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In the editorial of the March issue of the New England Journal of Medicine (NEJM), it is clearly stated that compelling results from the randomized, placebo-controlled CLEAR (Cholesterol Lowering via Bempedoic Acid and ACL-Inhibiting Regimen) Outcomes study could and should increase the use of bempedoic acid in patients with established atherosclerosis who have a high cardiovascular (CV) risk and cannot or do not want to take statins due to side effects. This clinical trial included a composite primary endpoint (CV death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization) in patients on bempedoic acid 180 mg (n=6992) reduced by 13% compared to patients on placebo (n=6978). The primary outcome occurred in 11.7% of patients on bempedoic acid compared to 13.3% on placebo; the absolute risk reduction was 1.6% (risk ratio 0.87; 95% confidence interval, 0.79 to 0.96; P=0.004). The participants were followed for 6 months. Bempedoic acid did not have a significant effect on CV death or all-cause mortality. The editor emphasizes that bempedoic acid cannot be considered an alternative to statins. High-quality evidence exists for the benefits of statins, and clinicians should continue to prescribe them at the maximum tolerable doses for appropriate patients. Although bempedoic acid also lowers LDL cholesterol levels in patients taking statins, the clinical benefit of simultaneous use is not known/confirmed. The editor also highlights that two observations from the CLEAR Outcomes study should be further investigated - the suggestion that bempedoic acid has a greater effect in primary prevention and the finding that there was no effect of the drug on mortality. Is this due to effective concomitant therapy, a short follow-up period, or an actual lack of the drug's effect on mortality? With this report, bempedoic acid is added to the list of alternatives to statins for primary and secondary prevention in patients with a high CV risk. The study has provided numerous data and clarified the effectiveness and safety of the drug. The drug is approved in the European Union under the name Nilemdo and is intended for standalone use as well as for use with statins and other lipid-lowering medications. It is not on the list of drugs covered by the Croatian Health Insurance Fund (HZZO). LiteraturE: 1. Goldberg AC, Leiter LA, Stroes ESG, et al. Effect of Bempedoic Acid vs Placebo Added to Maximally Tolerated Statins on Low-Density Lipoprotein Cholesterol in Patients at High Risk for Cardiovascular Disease: The CLEAR Wisdom Randomized Clinical Trial. JAMA. 2019;322(18):1780–1788. doi:10.1001/jama.2019.16585 2. Nissen SE, Lincoff AM, Brennan D, et al. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. N Engl J Med. DOI: 10.1056/NEJMoa2215024

Women most commonly take metformin for diabetes or polycystic ovary syndrome. Metformin crosses the placenta and reaches fetal plasma concentrations comparable to those in the mother. Animal studies have not shown any harmful effects during pregnancy, embryonic or fetal development, birth, and postnatal development. In 2022, based on the results of the CLUE study, designed and sponsored by Merck pharmaceutical company, and other safety data, the Summary of Product Characteristics for metformin was modified to include the possibility of considering metformin use during pregnancy, as monotherapy or in combination with insulin. Data on the effects of metformin on pregnancy and pregnancy outcomes are still limited. The latest safety data for metformin during pregnancy come from a cohort study conducted in Finland, the CLUE study, with results published in 2022. The study followed pregnancy outcomes in women exposed to metformin only (n=3967), insulin only (n=5273), and a combination of metformin and insulin (n=889) from 2004 to 2016. The primary outcomes were child obesity, hypoglycemia, hyperglycemia, diabetes, hypertension, polycystic ovary syndrome, and developmental disorders (motor, social). The study did not find an increased risk associated with metformin exposure (alone or in combination with insulin) compared to insulin use alone. However, there was an increased risk of low birth weight (a secondary outcome) with metformin compared to insulin, suggesting caution in pregnancies with a risk of fetal malnutrition. A meta-analysis of studies published up to 2014 did not find an increased risk of malformations in children of around 1000 women exposed to metformin during the first trimester of pregnancy. Another cohort study presented as a congress abstract in 2021, which included around 3000 pregnancies with metformin exposure, did not find an increased risk of congenital malformations following metformin use during pregnancy. However, another cohort study with 392 pregnancies exposed to metformin during the first trimester found a higher risk of congenital malformations in women exposed to metformin (5.1% compared to 2.1% in the control group). The authors explained this difference by an increase in intrinsic risk due to diabetes. Two published case-control studies found a possible association between metformin use in the first trimester and an increased risk of congenital malformations (cardiac, pulmonary) in one study and an increased risk of atrial septal defect and limb defects in the other study where metformin was used for infertility treatment. Contradictory study results may be attributed to different indications for use, study design, and overall do not support clear conclusions about potential risks. In clinical practice, available data on monitoring pregnancy outcomes in women taking metformin during pregnancy do not suggest a significant risk of malformations with metformin use in the first trimester, but they do not exclude the possibility of rare malformations. Longer-term data on pregnancy outcomes are needed to better assess the long-term risk of metformin use in early pregnancy. If a pregnant woman requires treatment for elevated glucose levels, insulin remains the first-line treatment since insulin does not cross the placenta. If metformin use is considered, it is important to inform the pregnant woman about its benefits and the still present uncertainties related to potential risks. Literature: 1. Prescrire Redaction. Metformin during pregnancy: possible risk of malformations. Rev Prescrire 2023; 23: 46-8. 2. Panchaud A, Rousson V, Vial T, et al. Pregnancy outcomes in women on metformin for diabetes or other indications among those seeking teratology information services. Br J Clin 2018; Pharmacol 2018; 84: 568–78. 3. Brand KMG, Saarelainen L, Sonajalg J, et al. Metformin in pregnancy and risk of adverse long-term outcomes: a register-based cohort study. BMJ Open Diabetes Research and Care 2022;10:e002363. 4. Nguyen L, Chan SY, Teo AKK. Metformin from mother to unborn child - Are there unwarranted effects? EBioMedicine 2018; 35: 394-404.

