Choosing a medication to treat osteoarthritis

Pharmacoeconomics is a science whose goal is the economic evaluation of the effectiveness of costs and results associated with the use of drugs. In Western European countries, it has been developing since the 60-70s of the 20th century.

The subject of research in pharmacoeconomics is:

1. results of pharmacotherapy, if possible, conducting a comparative analysis of at least two different treatment regimens (technologies),
2. safety and efficacy of new drugs,
3. economic costs of conducting pharmacotherapy and diagnostics,
4. pharmacoepidemiological statistics that reflect the relationship between the exposure to a drug and its benefit/risk profile during the treatment of a particular disease in a specific population after the drug has been introduced to the market,
5. data from randomized clinical trials of a drug in a group of patients (population),
6. data on pharmaceutical provision of patients, analysis of consumption and forecasting of the need for a medicinal product,
7. the need for drugs (calculated in absolute and relative terms, as well as in economic indicators).

The objects of study of pharmacoeconomics are:

1. costs (in value terms) for effective pharmacotherapy using different technologies, where one of the technologies is associated with pharmacotherapy, while the other may include additional therapeutic measures,
2. the effectiveness of pharmacotherapy expressed in biological health parameters (for example, changes in glycemia levels in patients with diabetes, lipidemia levels, prolongation of life),
3. the effectiveness of treatment regimens (determined using pharmacoepidemiological studies; during observation, both the drug's effectiveness indicators and all observed side effects in the population are recorded).

The general structure of economic costs of disease is divided into direct, indirect and additional.

1. Direct costs include:
   • Costs of diagnosing the disease.
   • The cost of the medicine required for the course of treatment.
   • Cost of laboratory tests.
   • Costs of eliminating side effects of a drug.
   • Cost per bed-day.
   • Salaries of medical workers.
   • Costs for delivery of medicines, patient nutrition.
   • Expenses for payment of disability benefits (from social insurance funds).
2. Indirect or indirect medical costs - related to economic damage from the reduction of the patient's time of employment, his premature death. These are costs related to the inability of a citizen during illness to be useful to society, to participate in the production process.
3. Additional non-material costs associated with the disease are caused by the patient’s psycho-emotional experiences and the deterioration in his quality of life (for these reasons, they are difficult to quantify).

The economic costs of osteoarthritis are of particular interest due to the high medical, social and economic burden on society caused by this disease (along with rheumatoid arthritis).

A Study of the Costs of Musculoskeletal Diseases (Arthritis) in the United States

Year	Costs for patients with arthritis
	Total, billion dollars	Direct, % of total costs
1992	64.8	23
1995	82.4	23.6

Note: *59% of direct costs were for social care of patients and visits of nursing staff; 15.5% of direct costs were for drug treatment, and most of them were due to the use of NSAIDs.

In recent years, there has been an intensive growth in pharmacoeconomic research, which is associated with a number of reasons, including: increasing health care costs, the need to solve the problem of treating a number of diseases (HIV, cancer), the emergence of new technologies, improving the quality of life, increasing life expectancy, as well as the urgent need to analyze the cost/effectiveness ratio.

The following methods of pharmacoeconomic analysis are fundamental for pharmacoeconomics:

1. "Cost-effectiveness analysis" (CEA) - evaluates changes in any parameter that changes in a pathophysiological condition, for example: blood pressure indicators, as well as a reduction in financial costs.
2. "Cost-benefit analysis" (CBA) is an economic analysis of the cost-benefit ratio, in which the benefit obtained from the use of a specific drug is expressed in monetary terms through costs if direct cost savings are not immediately obvious.
3. Cost-utility analysis (CUA) is an analysis in which effects are expressed in terms of their utility to the consumer, and the costs of some additional increase in life expectancy (for example, the cost of an additional year of full life) or other indicator of value to the patient are estimated.
4. "Cost-minimization" is an assessment of the reduction of financial costs of treatment.
5. Analysis of the relationship between the economic costs of treatment and the patient's quality of life, which is assessed by the indicator of the additional number of years of standard quality of life (QALY index - Quality Adjusted Life Years).

Pharmacoeconomic assessments can be used, in particular, to make decisions on specific technologies (standards) of treatment, registration and purchase of a drug, pricing, in assessing the results of clinical trials, etc. Thus, often a full course of treatment with a more expensive drug costs the patient significantly less than when using an inexpensive drug, due to the rapid and persistent manifestation of the therapeutic effect and the reduction in the duration of hospitalization, since the cost of drugs is only 10-20% of the total hospital costs.

Conducting expert assessments of drugs includes evaluation of the following parameters:

• Immediate clinical effects.
• Frequency of complications.
• Years of life saved.
• Frequency of disability according to VTEK reports on incapacity for work.
• Change in quality of life.
• Saved years of "quality" life.
• Satisfaction of patient expectations or preferences (40% is considered normal).
• Socio-demographic indicators.
• Budgetary costs.

