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Beta-blockers are an indispensable element of drug therapy in heart failure (HF). Several multicenter trials have confirmed the beneficial effects of some of them on the survival, hospitalizations, morbidity, and the various clinical aspects of this disease.

The treatment with beta-blockers reduces hospitalizations (total and cardiovascular in HF), improves the functional class and leads to delayed worsening of HF. This benefit has been consistently observed in subgroups of different age, sex, functional class, left ventricular ejection fraction (LVEF), ischemic or non-ischemic etiology (Grade of recommendation I, level of evidence A).

In patients with LV systolic dysfunction, with or without symptomatic heart failure after acute MI, long-term treatment with beta-blockers in addition to ACE inhibition is recommended, in order to reduce mortality (degree of recommendation I, level of evidence B) .

In patients with HF there may be differences in the clinical effect of the different beta-blockers. Four beta-blockers are mainly recommended for the treatment of HF, depending on the case – bisoprolol, carvedilol, metoprolol succinate or nebivolol (degree of recommendation I, level of evidence A).

What are the differences of carvedilol in comparison with the other three?

In addition to beta-1, carvedilol blocks beta 2 and alpha 1-adrenoceptors and has antioxidant properties. Sarvedilol improves the left ventricular ejection fraction in patients with chronic heart failure (CHF).

Moreover, in cases of CHF and left ventricular dysfunction after myocardial infarction (MI), the treatment with carvedilol limits the remodelling of the left ventricle.

The study COPERNICUS- Carvedilol Prospective Randomized Cumulative Survival Study (with 2289 participants) demonstrated that carvedilol significantly reduced mortality and hospitalizations for severe (grade III-IV in NYHA) CHF. Another study – CAPRICORN -Carvedilol Post-Infarction Survival Control in Left Ventricular Dysfunction (1959 patients with LV systolic dysfunction after-MI) demonstrated the beneficial effects of carvedilol in infarction condition – that it reduced mortality.

The particular importance of the antioxidant properties of carvedilol are as follows:

– Reduction of the oxidative stress on cardiomyocytes – a delay of the remodelling of the ventricular wall;

– Reduction of the importance of the “reperfusion syndrome” – in some patients with MI and reperfusion  a fulminant HF is developed afterwards. Sarvedilol limits the “oxygen shock” on the cells;

– Improving the opportunities for the production of nitric oxide.

What is the importance of the alpha-1 blockade induced by carvedilol?

In HF the heart works with a decreased flow, against an increased peripheral vascular resistance.

By blocking the alpha-1-adrenergic receptors in the periphery, carvedilol causes vasodilation, reduces the peripheral vascular resistance and hence decreases the afterload of the heart, therefore, limiting the hypertrophy of the left ventricle and the subsequent diastolic dysfunction.

Hence the additional effect of carvedilol on the development of HF – functional class improvement, and improvement of the quality of life.

Tchaikapharma – High Quality Medicines Inc. produces licensed Dilatrend (carvedilol) and is a Marketing Authorization Holder of the product.

Dilatrend has been in the list of NHIF since the 16^th of November 2014, with the following codes:
Dilatrend 6.25 mg x 28 tabl. – CG 221
Dilatrend 12.5 mg x 28 tabl. – CG 220
Dilatrend 25 mg x 28 tabl. – CG 219

Interview with Nikolay Hadjidonchev, Chairman of the Bulgarian Generic Pharmaceutical Association “BGPharmA”

For two years you are fighting to get a precise breakdown of costs for medicines by the health insurance fund, more precisely this is normal request for transparency. Have the NHIF or the Health Ministry shown will during this period?

There should be some form of transparency, which will allow monitoring of the expenses for the various medicines. The information system of the health insurance fund must allow this to be done electronically, the system should allow transparency of the expenses and this information should be publicly available. We have received so far only data at our request for the expenses for some medicines.

Are you satisfied that the necessity of the pro generic orientation is realized by all political parties?