Immunotherapy has become the primary treatment for patients with various types of cancer, offering the potential to extend their survival. Typically, immunotherapy is administered until disease progression or unacceptable toxicity, or up to the recommended maximum duration in patients without disease progression. Recently, the criteria for the use of PD-1/PD-L1 immune checkpoint inhibitors, such as pembrolizumab (Keytruda), nivolumab (Opdivo), durvalumab (Imfinzi), and atezolizumab (Tecentriq), have been modified by the Croatian Health Insurance Fund (HZZO). According to the new criteria, the duration of treatment is limited to a maximum of 24 months for all drugs except for adjuvant treatment in melanoma (nivolumab, pembrolizumab), where the duration is limited to one year. The optimal duration of immunotherapy in cancer treatment is still not well-established. Guidelines from ESMO (European Society for Medical Oncology) and NCCN (National Comprehensive Cancer Network) recommend a duration of two years in the first-line setting. However, most clinical trials have arbitrarily limited the duration to two years, and there is a lack of definitive clinical studies to determine the optimal duration. The main efficacy outcomes monitored in clinical studies with immunotherapy are progression-free survival (PFS) and overall survival (OS). Some evidence suggests that patients treated with immunotherapy for one year may have a shorter PFS compared to those treated for a longer period. However, data from real-world studies indicate that longer treatment duration may lead to better survival rates, with the risk of disease relapse after treatment cessation depending on the initial response achieved. The decision to continue or stop immunotherapy after two years is still a matter of debate among healthcare professionals. Some argue that stopping treatment after achieving a complete or partial response might be appropriate, especially considering the potential toxicity and costs associated with long-term treatment. Prospective clinical trials are currently underway to explore early discontinuation criteria and biomarkers that could help quantify the risk of disease recurrence. These studies aim to determine the optimal duration of treatment and indications for discontinuation while taking into account patient response and other factors. The choice between continuous immunotherapy and a fixed duration is challenging, as toxicity and costs play significant roles. While most side effects occur within the first 6-9 months of treatment, some patients may experience severe toxicity later on. Additionally, the financial burden of long-term immunotherapy could strain healthcare systems and impact access to care. In conclusion, the optimal duration of immunotherapy remains uncertain, and an arbitrary cutoff of two years may not be appropriate for all patients. Individualized treatment decisions should consider patient response, toxicity, quality of life, and the potential for long-term disease control. Further research is needed to identify the best approach to immunotherapy duration and its impact on overall survival. Literature: 1. Waterhouse DM, Garon EB, Chandler J, et al. Continuous Versus 1-Year Fixed-Duration Nivolumab in Previously Treated Advanced Non-Small-Cell Lung Cancer: CheckMate 153. J Clin Oncol 2020;38: 3863-73. 2. Ghisoni E, Wicky A, Bouchaab H, et al. Late-onset and long-lasting immune-related adverse events from immune checkpoint-inhibitors: An overlooked aspect in immunotherapy. Eur J Cancer 2021; 149: 153-64. 3. Marron TU, Ryan AE, Reddy SM, et al. Considerations for treatment duration in responders to immune checkpoint inhibitors. J Immunother Cancer 2021; 9: e001901. oi: 10.1136/jitc-2020-001901. PMID: 33653801; PMCID: PMC7929825. 4. Yin J, Song Y, Tang J, Zhang B. What is the optimal duration of immune checkpoint inhibitors in malignant tumors? Front Immunol. 2022 Sep 26;13:983581. doi: 10.3389/fimmu.2022.983581. PMID: 36225926; PMCID: PMC9548621. 5.Geier M, Descourt R, Corre R, et al. Duration of nivolumab for pretreated, advanced non-small-cell lung cancer. Cancer Med 2020; 9: 6923-32.