The results obtained are interpreted into calculations that serve as the basis for developing a list of vital drugs and national guidelines for physicians on the use of drugs, drawing up protocols for patient management, developing drug formularies, and compiling formulary lists.

An example of a pharmacoeconomic study is the economic evaluation of meloxicam versus diclofenac, piroxicam and rofecoxib conducted in the UK, on the basis of which therapeutic strategies in the treatment of osteoarthritis were modelled. The cost/effectiveness analysis of two traditional and most frequently prescribed NSAIDs (modified-release diclofenac and piroxicam) and two new COX-2 inhibitors (meloxicam and rofecoxib), as well as an assessment of the impact of these drugs on the UK national health system budget, shows the following.

The following premises served as the basis for conducting the study:

• The global market for NSAIDs for the treatment of osteoarthritis and rheumatoid arthritis is $12.1 billion;
• Rheumatic diseases are one of the most common reasons for visiting general practitioners and affect one in ten people worldwide;
• In 1998, 33 million prescriptions were written for musculoskeletal conditions worth £254 million;
• In 1997, the total cost of arthritis (the sum of direct and indirect costs) was £733 million;
• Osteoarthritis is the most important cause of disability, ranking second after cardiovascular disease as a cause of severe disability;
• There are 500-600 new cases of osteoarthritis diagnosed per 250,000 people in the UK each year;
• the prevalence of osteoarthritis increases from 2% in women under 45 years of age to 30% at the age of 45-64 years and up to 68% over 65 years of age;
• for men these figures are 3.25 and 58% respectively;
• It has been established that about 50% of all prescribed NSAIDs are intended to treat pain due to osteoarthritis, 15% - for rheumatoid arthritis;
• Meloxicam was launched on the UK market in 1996;
• In vitro and experimental pharmacological studies have shown that meloxicam is a selective COX-2 inhibitor;
• Meloxicam causes fewer gastrointestinal side effects than traditional NSAIDs such as diclofenac;
• the efficacy of meloxicam and rofecoxib is equivalent to that of traditional NSAIDs;
• The use of NSAIDs is associated with side effects that range from mild dyspepsia to ulcerogenic effects and their complications in the form of perforation and bleeding, as well as complications from the kidneys, liver and cardiovascular system in patients at risk.

Because data on the four NSAIDs could not be collected over the same time period, two trial periods were examined: 4 weeks and 6 months.

4-week study period. Data on meloxicam, diclofenac and piroxicam (incidence of adverse events and duration of hospitalization over a 4-week period) were based on the results of 2 large, double-blind, randomized, parallel-group clinical trials MELISSA and SELECT (meloxicam 7.5 mg was compared with the non-selective NSAIDs diclofenac MR - 100 mg and piroxicam - 20 mg). Both trials reflected the analysis of NSAID prescription. In the MELISSA study, 4635 patients received meloxicam and 4688 patients received diclofenac, in the SELECT study, 4320 patients received meloxicam and 4336 patients received piroxicam. The patients included in the trials were over 18 years of age and were diagnosed with osteoarthritis, primarily affecting the hip, knee, upper limb and spine joints in the acute phase.

6-month study period. Comparable data for rofecoxib were collected over a 6-month period. Data for rofecoxib and diclofenac were obtained from the FDA Medical Advisory Report (Trial 069, n=2812). The 6-month data for meloxicam were based on the results of two double-blind studies using the drug at a dose of 7.5 mg (n=169) and at a dose of 15 mg (n=306). It should be noted that the FDA report included data on gastrointestinal adverse events only, while the two clinical trials for meloxicam included data on all adverse events.

Comparative data on the frequency of development of adverse events (AE) from the digestive tract when taking NSAIDs strong>meloxicam and diclofenac - (according to the MELISSA trial)

Indicator	Meloxicam 7.5 mg	Diclofenac 100 mg
Number of patients taking NSAIDs	35	4688
Number of hospitalizations due to adverse events	3 (0.06%)	11 (0.23%)
Average hospital stay due to adverse events	1.7 days	11.3 days
Total number of days hospitalized due to adverse events	5	121
Total number of days spent in the intensive care unit due to PE	0	31

A model, also called a 'decision tree', was used to model the cost of treatment with each NSAID, taking into account the following factors:

1. Risk factors for the development of gastrointestinal side effects include age, history of peptic ulcer, concomitant use of corticosteroids and anticoagulants.
2. Approximately 25% of individuals taking NSAIDs have endoscopically confirmed ulcers.
3. Although serious side effects (ulcer, bleeding, perforation) are relatively rare, they can cause death.
4. Each year in the United States, NSAID-induced gastropathy is the cause of more than 70,000 hospitalizations and more than 7,000 deaths.

Although the incidence of bleeding, ulceration and perforation is low, the associated costs can be significant (laparoscopy £848-£1200, endoscopy £139-£200, intensive care unit admission £910-£2500).

