, it is even more important that ticagrelor has been included to the Basic Medication List (with no co-payment) of the Croatian Health Insurance Fund for the treatment of patients with STEMI that have received primary PCI with stent implantation, based on the recommendation of the authorized interventional cardiologist, for a duration of up to 6 months. This should be seen as motivation and the first step towards the availability of optimal antithrombotic therapy on the Basic Medication List for all patients with acute coronary syndrome over the whole duration of DAPT. ## Non-ST segment elevation acute myocardial infarction Non-ST segment elevation myocardial infarction (NSTEMI) carries a poor long-term prognosis (partly due to population characteristics which include advanced age and multiple comorbidities), and it is this area where it is possible to significantly improve patient outcomes. Data from PCI centers differ significantly, but an unacceptably limited availability of coronary angiography (and revascularization) is noticeable in many Croatian regions. The first issue is immediately clear when looking at risk stratification of individual patients (in practice, recommended models using point scales such as GRACE are rarely applied), which defines the time frame for invasive treatment (within 2, 24, or 72 hours) (24). The solution for this problem might be the organization of a “NSTEMI Network” – currently this is prevented by lack of personnel and technical and financial requirements; although there is daily cooperation between regional hospitals and PCI centers, the time delay depends on the availability of hospital beds and the capacities of the interventional teams. ## Secondary prevention and rehabilitation Care for patients with acute coronary syndrome does not stop at the point of revascularization. This is a population at-risk that requires strict risk factor correction, in line with current guidelines (25). It is especially important to adhere to target arterial pressure and LDL-cholesterol values (high doses of statins ± ezetimibe). Rehabilitation is exceptionally important for these patients, whether in stationary or ambulatory form, since it allows for lifestyle changes and risk reduction for future CV events. ## CONCLUSION The current situation regarding CHD care in the Republic of Croatia is far from ideal and fraught with numerous limitations, and we face many challenges in the near and far future. The scope of the problem requires each component of the system to do its job – the individual patient by adhering to a healthy lifestyle, the state in its role as the health policymaker, treasurer, and health advocate, the physician in primary healthcare, and the cardiologist. The interventional cardiologist holds one of the central roles in CHD treatment – unfortunately, there is still no formal education program for interventional cardiology in the Republic of Croatia. There is also no system for the follow-up and evaluation of work and licensing of interventional cardiologists, which is one of the main tasks of the Registry of Invasive and Interventional Cardiology that is being created. It will allow much needed quality control of the whole system and facilitate the forming of logistic and personnel plans for the development of the field. On the other hand, it will be necessary to invest further efforts to, given the fairly well-defined duties, more appropriately value and appreciate the specificities and rights stemming from working in this area of cardiology.

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