We are pleased that at least it is included in the election campaign of almost all political parties. Now the question is of the pro generic policy that all use as mantra, to give it meaning and to implement adequately.  What does adequately mean? When you have a pro generic policy, it is not acceptable to have part of the population with chronic diseases to cover most of the costs for the treatment. It is not acceptable, when you are insured and you have high blood pressure or hearth problem, to have to cover most of the costs for the treatment. A base possibility should be provided for free of charge therapy based on generic medicines. Everybody, especially people without income, pensioners should be guaranteed one free of charge package for chronic diseases. From there on everybody has the possibility to pay the surcharge or to purchase other medicines if so wishes. When we are talking of pro generic policy, the main direction we stand for, and the appeal here is to the public – the generic medicines for many years have proven their effectiveness and are means by which all developed countries save and cope with the rising prices. People live longer and the medicines in number of packages increase.

Have you calculated how much this would cost, based on the number of chronically ill?

It is very difficult for us to calculate without adequate information from the fund. So far we have information from IMS. The exact number of the patients is in the database on the NIHF. As an association we have a close standpoint with the Bulgarian Medical Association, but we have to unite with all the participants in the process such as patient societies, the pharmaceutical union, the association of owners of pharmacies and others. Calculations should me made, the legislature should be changed and once and for all we should find a way to guarantee a basic, free of charge package of medicines for the major diseases of every insured patient. The pro generic policy means also to stop partial reforms and short term initiatives and to follow a strategy to ensure adequate healthcare Bulgarian patient. This can be achieved now only if all political forces unite on some main reforms in health care and which will be guaranteed adequate long term financing. Judging from the statements of all the politicians, there are no differences in the basic key guidelines of health care. Now is the time to rally around a cause, the future of the nation depends on solving the demographic problem and healthcare reforms. This is a national salvation. Along with the economic development, which is a key task, answer should be provided to how the health care will be finances, will the health care fund be demonopolized, how the collection of the contributions will be increased, the national health card, the number of hospitals and how the state will provide adequate insurance to people for whom it is responsible. Everything is a matter of vision and political will. And when you have a large number of analogs, it is normal to base treatment of the disease on the basis of generic medicines in order to free resources for those diseases which are treated only with medications without analog. Pro-generic policy does not mean use of only generic medicines. Advanced countries use whenever possible mainly generic medicines in order to free financial resources for expensive original medicines that have no alternative. And why the diseases, the treatment of which is possible with a wide range of generic medicines, should be treated with more expensive original? This decision should be left to the patient in accordance with his/her financial capabilities and under the guidance of a doctor. Today this possibility is usually not provided to the patient. Do not forget that Bulgaria has for years a very strong generic industry. Pharmaceutical manufacturing is the leading sector according to the latest World Bank report, creates gross domestic product, jobs, and pays taxes, insurances. We have potential; the people employed in this sector, 10% of the employed in Europe in the pharmaceutical industry are in Bulgaria. In which other industry we have such allocation? Therefore we should enable it to continue to invest, export from Bulgaria, have adequate regulations, have high quality and here we can look at the changes that are planned related to the Drug Agency, we need professionalism, we need support. The Drug Agency must be open to the problems of Bulgarian generic industry and create normal environment for its development and growth.

Other countries more or less find mechanisms to support the generic industry.

This is a matter of state policy and promoting the local economy and employment with adequate regulations. In the EU some countries such as Slovenia and Hungary have similar practices. Everything again comes to economic vision and political will. We are preparing now a White Paper with medicines that have been withdrawn from the Bulgarian market and the production is discontinued because of impossibility to be sold. When s generic product is withdrawn due to economic reasons and there is no other generic product on the market, only one alternative remains – medicines with patent protection, respectively with much higher price. Thus the expenses for treatment are increasing instead of decreasing. Time and in-depth analysis would show to what extent price referencing really contributed to the reduction of the costs of the state. There is now an unfavorable trend generics to be withdrawn from the Bulgarian market, the moment when companies will be forced to rethink their presence here is not far away. Products are withdrawn which are basic therapy and often do not have a second or third similar generic product.

