Choosing a medicine to treat osteoarthritis

Pharmacoeconomics is a science whose aim is to economically assess the effectiveness of costs and results associated with the use of medicines. In Western Europe, it has been developing since the 60-70s of the XX century.

The subject of the study of pharmacoeconomics are:

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

Objects of study of pharmacoeconomics are:

1. costs (in cost parameters) for effective pharmacotherapy with different technologies, one of the technologies associated with pharmacotherapy, and the other may include additional therapeutic measures,
2. the effectiveness of pharmacotherapy, expressed in biological health parameters (for example, changes in the level of glycemia in diabetic patients, lipidemia levels, prolongation of life),
3. the effectiveness of treatment regimens (determined with the help of pharmacoepidemiological studies, when observed, both the efficacy of the drug and all observed side effects in the population are recorded).

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

1. Direct costs include:
   • Costs for diagnosis of the disease.
   • The cost of the medication needed for the course of treatment.
   • The cost of laboratory research.
   • Costs to eliminate side effects of the drug.
   • The cost of a bed-day.
   • Salary of medical workers.
   • Costs for the delivery of a drug, food for the patient.
   • Costs for the payment of assistance due to disability (from social insurance funds).
2. Indirect or indirect medical costs - associated with economic damage from reducing the time of employment of the patient, his premature death. This is the cost associated with the impossibility of a citizen in the period of illness to be useful to society, participate in the production process. 
3. Additional intangible costs associated with the disease are due to the psycho-emotional experiences of the patient and the deterioration in the quality of his life (for these reasons they are difficult to quantify). 

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

Investigation of expenses for diseases of the musculoskeletal system (arthritis) in the USA

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 nurses; 15.5% of direct costs were expenses for medical treatment, and most of them are due to the use of NSAIDs.

In recent years, there has been an intensive growth in pharmacoeconomic research, which is due to a number of reasons, including: increased health care costs, the need to address the treatment of a number of diseases (HIV, cancer), the emergence of new technologies, improved quality of life, and the urgent need to analyze the cost / effectiveness ratio.

The main methods for pharmacoeconomics are the following methods of pharmacoeconomic analysis:

1. "Cost-effectiveness analysis" (CEA) - assess changes in any parameter that changes in the pathophysiological state, for example: blood pressure indicators, as well as reducing financial costs. 
2. Cost-benefit analysis (CBA) is an economic cost-benefit analysis in which the benefits derived from the use of a particular drug are expressed in monetary terms through costs if direct savings are not immediately apparent.
3. Cost-utility analysis (CUA) is an analysis in which effects are expressed through their utility to the consumer and estimate the cost of some additional increase in life expectancy (for example, the cost of an additional year of full-time life) or another indicator that has value for the patient.
4. "Cost minimization" (cost-minimization) - an estimate of the reduction in financial costs of treatment. 
5. Analysis of the relationship between the economic costs of treatment and the quality of life of the patient, which is estimated by the indicator of additional years of standard quality of life (QALY index - Quality Adjusted Life Years).

Pharmacoeconomic assessments can be used, in particular, to decide on specific technologies (standards) for treatment, registration and purchase of a medicinal product, pricing, evaluation of the results of clinical trials, etc. So, quite often the full course of treatment with a more expensive drug costs the patient much cheaper than using an inexpensive medication, due to rapid and persistent manifestation of the therapeutic effect and shortening of hospitalization, since the cost of medicines is only 10-20% of the total hospital costs.

Conducting expert evaluations of drugs includes the assessment of the following parameters:

• Immediate clinical effects.
• The frequency of complications.
• Saved years of life.
• Frequency of invalidity submitted by the WTEC on incapacity for work.
• Change in the quality of life.
• Saved years of "quality" life.
• Satisfaction of the patient's expectations or preferences (40% is considered the norm).
• Socio-demographic indicators.
• Budgetary costs.

The results are interpreted in calculations that serve as the basis for the development of a list of vital medicines and national guidelines for physicians on the use of medicines, the preparation of patient records, the development of drug forms, the compilation of formular lists.

An example of a pharmacoeconomic study is the UK economic assessment of meloxicam compared with diclofenac, piroxicam and rofecoxib, on the basis of which therapeutic strategies for the treatment of osteoarthritis have been modeled. Cost-effectiveness analysis of two traditional and most commonly prescribed NSAIDs (diclofenax modified release and piroxicam) and two new COX-2 inhibitors (meloxicam and rofecoxib), as well as an assessment of the effect of these drugs on the national health system budget of the UK, shows the following.

