The impact of postmenopausal hormone therapy on health and use of health services: experience from the Estonian Postmenopausal Hormone Therapy (EPHT) trial

Abstract

Vaihdevuosien hormonihoito lisää terveydenhuollon kustannuksia

Virossa tehty vaihdevuosien jälkeinen hormonihoitotutkimus EPHT (Estonian Postmenopausal Hormone Therapy Trial) oli satunnaistettu koe, johon osallistui 1 823 tervettä virolaisnaista vuosien 1999-­2004 aikana. Naiset olivat 50-­64-vuotiaita silloin, kun heidän tietonsa poimittiin Viron väestörekisteristä. 59 % naisista oli 50-­59-vuotiaita. Heidän vointiaan seurattiin vuosittaisilla lääkärintarkastuksilla ja kansallisista terveysrekistereistä. Lisäksi naisille lähetettiin vuosittain kyselylomake. Keskimääräinen seuranta-aika oli 3,4 vuotta.

Kokeessa tutkittiin vaihdevuosien jälkeisen hormponihoidon vaikutusta sepelvaltimotautiin, verenkiertoelinten sairauksiin, luunmurtumiin ja syöpiin. Siinä verrattiin myös hormonoitoa saaneiden naisten ryhmän terveyspalveluiden käyttöä ja terveydenhuollon kustannuksia sekä naisten raportoimia oireita ja elämänlaatua niiden naisten ryhmään, jotka eivät saaneet mitään hoitoa.

Vaikka hormonihoito helpotti kuumia aaltoja ja nukkumisvaikeuksia, se lisäsi vuotojaksojen määrää ja aiheutti muitakin sivuvaikutuksia. Yleisessä elämänlaadussa ryhmien välillä ei ollut eroa.

Hormonihoitoa saaneiden naisten terveyspalveluiden käyttöä ja terveydenhuollon kustannuksia ei ole aikaisemmin tutkittu satunnaistetulla kontrolloidulla kokeella. EPHT-kokeessa hormonihoito lisäsi terveydenhuollon kokonaiskustannuksia, koska hormonihoitoa saaneet naiset kävivät useammin perhelääkärin vastaanotolla ja heillä oli yleensäkin enemmän terveydenhuoltokäyntejä. Heille tehtiin myös enemmän kohdun ultraäänitutkimuksia ja sydänfilmejä kuin naisille, jotka eivät käyttäneet hormonihoitoa. Eri ryhmien välillä ei ollut eroa sairaalassaoloajoissa tai sairaslomien pituudessa. Lääkekustannukset olivat hormonihoita saaneiden ryhmässä myös korkeammat. Tässä ryhmässä naisille määrättiin enemmän verenpainelääkkeitä ja emättimen paikallishoitoon lääkkeitä hiivataudin vuoksi, mutta vähemmän unilääkkeitä.

EPHT-tutkimuksen tulokset osoittivat, että hormonihoitoryhmässä naisilla oli vähemmän luunmurtumia kuin ryhmässä, jossa ei hormonihoitoa annettu. Hormonihoidolla ei ollut myönteisiä vaikutuksia sepelvaltimotautiin, eikä tilastollisesti merkitseviä vaikutuksia aivoverenkierron sairauksiin ja syöpien esiintymiseen.

Yhdysvaltalainen Women's Health Initiative (WHI) oli ensimmäinen satunnaistettu vaihdevuosihormonihoitokoe, joka tehtiin suhteellisen terveillä vaihdevuodet ohittaneilla naisilla. EPHT-kokeeseen osallistuneet naiset olivat noin 5 vuotta nuorempia kuin WHI-kokeessa. Virolaiskokeessa naiset olivat myös eri terveysmittareilla katsottuna terveempiä kuin naiset WHI-kokeessa.

Viimeisin tutkimustieto WHI-kokeesta osoittaa, että hormonihoito saattaa pienentää sepelvaltimotautia 50-­59-vuotiaiden naisten alaryhmässä, mutta tulos ei ollut tilastollisesti merkitsevä. Estrogeenilla on monimutkaisia biologisia vaikutuksia ja se saattaa vaikuttaa sepelvaltimotautiin ja muihin tuloksiin useita eri reittejä. Kuitenkin aivohalvausten riski oli kohonnut kaikissa ikäryhmissä WHI-kokeessa. EPHT-kokeessa ei mikään alaryhmä hyötynyt hormonihoidosta tutkittaessa sepelvaltimotaudin esiintymistä, ei myöskään naisilla, jotka olivat 50-­53 vuotta aloittaessa hormonihoidon.

Estonian Postmenopausal Hormone Therapy trial [ISRCTN35338757]

Introduction: At the time of starting the trial, the knowledge of long-term effects of hormone therapy (HT) was based on non-experimental studies, but the use of HT was rapidly increasing. The main anticipated long-term benefits of HT were to be prevention of osteoporosis and related fractures and a possible prevention of cardiovascular diseases. In addition to studying the long-term health effects of HT, the aim of the EPHT trial was to ascertain the effect of HT on health-related quality of life, symptoms of menopause, on the use of health services and health care costs.