What is the share of the generic industry in the payments of the Health Insurance Fund?

The total medicine market in Bulgaria, according to the official data from the IMS Health – 259 million packages were sold in 2013 and the distribution between originals and generics is 58 mln. to 201 mln. packages. This in percentage is 22.4% to 77.6%. Compared to the previous 2012, the market growth in the packages is respectively 10% for the originals and 1% for the generics. In value the numbers are as follows: the total market was BGN 2.343 billion, as the 58 mln. packages of originals were BGN 1.228 billion., and for the 201 mln. packages of generic were spent BGN 1.115 billion. In percentage the ratio is 52.4% to 47.6%. The growth in the value of the originals from the previous 2012 was 12% compared to 2% for generics. In the first half of 2014 the value of the originals continued to grow and it seems that the trend of increase of the cost of original medicines, which account for more than half the financial resources of public funds and the amounts paid by the patients, is deepening. How these indicators are placed in the estimates of the NHIF is confidential information, which we do not have. Unfortunately biggest expense of the health insurance fund is for medicines protected by patent, mainly used in oncology, rare diseases and others. For a large group of medicines with expired patent protection the costs are for much more patients and they are primarily for socially significant diseases – hypertension, ischemic heart disease, cerebrovascular disease, diabetes and others. In this large group is the key role of generic medicines, but they are not used enough and rationally. The original medicines in this group of medications with expired patent protection retained above 40% of the market and the low percentage of reimbursement by the Fund for these diseases – 25-50%, the patients pay a lot for their medicines and so at the lowest prices in the EU, to the Bulgarians the medicines seem expensive. There is no policy, neither in the Fund nor in the Ministry of Health, to create conditions for doctors to prescribe mainly generic medicines if the treatment option is available with them. At the same time there were negative campaigns by patient’s organizations and as a result – withdrawal from the market of generic drugs. This happened with the immunosuppressants and the Fund had to pull out additional BNG 1 million to pay the therapy with original medicines. None of us ever spoke of automatic replacement. Everything depends on the doctors and they must it adequately. But when you have for example a new drug that is cheaper, it is normal for the new patients to start with it. Then there will be no problems with the potential risks when changing one drug to another. But when we reject in general generic and biosimilar medicines, this leads to serious concerns, speculation with fears of patients and unsubstantiated comments … ineffective, unclear safety! Nowadays we cannot speculate about their quality in Bulgaria when hundreds of thousands of patients are treated with these drugs in Western Europe.

And at the same time there is not even one signal about the qualities of the medicines to the BDA. So I say that we must think responsibly and the liability is not only of the reimbursement authority or the Ministry of Health, it is also of the doctors and patient associations.

When we talk about pro-generic policy, there are several elements. One of them is clear mechanism of stimulation of generic prescription. But the main figure is patient. He should get quality, efficient, safe, accessible and free medical treatment when insured. Generic medicines make it possible to treat large numbers of patients, and also to the release of funds with which to pay for unique innovative therapies.

The devices that can unravel DNA strands are overpowering, quite large and certainly not mobile. Developers from Oxford created MinION. This is a portable DNA reader that fits in a person’s hand. Using the USB it can be connected to any computer and read the sequence of the DNA strands of the material placed in the reader. The device, which saves the huge technical resources needed for such tasks, will hit the market with the quite affordable price of $ 900.

MinION uses a biomechanical screen and smart enzymes, which pull the DNA strand through a small hole. Moving through there, each base pair is electrically tested for consistency and ultimately the entire chain is read. Although it is a portable model, in no way can it be said that it is for home use. A laboratory for the extraction of the DNA sample to enter the device is still required. Still, it is expected that the freaks of personal freedom will be immediately horrified because of the low price and the mobility of the device. The fear that in the future the request for a DNA sample for testing will become a standard even more than the question of a person’s date of birth, raises concerns.