The basis for the study was the following prerequisites:

• 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 causes of treatment for general practitioners and affect one in every ten people in the world;
• in 1998, 33 million prescriptions were issued for the amount of 254 million pounds sterling for musculoskeletal disorders;
• in 1997, the total cost of arthritis (the sum of direct and indirect costs) was 733 million pounds sterling;
• osteoarthrosis is the most important cause of disability, second only to cardiovascular disease as a cause of severe disability;
• 250 000 people in the UK are diagnosed every year with 500-600 new cases of osteoarthritis;
• the prevalence of osteoarthritis increases from 2% of women - up to 45 years old to 30% at the age of 45-64 years and 68% - over 65 years;
• in men, these figures are 3.25 and 58%, respectively;
• it has been established that about 50% of all prescribed NSAIDs are intended for the treatment of pain due to osteoarthritis, 15% for rheumatoid arthritis;
• meloxicam entered the UK market in 1996;
• in in vitro studies and experimental pharmacological studies, it has been established that meloxicam is a selective inhibitor of COX-2;
• meloxicam causes fewer side effects from the digestive tract compared to traditional NSAIDs, such as diclofenac;
• the efficacy of meloxicam and rofecoxib is equivalent to that of conventional NSAIDs;
• the use of NSAIDs is associated with side effects that range from mild dyspepsia to ulcerogenic effect and its complications in the form of perforation and bleeding, as well as complications from the kidneys, the liver and the cardiovascular system in patients at risk.

Since the data on the four NSAIDs could not be collected in the same time period, 2 test periods of 4 weeks and 6 months were examined.

4-week test period. Data on meloxicam, diclofenac and piroxicam (the incidence of side effects and duration of hospitalization for the 4-week period) were based on the results of 2 large-scale double-blind randomized trials involving parallel groups of MELISSA and SELECT clinical trials (compared to meloxicam 7.5 mg with nonselective NSAIDs diclofenac MR - 100 mg and piroxicam - 20 mg). Both tests reflected the analysis of the NSAID designation. In the MELISSA study, 4635 patients received meloxicam and 4688 diclofenac; SELECT 4320 received meloxicam and 4336 piroxicam. Patients enrolled in the trial were over the age of 18 years, they were diagnosed with osteoarthritis with a predominant lesion of the hip, knee joints, upper limb joints and spine in the exacerbation phase.

6-month testing period. Comparable data on rofecoxib were collected for a 6-month period. Data on rofecoxib and diclofenac were obtained from the report of the FDA medical advisors (test 069, n = 2812). The data for 6 months on meloxicam were based on the results of 2 double-blind studies using a drug at a dose of 7.5 mg (n = 169) and a dose of 15 mg (n = 306). It should be borne in mind that the FDA report only contained data on side effects from the digestive tract, while two clinical trials on meloxicam - data on all adverse side effects.

Comparative data on the incidence of side effects (PE) from the digestive tract during the intake of strong> meloxicam and diclofenac - (according to the MELISSA test)

Index	Meloxicam 7.5 mg	Diclofenac 100 mg
Number of patients taking NSAIDs	35	4688
The number of hospitalizations due to side effects	3 (0.06%)	11 (0.23%)
Average hospitalization due to side effects	1,7 days	11.3 days
Total number of days of hospitalization due to side effects	5	121
The total number of days spent in the resuscitation department due to PE	0	31

To model the cost of treatment for each NSAID, a model was used, also called a decision tree, taking into account the following factors:

1. The risk factors for side effects from the digestive tract include age, the presence of a peptic ulcer in an anamnesis, the concomitant use of GCS and anticoagulants.
2. About 25% of people taking NSAIDs have endoscopically confirmed ulcers.
3. Although serious side effects (ulcer, bleeding, perforation) are relatively rare, they can be the cause of death.
4. Every year in the United States, NSAID-induced gastropathies are the reason for more than 70,000 hospitalizations and cause more than 7,000 deaths.

Although the incidence of bleeding, ulcers and perforations is low, the costs associated with them can be significant (laparoscopy - 848-1200 pounds sterling, endoscopy - 139-200 pounds sterling, hospitalization in the intensive care unit - 910- 2500 pounds sterling).