Statins have an important role in the treatment and prevention of cardiovascular disease, but the question of uncertainties regarding their risk-benefit ratio for elderly patients is often raised. When initiating statin therapy it is important to take into account age-related pharmacodynamic and pharmacokinetic changes that increase the risk of statin adverse reactions. Also, possible drug-drug interactions, co-morbidities that shorten life expectancy and assumed therapy adherence should be taken into account. Population of the elderly patients is very heterogenous in terms of chronological age, ageing-related biological changes, co-morbidities and indications for a statin (primary or secondary prevention). For statins in secondary prevention, there is consistency among international guidelines and relevant publications that statins are indicated regardless of the age. Although an individual approach for the use of statins in primary prevention according to the cardiovascular (CV) risk is recommended, many international guidelines recommend starting statin therapy in all patients under 75 years of age with elevated CV risk. Chronological age > 75 years does not represent per se a contraindication to initiate statin in primary prevention but parameters as co-morbidities, frailty, life expectancy and expected drug adherence have to be considered. In conclusion, chronological age is not a reason to avoid statins because patients with the same age could significantly differ regarding their health status and vitality/frailty. The question a clinician should ask himself is whether the expected time to benefit from statin treatment will be longer than the expected time to harm (adverse effects) or the expected patient's life expectancy. You can read more about this topic in the next issue of Pharmaca (in Croatian) in the article authored by Suzana Mimica and Zvonimir Čagalj. #statins #sideeffects #adverseeffects #elderly #age #pharmacotherapy #clinicalpharmacology #rationalpharmacotherapy #evidencebasedmedicine #insurance #reimbursement

INTRODUCTION Fingolimod (Gilenya) is an oral immunosuppressant used as a disease-modifying drug in the treatment of relapsing-remitting multiple sclerosis. The guideline of the Croatian Health Insurance Institute for the use of fingolimod (N457) is: "As monotherapy in highly active relapsing-remitting multiple sclerosis with phases of relapse and remission with EDSS <= 6 and absence of pregnancy- I. in patients with active disease and who have not responded to a complete and appropriate treatment regimen with at least one course-modifying therapy (interferon beta, glatiramer acetate, teriflunomide, dimethyl fumarate), or when the criteria for discontinuation of the therapy according to current guidelines in the drug list are met. The disease is considered active despite previous therapy when following criteria are met a) >= 4 new T2 hyperintensive lesions on MR, or b) >= 2 relapses. Treatment is approved by the Hospital Drug Committee for the next 6 months at the expense of the hospital budget, and afterwards at the expense of the Croatian Health Insurance- Fund for very expensive drugs. Treatment for patients with severe rapidly progressive relapsing-remitting multiple sclerosis is approved at the expense of the hospital budget. "(1). FINGOLIMOD AND LIVER DAMAGE One of the most common reasons for discontinuation of fingolimod therapy is an increase in transaminases, indicative of inflammation or damage to liver cells. During clinical trials with fingolimod, an increase in transaminase levels of at least 3-fold the upper limit of normal (ULN) was observed in 8% of adults and up to 5-fold the ULN in 1.8% of subjects. In addition, reintroduction of fingolimod into therapy was observed to result in liver damage in some patients, suggesting causality. In clinical trials, elevations in transaminases were recorded at different times during treatment, although most occurred during the first 12 months of treatment. Transaminase levels returned to normal within approximately 2 months after cessation of treatment (3). In late 2020, the European Medicines Agency (EMA) reported cases of liver failure in patients on fingolimod, including three cases requiring liver transplantation. Other drug agencies around the world have also issued warnings about the link between fingolimod and liver damage. The first signs of liver damage in these patients were elevated liver enzymes and bilirubin. The occurrence of these laboratory abnormalities was noted as early as 10 days after the first dose, but also after prolonged use of the drug (2). Due to the severity of this side effect, the Summary of Product Characteristics was amended; The EMA recommended monitoring of hepatic function, including bilirubin, before and during fingolimod treatment (at 1, 3, 6, 9, and 12 months during treatment) and 2 months after cessation of therapy due to the long half-life of fingolimod of 6 to 9 days ( 2). Pharmacokinetics of fingolimod Absorption of fingolimod is slow (12-16 hours) and extensive (bioavailability about 93%), and is not significantly affected by food. The pharmacologically active metabolite responsible for its efficacy is fingolimod phosphate. Fingolimod and fingolimod phosphate are highly bound to plasma proteins (> 99%) and are extensively distributed to tissues. Fingolimod is transformed in humans by reversible stereoselective phosphorylation into the already mentioned pharmacologically active (S) -enantiomer of fingolimod phosphate. Fingolimod