The situation with the private Cardiology Hospital in Vidin should be recorded in textbooks as an example of how power is misused without punishment

– Dr. Katzarov how is power (mis)used without punishment in the structure of healthcare? You specify the situation with the private Cardiology Hospital in Vidin as an example in this respect. Why?
– The situation with the private Cardiology Hospital in Vidin should be recorded in textbooks as an example of how power can be abused without punishment. In early 2013, a private company entered into a lease of several abandoned premises.

The investment in repairs and equipment exceeds 3 million BGN. By the end of 2013, the hospital was fully equipped and over 30 employees were employed on permanent contracts. In January 2014 the Regional Health Inspection issued a statement that the new hospital fully met the requirements for receiving an authorization to operate. All documents were filed with the Ministry of Health. The Minister of Health, according to the Law on Healthcare Institutions, was required within 30 days to issue an authorization to operate or give a reasoned refusal. Dr. Tanya Andreeva, the Health Minister at that time, in violation of the law did neither one of these things, nor the other. For ten months the MH was silent. For ten months over 30 people – doctors, nurses and other staff – received salaries, but did not work. The new hospital appealed to the Supreme Administrative Court the silent refusal of the Minister of Health. The Supreme Administrative Court repealed the silent refusal as unlawful and issued directions to the Ministry to make a decision to issue an authorization to operate. Then followed another absurdity – the Ministry of Health appealed the decision of the Supreme Administrative Court before five judges.

– Why are you defining this appeal as a new absurd?
– It is absurd because the silent refusal – there is no ruling and this fact cannot be changed, even if fifty-member panel were to examine it. Obviously, it is a case of delay. A delay that will cost a lot to the state budget.

– How much will this delay cost to each one of us as taxpayers?
– When the five-member panel of the Supreme Administrative Court eventually confirms the decision to supersede, the state will not only pay for the unnecessary legal costs. There is every reason for the state to pay the existing but defunct hospital a compensation for any loss of profits – incurred investment costs, staff salaries and loss of potential revenue. The waste of money does not stop there. The state, in the face of its Health Minister, decided to “invest” 1.8 million BGN to purchase an angiograph for the State Hospital, although the adjacent private hospital had already purchased and installed one. Moreover, the State Hospital does not even have a Cardiology Department. Activities in the field of Cardiology at State of Hospital “St. Petka” are carried out in the Department of Internal Medicine. In this department works a cardiologist and “three more cardiologists, who have a diploma, but no more than that” who are appointed part-time, but they are not really working. In order to perform activities in Invasive Cardiology it is necessary to have a structure with III level of competence in Cardiology, and that means six cardiologists on a basic labor contract, of which two with a Certificate in Invasive Cardiology and the related equipment. Minister Andreeva transferred 600,000 BGN in advance; Minister Nenkov also joined the game, making the next transfer of 600,000 BGN. Thus by the end of the year Vidin will have two angiographs, but none of them will be working – one because it was not issued a permit, and the other – because there is no one to work with it. The state will bear the losses of several million BGN, while the sick, as it has happened so far, have no access to modern diagnosis and treatment.

– Are not these ministers responsible for the incurred financial losses to the state budget?
– One thing is certain, the ones who are guilty for this situation, Minister Andreeva and Minister Nenkov, will not suffer losses, as everything will be left for the taxpayers to pay. When they take the oath, Ministers promise to respect the Constitution and the laws of the country and, as good governors, to take care of public interest. Public interest has not been protected. Whose interest defended the Ministers – we do not know, because they have not given any explanation so far. This fact increases the suspicion of power abuse, and perhaps something else.

– Now the new ministers are to swear such an Oath. Is it possible for the parties to reach a consensus on healthcare when forming a new government?
– Each one of the elected in the Parliament parties has set among its priorities
to reform the healthcare system. This is one of the topics regarding which an agreement will be sought when forming the new government. Reaching an agreement on a plan to reform the health system is not only important, but much more complicated then reaching an agreement for example, for the construction of the “South Stream” or the exit from the crisis with the Corporate Commercial Bank – two other topics of talks for the new government.