The cost of various NSAIDs for a course of treatment lasting 28 days

A drug	The cost of NSAIDs for treatment (pounds sterling)
Diclofenac MR 100 mg	9.36
Piroxicam 20 mg	3.95
Meloxicam 7.5 mg	9.33
Rofecoxib	21.58

The cost of treatment with various NSAIDs per one patient

A drug	Cost per patient (pounds sterling)
Diclofenac MR 100 mg	51
Piroxicam 20 mg	35
Meloxicam 7.5 mg	Thirty

Note. The cost was calculated in 1998 prices.

The results of 6-month studies showed that the cost of treatment with meloxicam is lower (146 pounds sterling) compared with rofecoxib (166 pounds sterling), which leads to a saving of 3.33 pounds sterling per patient per month. Taking into account the annual consumption (the number of prescriptions written) of meloxicam, diclofenac and piroxicam, the total cost savings using meloxicam is more than 25 million pounds sterling per year.

Annual intake of various NSAIDs (calculated on the basis of the number of prescriptions written)

A drug	The number of prescriptions prescribed for NSAIDs for OA	The share of the NSAID market according to the number of recipes,%
Meloksikam	303,900	7.46
Piroxicam	109 800	2.70
Diclofenac	1,184,900	29.09

Of great interest are the generalized data of the Swiss comparative pharmacoeconomic analysis of the costs of treatment with generic and branded NSAIDs.

In another study, pharmacoeconomic indicators of 6-month-long celecoxib treatment of patients with osteoarthritis and rheumatoid arthritis were compared with other regimens of therapy: reference NSAIDs, NSAIDs + proton pump blockers, NSAIDs + antagonists _of H2-receptors, NSAIDs + misoprostol, diclofenac / misoprostol. To this end, the analytical model, the Celecoxib Outcome Measurement Evaluation Tool (COMET), was developed to assess the relative impact of a number of indicators (the risk of complications from the digestive tract, the effect of a dose on the cost of celecoxib treatment per day, the cost of treating complications, the relative risk of side effects the effects of celecoxib treatment compared to other NSAIDs) on the expected costs of celecoxib treatment.

The average doses of individual NSAIDs and the total daily costs of treating NSAIDs

A drug	The average dose (mg / day)	Average costs (Swiss francs) per day
Generic NSAIDs
Diclofenac	116	1.53
Ibuprofen	1206	1.34
Flurbiprofen	193	1.60
All NSAIDs are generic		1.49
Branded NSAIDs
Voltaren (diclofenac)	111	2.12
Brufen (ibuprofen)	1124	1.55
Tylur (acetemethacin)	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
Indocid (indomethacin)	116	0.93
Tilcotyl (tenoxicam)	13.3	1.68
Proxen (Naproxen)	760	2.53
All branded NSAIDs		1.87

Expected costs of 6-month treatment with celecoxib and other regimens

The scheme of baking	Expected costs (Swiss francs)
	Absolute	The difference with celecoxib
Celecoxib	435.06
NSAIDs	509.94	74.88
Diclofenac / misoprostol	521.95	86.89
NSAIDs + misoprostol	1033.63	598.57
NSAIDs + H 2 -PA	1201.09	766.03
NSAIDs + BPN	1414.72	979.66

Note. H ₂ -RA-antagonists of H2-receptors, BPN-blockers of the proton pump.

An analysis of the expected costs, depending on the risk of side effects from the digestive tract, showed that treatment with celecoxib is the least costly; the maximum expected costs were found using combinations of NSAIDs + misoprostol, NSAIDs + H ₂ -P and NSAIDs + BPN.

Thus, in comparison with other treatment regimens used in this study, the optimal cost-effectiveness ratio was noted with celecoxib therapy.

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 with the example of osteoarthritis testify to the need for the introduction of this practice in Ukraine. A preliminary analysis of the attitude of rheumatologists to this problem indicates an insufficient evaluation of the importance of pharmacoeconomics in their practical activities. According to the results of a survey conducted at the school of rheumatologists, 34% of doctors for the first time hear a report on pharmacoeconomics, 97% of respondents use the pharmacoeconomic approach when choosing a drug for the financial capabilities of the patient and consider the introduction of a world-known experience in Ukraine. However, 53% believe that pharmacoeconomics should not be taken into account in the practice of a rheumatologist. Further development of the physician's worldview in the rational use of the medicinal product should have a systematic approach that includes both administrative and educational activities, starting with the institutions of the Ministry of Health and the Medical Academy of Ukraine and ending with practical doctors. Undoubtedly, such work should be carried out taking into account the interests of patients.

[1], [2], [3], [4]