is eliminated by oxidative biotransformation catalyzed mainly by CYP4F2 (or CYP3A4) and possibly other isoenzymes, followed by degradation similar to that of fatty acids to inactive metabolites. Following oral administration, approximately 81% of the dose is slowly excreted in the urine in the form of inactive metabolites. The elimination half-life (t1/2) of fingolimod is 6-9 days. CONCLUSION Since the introduction of fingolimod on the market, numerous side effects have been reported with its use. The post-marketing data confirm the possibility of serious side effects, especially cardiac and hepatic. Adverse cardiac side effects have already been reported during clinical trials, and in 2017, based on additional safety data collected, the use of fingolimod in patients with severe heart disease was contraindicated (2). What does this mean for the clinical practice? Based on a limited number of randomized controlled clinical trials, indirect comparisons of therapeutic lines, observational studies, and clinical experience, the clinical utility of fingolimod compared to other disease-modifying drugs (eg interferon beta-1a, the only drug fingolimod was compared to in a randomized placebo-controlled trial ) is relatively modest (4, 5). Due to potentially serious side effects, the benefit-risk balance should be carefully weighed when deciding to initiate fingolimod or change the treatment line to fingolimod. In persons on fingolimod who have elevated transaminases 3x the ULN, more frequent monitoring of transaminase levels is recommended. Fingolimod therapy should be discontinued in subjects with a transaminase level greater than 5 times the ULN or a transaminase level greater than 3 times the ULN, with a concomitant increase in bilirubin to a value greater than 2x the ULN. Furthermore, fingolimod should be discontinued in case of liver damage without a known cause. References: 1. HZZO. Tražilica za lijekove. Gilenya (fingolimod). https://hzzo.hr/trazilica-za-lijekove?query=gilenya Pristup 11.7.2021. 2. Sažetak opisa svojstava lijeka Gilenya (fingolimod), Novartis Europharm Limited, 16.11.2020. 3. Direct Healthcare Professional Communication Gilenya (fingolimod) – Updated recommendations to minimise the risk of drug-i nduced liver injury (DILI). https://www.ema.europa.eu/en/documents/dhpc/direct-healthcare-professional-communication-dhpc-gilenya-fingolimod-updated-recommendations_en.pdf Pristup 11.7.2021. 4. Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults. Comparative efficacy. UpToDate, 2021. 5. NICE. Fingolimod for the treatment of highly active relapsing–remitting multiple sclerosis. https://www.nice.org.uk/guidance/ta254 Pristup 7.11.2021.

INTRODUCTION With aging poplation, dementia is becoming an increasing global problem. Alzheimer's disease is the most common form of dementia in the elderly and accounts for 60-80% of cases (1). Therefore, a growing interest in research into the prevention and treatment of dementia is justified. In this context, the use of vitamin D has been investigated for a long time. Below is an overview of currently available evidence on the effectiveness of vitamin D in this indication. WHY IS VITAMIN D IMPORTANT? Vitamin D is a vitamin that is synthesized in the skin after exposure to sunlight. After binding to the receptor, dihydroxy-vitamin D further participates in the expression of a number of genes involved in bone development and other functions. It's in vitro effect has been studied in many diseases. In addition to its effect on bone, vitamin D is also linked to the functioning of the immune system, and has been studied in the prevention and treatment of cardiovascular diseases and malignancies. Vitamin D deficiency has been associated with risk of developing immune diseases, neurological diseases (multiple sclerosis) and infections (especially respiratory) including COVID-19. But the American Food and Nutrition Board (FNB) concludes that the evidence for any effect attributed to vitamin D, other than a positive effect on bone health, is insufficient or contradictory. Due to its positive effect on bones, it is recommended that all adults take sufficient daily doses of vitamin D, preferably with food. The Recommended Daily Intake (RDA) of vitamin D is 600 IU (International Units; 15 mcg) in adults up to the age of 70. For persons older than 70, the RDA is 800 IU (20 mcg), but may be even higher (2). For pregnant and lactating women, the RDA is 600 IU (15 mcg). The optimal serum concentration of vitamin D for maintaining bone health is controversial, but according to the literature it is between 50 and 100 nmol / L. Levels below 30-50 nmol / l are considered deficient and <30 insufficient. The optimal serum concentration for other indications is not known. SIDE EFFECTS OF HIGH DOSES OF VITAMIN D Daily vitamin D intake of more than 4,000 IU in healthy individuals is generally not recommended. In patients with malabsorption (eg, celiac disease, gastrectomy, inflammatory bowel disease), the recommended doses will depend on the patient's ability to absorb vitamin D; high doses ranging from 10,000 to 50,000 IU are usually given. However, possible signs of toxicity should be monitored in these patients. Symptoms of toxicity are usually described at doses greater than 60,000 IU and are attributed to hypercalcemia and include confusion, polyuria, polydipsia, anorexia, vomiting, and muscle weakness (3). Chronic intoxication can cause nephrocalcinosis, bone demineralization, and pain. VITAMIN D AND PREVENTION OF