From 1993 to 1998, the Women s Health Initiative (WHI) trial recruited participants in the United States into a randomised HT trial with a planned duration of 8.5 years. In 1999, the European Women s International Study of Long Duration Oestrogen after Menopause (WISDOM) trial was started in the United Kingdom. The EPHT trial was planned to be done in co-operation with the WISDOM trial and the duration of the EPHT trial was planned to be five years. However, due to the premature stopping of the WHI trial and its findings, the WISDOM trial was cancelled at an early stage. Trial treatment in the EPHT trial was also stopped preterm, the decision being based on the published results from the WHI trial.

Objective: The aims of this study were to use the framework of a randomised preventive trial to study the effects of continuous combined HT among healthy women on the incidence of coronary heart disease, cerebrovascular disease, total cancer and bone fractures over time; to study the effect of HT on quality of life and symptom reporting; to study the use of health services and health care costs related to HT; and to study the use of prescription medication by HT users versus non-users.

Material and methods: 1823 postmenopausal women aged 50 to 64 years at the time of sampling were recruited into a randomised preventive trial in Estonia between 1999 and 2001. In order to study the utilization of health services and to determine the health care costs due to postmenopausal hormone therapy, a non-blind sub-trial was used in parallel to the blind one. Altogether, 796 women were recruited into the blind sub-trial and allocated either to active treatment or placebo, and 1027 women were recruited into the non-blind sub-trial and allocated either to open-label hormone therapy or no treatment.

The drug in oral daily use in the treatment arms contained 0.625 mg of conjugated oestrogens and 2.5 mg of medroxyprogesterone acetate or matched placebo. In the non-blind control arm, women used no treatment. Women within 3 years from menopause received daily orally 0.625 mg of oral conjugated oestrogens and 5.0 mg of medroxyprogesterone acetate or placebo in the treatment arms. The rate of women using more than 80% of allocated trial treatment dropped approximately 50% during the first trial year, and remained nearly the same throughout the trial. Less than 10% of women started taking prescribed HT in the non-blind control arm. The trial treatment was planned for five years, but after the release of the results from the WHI trial the Data Monitoring Committee recommended to stop trial treatment which was stopped preterm by May 2004.

The minimal follow-up time was 2.00 years and maximal 4.97 years. The mean follow-up time was 3.43 years for the ascertainment of clinical outcomes and use of health services, 3.60 years for analysing the effect of HT on health-related quality of life and menopausal symptoms and 4.40 for the analysis of prescription medication usage during the trial. Women were followed by annual questionnaires and annual linkages to the Estonian Cancer Registry, to the Estonian Health Insurance Fund and to the Estonian Mortality Database. The response rate was 75% to the first annual survey, 69% to the second annual survey, 68% to the third annual survey, and 81% to the final survey mailed at the end of the trial. There was no difference in the annual response rates between the trial arms. Follow-up through registries is assumed to have been complete.

Results: The combined hazard ratio for coronary heart disease after adjustment by blinding, age at recruitment and former oral contraceptive use in the HT arms was 1.12 (95% CI: 0.90-1.40). The adjusted hazard ratio in the HT arms for cerebrovascular disease was 1.24 (95% CI: 0.85-1.82) and for total cancer 1.36 (95% CI: 0.73-2.52). The adjusted hazard ratio for bone fractures in the HT arms was 0.61 (95% CI: 0.42-0.89).

There were less women in the HT arms reporting hot flushes (OR 0.54; 95% CI: 0.41-0.71) and sweating (OR 0.74; 95% CI: 0.58-0.93), but more women reporting vaginal bleeding (OR 8.40; 95% CI: 3.27-27.43) at the end of the trial. HT also alleviated sleeping problems, but had a negative effect on backache. There was no difference in the prevalence of other symptoms or quality of life scores between the trial arms over time.

Within the non-blind sub-trial, the number of all health care visits was 10% higher and the number of visits to family practitioners 16% higher per person-year in the HT arm. Per person-year, the number of vaginal sonograms was 14% and the number of electrocardiograms 19% higher in the HT arm of the non-blind sub-trial. Outpatient health care costs and drug expenses were higher in the non-blind HT arm. In the blind sub-trial, the number of gynaecologic operations, vaginal sonograms and total health care costs was higher in the HT arm.

The proportion of women using any prescription medication besides HT did not differ between the arms. The type of prescribed drugs varied between the arms. After combining data from both HT arms, the combined hazard ratio was 1.26 (95% CI: 1.05-1.53) for the use of calcium channel blockers, 1.48 (95% CI: 1.10-1.99) for local vaginal treatment, 0.70 (95% CI: 0.50-0.99) for hypnotics and sedatives and 0.77 (95% CI: 0.60-0.99) for selective serotonin reuptake inhibitors (SSRIs).

Conclusions: According to the results from the EPHT trial, combined HT reduced bone fractures in healthy women. The trial provided no evidence of benefits from combined HT for coronary heart disease, cerebrovascular disease, or total cancer. The results are consistent with the findings from the WHI trial.

Combined HT alleviated vasomotor symptoms and sleeping problems, but added bleeding episodes and backache among postmenopausal women, and had no effect on quality of life among participants of the EPHT trial.

Postmenopausal HT increased expenses on drugs and outpatient health care. The increase in outpatient health care costs was due to additional health care visits and medical procedures in the HT arms. HT did not increase the overall use of prescription medication other than hormone therapy, but the types of drugs used in hormone therapy and non-therapy arms varied, with increased use of calcium channel blockers for hypertension and local vaginal treatments for vaginal candidiasis and decreased use of hypnotics, sedatives and selective serotonin reuptake inhibitors in the HT arms.