– Why do you think that it is much more difficult to reach such an agreement?
– Healthcare concerns every person – we start our life in hospital, and many finish it there. Almost 10% of the gross domestic product passes under one form or another through the healthcare system, making it one of the most important ones for the economy and the country’s finances. The fact that healthcare is placed as a priority, however, does not imply that the reform will take place, much less that a successful health reform will take place.

– What is the basis, upon which such a successful healthcare reform can be built?
– In the pre-election party programs one can read many proposals – some good, others – not so good, third – frankly populist, and mutually exclusive. In the recent years, the debate on healthcare has focused on a few issues – the deficit in NHIF, the emergency aid, the debts of Public Hospitals, the quality of and the access to medical services, including the additional payment for them, the amount of the health insurance coverage, and the prices on medicines. Probably this is the reason that most people think of hospitals and ambulances when talking about healthcare. Healthcare is much more. Besides hospitals and ambulances, healthcare systems include the clean air, water, food, work conditions, health education, prevention, and other factors, which have a direct impact on public health. These areas also need serious changes, even though it seems easier to reach an agreement about them.

– Which is the difficult topic, according to you?
– The difficult topic is medical healthcare – seeking and receiving medical care. Before writing their healthcare reform plan, the ruling coalition has to answer one basic question: what is medical healthcare – a market for medical services or social work?

– Why do you identify this question as most important?
– The question is fundamental to the direction of the future health care reform because the measures to be taken by the government in one case and the other are opposed. If the ultimate goal is to make the patient the center of the healthcare system, the decision has to be to stimulate the market, because the user benefits most from the free market and the fair competition. The reform should be aimed at the deregulation, privatization, competition, freedom of choice, etc. If one wants administration to be at the center of healthcare, one has to treat it as social work. In this case, the reform should be aimed at strengthening the regulation, zoning, budgeting, subsidies, etc. There is a middle road, but it does not lead anywhere or it just leads to the spot we are at now. For information – have a look at the last several governments.

Three hospitals refused to admit for treatment a 47 year-old woman from Kazanlak with acute myocardial infarction. After a whole day of wandering between health facilities Dafinka Boneva was hospitalized at the University Hospital “St. George” in Plovdiv, where doctors saved her life. The treatment, however, will be paid by the Plovdiv health facility that accumulates debts because of the large number of patients admitted without health insurance. The doctors in Plovdiv warn that there is an agreement between small hospitals and emergency care such patients to be diverted only to large clinics.

The case of the 47 year-old Dafinka had to wander between different hospitals in serious condition, which is not a precedent – the doctors of the University Clinic in Plovdiv explain. The woman was referred by the Emergency Centre in Kazanlak to the hospital in Stara Zagora, from there to Haskovo, because she had no health insurance. Because everywhere refused to examine her, the patient with heart attack had to be transported all the way to University Hospital in Plovdiv.

Dr. Gincho Tonev – Head of Department of Invasive Cardiology – University Hospital “St. George”: “The order of the current Minister is patients in such conditions, with acute myocardial infarction to be hospitalized in the nearest hospital having the adequate structure, namely Invasive cardiology. This thing has not happened.”

In Plovdiv the patient received medical care and has already been discharged in good health. However, her treatment costs the hospital BGN 7 000 – amount that the woman can not pay. Cases like this are almost daily in the health facility.

Physicians claim that there is a tacit agreement between small hospitals and emergency care not to admit uninsured patients. Dr. Gincho Tonev – Head of Department of Invasive Cardiology – University Hospital “St. George”: “We all suspect such thing and we are almost certain.”

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In connection with the case the hospitals of the Bulgarian Cardiac Institute in Yambol, Veliko Tarnovo, Pleven, Shoumen and Varna declared their willingness to accept for treatment all patients in need of emergency cardiac care, regardless of their insurance status – 24 hours a day, 7 days a week. In emergency cases, for patients with acute condition, the specialized hospitals are ready to send modern ambulances with medical teams to any part of the country. “The vocation to save life stands far above any economic or bureaucratic obstacles” the BCI declared.