DEMENTIA Vitamin D deficiency is being investigated as a possible risk factor for the development of dementia (4). The brain has the ability to synthesize the active form of vitamin D (1.25 hydroxyvitamin D) within many cell types and brain regions, predominantly in the hypothalamus and the large neurons within the substantia nigra. Many genes important in the production of responses to routine signals and stimuli are regulated by vitamin D. Functionally, vitamin D plays a role in neuroprotection by modulating the production of nerve growth factor, neurotrophin, glial cell neurotrophic factor, nitric oxide synthase, and actylcholine transferase. But knowing the importance of vitamin D for the normal functioning of the organism does not automatically mean that its application in deficient conditions would be clinically useful. Such conclusions can only be drawn on the basis of evidence from properly designed randomized controlled trials with sufficient subjects involved, if available. There is some evidence that vitamin D deficiency is associated with cognitive deficits in the elderly but the clinical significance of this is unknown. One meta-analysis and systematic review included 37 studies with a comparative group (5). The majority of the studies included were cross-sectional studies, followed by controlled case studies and cohort studies (two), and only 3 studies were randomized controlled studies (highest level of evidence), but with a relatively small number of patients involved. The number of subjects included ranged from 27 to 17,099, and most included subjects older than 65. Studies included patients with Alzheimer's and other dementias. All studies determined the level of vitamin D (1.25 hydroxyvitamin D). Most studies used MMSE (Mini-Mental State Examination) as a test of cognitive function. In most studies, the relationship between vitamin D and cognitive function was determined by comparing vitamin D concentrations between patients diagnosed with dementia and controls, or the result of cognitive function tests between groups with different vitamin D concentrations. The main objections to the quality of the studies included in this meta-analysis were the process of blinding participants, selection of subjects, lack of adjustment for age and gender in results analysis, lack of knowledge on the methodology used in determining vitamin D levels, lack of knowledge on methods used for handling missing data. One of the main objections was the lack of data on the knowledge of the patient's cognitive status assessor about his vitamin D status. Thus, the included studies differed in the number of subjects, design, cognition tests used, methodology for determining vitamin D levels and patient grouping. It is therefore not surprising that a statistically significant heterogeneity was found between the included studies (cross-sectional studies and case studies with controls were included in the meta-analysis) regarding the evaluation of differences in vitamin D levels [mean difference was −15.0 nmol / L 25 (OH) D [−26.2, −3.9)] as well as in the evaluation of differences in MMSE results [mean difference in MMSE results was 1.2 (0.5, 1.9)] between the compared groups. For those less familiar with the meta-analysis methodology, statistically significant heterogeneity points to significant differences between the included studies that do not allow valid conclusions to be drawn from the obtained meta-analysis results (6). Although the heterogeneity of the included studies was significant in this meta-analysis, its results suggested a possible association between vitamin D levels and cognitive impairment, but this effect appears to be modest, if any, and of unknown clinical significance. As previously mentioned, three randomized controlled clinical trials were included in the systematic review. The intervention in 2 of the 3 randomized controlled clinical trials was the administration of a multivitamin preparation that also contained vitamin D, and in only one placebo-controlled study the intervention was the administration of 9,000 IU of vitamin D2 over 8-40 weeks; no significant differences in cognitive outcomes were observed in this study. However, it should be noted that the number of included patients was small (n = 82). Most of these studies did not take into account the variability in vitamin D status. In addition, people with cognitive impairment have a higher risk of malnutrition and spend less time outdoors. Due to these objections, it is impossible to exclude reverse causality as an alternative explanation of the study results (dementia as a cause of vitamin D deficiency, and not vice versa). Two previously published meta-analyzes found no significant association between 1.25 hydroxyvitamin D levels and dementia (7.8). Whether vitamin D supplementation in healthy individuals or those with vitamin D deficiency reduces the risk of cognitive decline or dementia is unclear, but limited evidence does not support this. For valid conclusions, we need the results of controlled randomized intervention studies with a sufficient number of patients included. Meanwhile, due to the lack of evidence of its usefulness, prescribing vitamin D to prevent dementia is not recommended. OTHER INTERVENTIONS IN PREVENTION OF DEMENTIA In general, physical activity, social interaction, and cognitive activities are recommended for all patients, especially those at risk for developing dementia. Timely and good treatment of hypertension is especially important because