Cost of various NSAIDs for a 28-day course of treatment

Preparation	Cost of NSAIDs per course of treatment (£)
Diclofenac MR 100 mg	9.36
Piroxicam 20 mg	3.95
Meloxicam 7.5 mg	9.33
Rofecoxib	21.58

Cost of treatment with various NSAIDs per patient

Preparation	Cost per patient (GBP)
Diclofenac MR 100 mg	51
Piroxicam 20 mg	35
Meloxicam 7.5 mg	30

Note: The cost was calculated in 1998 prices.

Results from a 6-month study showed that meloxicam was cheaper to treat (£146) than rofecoxib (£166), resulting in a saving of £3.33 per patient per month. Taking into account the annual consumption (number of prescriptions written) of meloxicam, diclofenac and piroxicam, the total cost saving with meloxicam is more than £25 million per year.

Annual consumption of different NSAIDs (calculated based on the number of prescriptions filled)

Preparation	Number of NSAID prescriptions written for OA	NSAID market share by prescription volume, %
Meloxicam	303 900	7.46
Piroxicam	109 800	2.70
Diclofenac	1 184 900	29.09

Of great interest are the summarized data from a comparative pharmacoeconomic analysis of the costs of treatment with generic and branded NSAIDs conducted in Switzerland.

Another study analyzed the pharmacoeconomic indicators of 6-month treatment with celecoxib in patients with osteoarthritis and rheumatoid arthritis in comparison with other treatment regimens: reference NSAID, NSAID + proton pump blocker, NSAID + H ₂ -receptor antagonist, NSAID + misoprostol, diclofenac / misoprostol. For this purpose, an analytical model was developed - the Celecoxib Outcome Measurement Evaluation Tool (COMET), which made it possible to estimate the relative impact of a number of indicators (risk of complications from the digestive tract, the effect of the dose on the cost of celecoxib treatment per day, the cost of treating complications, the relative risk of side effects of celecoxib treatment compared to other NSAIDs) on the expected costs of celecoxib treatment.

Average doses of individual NSAIDs and total daily costs of NSAID treatment

Preparation	Average dose (mg/day)	Average cost (Swiss francs) per day
Generic NSAIDs
Diclofenac	116	1.53
Ibuprofen	1206	1.34
Flurbiprofen	193	1.60
All NSAIDs Generics		1.49
Branded NSAIDs
Voltaren (diclofenac)	111	2.12
Brufen (ibuprofen)	1124	1.55
Tilur (acemetacin)	143	2.03
Aulin (nimesulide)	198	1.24
Felden (piroxicam)	24.2	1.65
Nisulide (nimesulide)	222	1.3
Mobicox (meloxicam)	9.71	2.04
Lodin (Etodolac)	636	2.81
Apranax (naproxen)	996	2.85
Indocide (indomethacin)	116	0.93
Tilcotil (tenoxicam)	13.3	1.68
Proxen (naproxen)	760	2.53
All branded NSAIDs		1.87

Expected costs for 6 months of treatment with celecoxib and other regimens

Baking pattern	Expected Costs (Swiss Francs)
	Absolute	Difference with celecoxib
Celecoxib	435.06
NSAIDs	509.94	74.88
Diclofenac/misoprostol	521.95	86,89
NSAIDs + misoprostol	1033.63	598.57
NSAIDs+H2 - RA	1201.09	766.03
NSAIDs+BPN	1414.72	979.66

Note: H2 _- RA- H2-receptor antagonists, BPN-proton pump blockers.

Analysis of expected costs depending on the risk of developing side effects from the gastrointestinal tract showed that treatment with celecoxib was characterized by the lowest costs; the maximum expected costs were found when using combinations of NSAIDs + misoprostol, NSAIDs + H2 _- R and NSAIDs + BPN.

Thus, compared with other treatment regimens used in this study, celecoxib therapy demonstrated an optimal cost/effectiveness ratio.

From 1992 to 1995, total costs (direct and additional) increased by 27.1%. From 1988 to 1995, total costs increased by 70.6%.

Thus, the presented data on pharmacoeconomics using osteoarthrosis as an example indicate the need to implement this practice in Ukraine. A preliminary analysis of the attitude of rheumatologists to this problem indicates an insufficient assessment of the importance of pharmacoeconomics in their practical activities. According to the results of a survey conducted during classes at the school of rheumatologists, 34% of doctors hear a report on pharmacoeconomics for the first time, 97% of respondents use the pharmacoeconomic approach when choosing a drug in relation to the financial capabilities of the patient and consider it necessary to implement the experience known in world practice in Ukraine. However, 53% believe that pharmacoeconomics should not be taken into account in the practical activities of a rheumatologist. Further formation of a doctor's worldview in matters of rational use of a drug should have a systemic approach, which includes both administrative and educational activities, starting with institutions of the Ministry of Health and the Academy of Medical Sciences of Ukraine and ending with practicing doctors. Of course, such work should be carried out taking into account the interests of patients.

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