of the proven association with an increased risk for vascular dementia and Alzheimer’s disease (9). Although a healthy diet is associated with positive health outcomes, including cognitive health, the evidence is insufficient to conclude that specific dietary regimens or dietary supplements are useful in reducing the risk of developing dementia. This applies to the use of omega-3 fatty acids, the Mediterranean diet and small amounts of alcohol. Prospective and randomized controlled clinical trials have not shown the benefit of the use of vitamins, statins, cholinesterase inhibitors, estrogen substitution, or the use of nonsteroidal antirheumatic drugs in the prevention of dementia. OTHER VITAMINS Multivitamin preparations have not shown efficacy in preventing dementia or slowing cognitive decline in dementia (10,11). Despite some evidence that elevated serum homocysteine ​​levels and / or decreased folate, vitamin B6, and vitamin B12 levels may be associated with cognition impairment and dementia risk, there is no convincing evidence from clinical trials of the benefit of vitamin use in dementia prevention (12,13). Although vitamin E has not been shown to be useful in preventing dementia, it may have limited benefit in slowing the progression of mild to moderate Alzheimer's disease (14,15). However, data from randomized studies are ambiguous (16). As high doses of vitamin E have been consistently associated in clinical trials with increased mortality and heart failure in patients with cardiac disease, the use of vitamin E in the prevention of dementia and for other forms (except mild to moderate Alzheimer's disease) of dementia is not recommended. CONCLUSION The only proven beneficial effect of vitamin D is its effect on bone health. In other indications in which the effect of vitamin D supplementation has been investigated, clinical trials do not provide solid evidence to justify recommendations for its use. These include the prevention and treatment of dementia, cardiovascular disease, multiple sclerosis, malignancies and infections including COVID-19. Evidence for the effect of vitamin D on the prevention of dementia is qualitatively modest, but does not provide justification for routine prescribing of vitamin D in this indication. The only evidence-based indication for prescribing vitamin D is deficiency / insufficiency and the use of recommended doses in the prevention of osteoporosis. REFERENCES: 1. Livingston G, i sur. Lancet. 2017 Dec 16;390(10113):2673-2734. 2. Dietary Reference Intakes for Calcium and Vitamin D. https://www.nap.edu/resource/13050/Vitamin-D-and-Calcium-2010-Report-Brief.pdf Pistup 11.06.2021. 3. Barger-Lux MJ, i sur. J Clin Endocrinol Metab. 2002 Nov;87(11):4952-6. 4. Buell JS, i sur. Mol Aspects Med. 2008 Dec;29(6):415-22. 5. Balion C, i sur. Neurology. 2012 Sep 25;79(13):1397-405. 6. Higgins JPT, i sur. (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.2 (updated February 2021). Cochrane, 2021. Available from www.training.cochrane.org/handbook. 7. Annweiler C, i sur. Neuropsychobiology. 2010 Aug;62(3):139-50. 8. Barnard K, i sur. Am J Geriatr Pharmacother. 2010 Feb;8(1):4-33. 9. Barnes DE, Yaffe K. Lancet Neurol. 2011 Sep;10(9):819-28. 10. Grima NA, i sur. J Alzheimers Dis. 2012;29(3):561-9. 10. Grima NA, i sur. J Alzheimers Dis. 2012;29(3):561-9. 11. Grodstein F, i sur. Ann Intern Med. 2013 Dec 17;159(12):806-14. 12. Livingston G, i sur. Lancet. 2017 Dec 16;390(10113):2673-2734. 13. Aisen PS, i sur. JAMA. 2008 Oct 15;300(15):1774-83. 14. Dysken MW, i sur. JAMA. 2014 Jan 1;311(1):33-44. 15. Sano M, i sur. N Engl J Med. 1997 Apr 24;336(17):1216-22. 16. Galasko DR, i sur. Arch Neurol. 2012 Jul;69(7):836-41.

INTRODUCTION The invention of COVID-19 vaccines represents probably the greatest success so far in the fight against the pandemic caused by the SARS-CoV2 virus. Despite numerous efforts and research, there is still no specific drug for the treatment of COVID-19. Therefore, it could be concluded that population vaccination and the acquisition of so-called "herd immunity" is currently the best way to combat this pandemic, or at least to slow it down. However, like any other intervention or drug used in medicine, vaccines carry a certain risk of mild or severe side effects and allergic reactions. This may cause fear of vaccination in general or fear of vaccination with a particular type of vaccine against COVID-19. Furthermore, an additional problem is the necessity to produce and distribute huge quantities of vaccines, where delays in the production of individual vaccines could lead to delays in vaccination with the second dose. The third problem is the fact that the virus itself is prone to mutations and result in the emergence of new variants, some of which in the future may be resistant to immunity acquired by some or all previously available vaccines (1, 2). Do we have a solution to some of the above problems? MIX AND MATCH One of the potential solutions is the application of a "mix and match" vaccination regime. The name "mix and match" represents a well-known approach where one vaccine is used in the first vaccination, and then another vaccine in the re-vaccination. Regarding the available COVID-19 vaccines, this would mean the following: if a person is vaccinated with the first dose of one of the available mRNA vaccines (Pfizer- BioNTech or Moderna), then a vector vaccine can be used for the second dose (eg, AstraZeneca or Johnson & Johnson ), and the reverse approach is applicable where a person primarily vaccinated with a vector vaccine could be vaccinated with an mRNA vaccine. The idea behind such a vaccine combination approach is that different vaccines stimulate the immune system in different ways (because vaccines differ) and thus could trigger a more comprehensive and stronger immune response (1, 3). However, the question arises whether we have enough data or clinical studies that confirm that this approach is really effective and safe? According to the guidelines of the World Health Organization (WHO) and the US Centers for Disease Control and Prevention (CDC) - not yet. Namely, the current position and recommendation of the WHO is that there is not enough data based on studies conducted so far to recommend this approach, so the current recommendation is to use the same vaccine for both doses, and the same position is shared by the US CDC (4, 5). However, some countries, such as Germany, Canada and Italy, have already approved the mix and match approach based on the data available so far (6). WHAT DO THE DATA SAY? Unfortunately, there are still no published studies or peer-reviewed and publishe scientific articles in this regard. Nevertheless, unreviewed results and data from several studies conducted in Germany, Spain, and the United Kingdom are available online. A Spanish study was conducted on more than 600 subjects, and the data suggest that people vaccinated with Pfizer-BioNTech after receipt of the first dose of AstreZeneca have a significant increase in IgG antibody titers and the presence of neutralizing antibodies in 100% of subjects. Subjects developed common adverse reactions such as injection site pain, headache, and muscle aches, but no serious adverse reactions were reported. However, it should be noted that the study was conducted in people over 60 years of age and that there was no control group of persons vaccinated according to the currently approved protocol, ie with two doses of the same vaccine (eg AstraZeneca vaccine), which prevents comparisons of post-vaccination responses between the mix and match protocol and the standard vaccination protocol (7). Another study, conducted on a cohort of 340 health professionals in Germany, provides a partial answer to this question. In this study, subjects were vaccinated with two doses of Pfizer BioNTech vaccine or a combination of AstraZeneca (1st dose) / Pfizer-BioNTech (2nd dose). According to their preliminary analyzes, the combination of AstraZeneca / Pfizer-BioNTech vaccine is well tolerated (comparable number of systemic reactions to the vaccine with the group vaccinated with two doses of Pfizer-BioNTech vaccine), results in comparable immunogenicity with even slightly increased avidity (total binding strength) of IgG antibodies and a stronger T lymphocyte response in a mixed vaccination protocol (8). But the clinical significance of these findings is not yet clear. Similar results were obtained by other groups of researchers from Germany, with subjects receiving the AstraZeneca / Pfizer-BioNTech vaccine combination having a significantly higher number of specific CD4 and CD8 T lymphocytes with a high titer of neutralizing antibodies against several virus strains (B.1.1.7 , B.1.351 and P.1) (9, 10). Preliminary data from a multicenter randomized study conducted in the United Kingdom called Com-COV are also available (11). This study aims to examine several different mix and match vaccination protocols, including a group of subjects who will receive one of the available vector vaccines after an mRNA vaccine, which has not been studied so far. Preliminary data from this study show that the number of systemic adverse reactions in the mixed protocol after the second dose of vaccine is higher compared to standard protocols, which is inconsistent with data from other studies, but may be due to different age of included subjects or different time periods elapsed between two doses of COVID-19 vaccine (8). In addition to the studies mentioned here, it is necessary to highlight two other clinical studies that are currently ongoing. The first is a US study conducted by the National Institute of Health (NIH), which, among other things, aims to examine the safety and efficacy of vaccination with a third dose of COVID-19 vaccine in people who are fully vaccinated according to the standard protocol. Subjects will receive a different vaccine for the third vaccine dose (mRNA vs vector vaccine). The significance of this study is reflected in the fact that it is still unknown whether additional re-vaccination will be required for those who have been vaccinated. In this regard, the use of a different vaccine could be of particular importance. Namely, the problem of frequent use of vector vaccines could be the development of an immune response to the vector itself, for example the adenovirus, where the person's immune system could eliminate the adenovirus, and thus the message it carries before it reaches cells, which could lead to reduced vaccine efficacy. On the other hand, a problem with mRNA vaccines can be created by the increased frequency of side effects with revaccination (12, 13). Another study is a Canadian study called MOSAIC, which aims to examine the safety and efficacy of COVID-19 vaccines with respect to the different time intervals between two doses of the same or different vaccines, and the duration of the protective effect in such conditions (14). CONCLUSION The combination of different types of COVID-19 vaccines, if shown to be safe and effective, could be useful in several ways - it would enable vaccination of persons with history of severe immediate-type allergic reactions with a different type of vaccine as well as continuation of vaccination programs if problems in vaccine production or distribution arise. Preliminary data suggest that this regimen could lead to a stronger and more comprehensive immune response and thus provide greater protection against mutated strains of the virus as well. However, currently available data are too limited to recommend the "mix and match" vaccination regime, although it has been approved in a few countries. In addition, most studies addressing this question monitor the effects of vaccination when a vector vaccine (Vaxzevria) is used for the first dose and an mRNA vaccine for the 2nd dose. Data on the reverse order are extremely limited (Com-COV study). This is certainly an interesting approach for which there is a rational. We have to be patient and wait for the final results of ongoing clinical studies and evaluation of their results from the competent authorities. Until then, it should be pointed out once again that according to the current guidelines of all relevant health organizations, the benefits of vaccination with any available vaccine, if there are no contraindications, far outweigh the potential risks. Accordingly, we once again recommend vaccination as the best way to combat the COVID-19 pandemic. What are the current recommendations in Croatia? The website of the Croatian Institute of Public Health states the possibility of an exception to the rule that both doses of vaccine should be from the same manufacturer; this is a situation when a person develops a serious side effect following the first dose of the vaccine (only Vaxzevria vector vaccine from AstraZenec is listed as an example) such as a bleeding disorder or thromboembolism that cannot be explained by another reason, etc. The physician who treated the side effect should be involved in the decision to vaccinate the patient with the same or a different vaccine (10). References: 1. Covid-19 vaccine mixing: the good, the bad and the uncertain. https://www.clinicaltrialsarena.com/analysis/covid-19-vaccine-mixing-the-good-the-bad-and-the-uncertain/ . Access: 18.06.2021. 2. A mix-and-match approach to COVID-19 vaccines could provide logistical and immunological benefits. https://www.pbs.org/newshour/health/a-mix-and-match-approach-to-covid-19-vaccines-could-provide-logistical-and-immunological-benefits. Access: 21.06.2021. 3. COVID: Are mix-and-match vaccines the way forward? https://www.dw.com/en/mix-and-match-vaccines-biontech-astrazeneca-better-than-one-shot/a-57819127. Access: 21.06.2021. 4. Interim recommendations for use of the Pfizer–BioNTech COVID-19 vaccine, BNT162b2, under Emergency Use Listing. https://apps.who.int/iris/bitstream/handle/10665/341786/WHO-2019-nCoV-vaccines-SAGE-recommendation-BNT162b2-2021.2-eng.pdf?sequence=1&isAllowed=y. Access: 20.06.2021. 5. Interim Clinical Considerations for Use of COVID-19 Vaccines Currently Authorized in the United States. https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vaccines-us.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fvaccines%2Fcovid-19%2Finfo-by-product%2Fclinical-considerations.html#Interchangeability. Access: 20.06.2021. 6. Factbox: Countries weigh 'mix and match' COVID-19 vaccines. https://www.reuters.com/world/middle-east/countries-weigh-mix-match-covid-19-vaccines-2021-05-24/ Access: 20.06.2021. 7. Borobia AM, i sur. Reactogenicity and immunogenicity of BNT162b2 in subjects having received a first dose of ChAdOx1S: initial results of a randomised, adaptive, phase 2 trial (CombiVacS). Dostupno putem linka: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3854768. 8. Hillus D, i sur. Safety, reactogenicity, and immunogenicity of homologous and heterologous prime-boost immunisation with ChAdOx1-nCoV19 and BNT162b2: a prospective cohort study. Available through: https://www.medrxiv.org/content/10.1101/2021.05.19.21257334v2. 9. Barros-Martins J, i sur. Humoral and cellular immune response against SARS-CoV-2 variants following heterologous and homologous ChAdOx1 nCoV-19/BNT162b2 vaccination. Dostupno putem linka: https://www.medrxiv.org/content/10.1101/2021.06.01.21258172v1. 10. Schmidt T, i sur. Immunogenicity and reactogenicity of a heterologous COVID-19 prime-boost vaccination compared with homologous vaccine regimens. Dostupno putem linka: https://www.medrxiv.org/content/10.1101/2021.06.13.21258859v1. 11. Shaw RH, i sur. Heterologous prime-boost COVID-19 vaccination: initial reactogenicity data. Lancet. 2021;397(10289):2043-2046. doi: 10.1016/S0140-6736(21)01115-6. 12. NIH clinical trial evaluating mixed COVID-19 vaccine schedules begins. https://www.nih.gov/news-events/news-releases/nih-clinical-trial-evaluating-mixed-covid-19-vaccine-schedules-begins. Access: 22.06.2021. "MIX AND MATCH"CHens when you mix doses of the Pfizer and AstraZeneca vaccines? A new study is starting to reveal the answer. https://fortune.com/2021/05/12/what-happens-when-you-mix-doses-of-the-pfizer-and-astrazeneca-vaccines-a-new-study-is-starting-to-reveal-the-answer/. Access: 22.06.2021. 14. MOSAIC: Mix and Match COVID-19 Vaccines. https://centerforvaccinology.ca/study/mosaic-mix-and-match-covid-19-vaccines/ Pristup: 22.06.2021. 10. HZJZ. Privremena dopuna preporukama o cijepljenju protiv bolesti COVID-19. https://www.hzjz.hr/sluzba-epidemiologija-zarazne-bolesti/privremena-dopuna-preporukama-o-cijepljenju-protiv-bolesti-covid-19/ Access 6.7.2021."