Cost-effectiveness of 'immediate IVF' versus 'delayed IVF': a prospective study.

STUDY QUESTION: How does the cost-effectiveness (CE) of immediate IVF compared with postponing IVF for 1 year, depend on prognostic characteristics of the couple? SUMMARY ANSWER: The CE ratio, i.e. the incremental costs of immediate versus delayed IVF per extra live birth, is the highest (range of €15 000 to >€60 000) for couples with unexplained infertility and for them depends strongly on female age and the duration of infertility, whilst being lowest for endometriosis (range 8000-23 000) and, for such patients, only slightly dependent on female age and duration of infertility. WHAT IS KNOWN ALREADY: A few countries have guidelines for indications of IVF, using the diagnostic category, female age and duration of infertility. The CE of these guidelines is unknown and the evidence base exists only for bilateral tubal occlusion, not for the other diagnostic categories. STUDY DESIGN, SIZE, DURATION: A modelling approach was applied, based on the literature and data from a prospective cohort study among couples eligible for IVF or ICSI treatment, registered in a national waiting list in The Netherlands between January 2002 and December 2003. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 5962 couples was included. Chances of natural ongoing pregnancy were estimated from the waiting list observations and chances of ongoing pregnancy after IVF from follow-up data of couples with primary infertility that began treatment. Prognostic characteristics considered were female age, duration of infertility and diagnostic category. Costs of IVF were assessed from a societal perspective and determined on a representative sample of patients. A cost-effectiveness comparison was made between two scenarios: (I) wait one more year and then undergo IVF for 1 year and (II) immediate IVF during 1 year, and try to conceive naturally in the following year. Comparisons were made for strata determined by the prognostic factors. The final outcome was a live birth. MAIN RESULTS AND THE ROLE OF CHANCE: The gain in live birth rate of the immediate IVF scenario versus postponed IVF increased with female age, and was independent from diagnostic category or duration of infertility. By contrast, the corresponding increase in costs primarily depended on diagnostic category and duration of infertility. The lowest CE ratio was just below €10 000 per live birth for endometriosis from age 34 onwards at 1 year duration. The highest CE ratio reached €56 000 per live birth for unexplained infertility at age 30 and 3 years duration, dropping to values below € 30 000 per live birth from age 32 onwards. It reached values below €20 000 per live birth with 3 years duration at age 34 and older. The CE ratio was in between for the three other diagnostic categories (i.e. Male infertility, Hormonal and Immunological/Cervical). LIMITATIONS, REASONS FOR CAUTION: We applied estimates of chances with IVF, excluding frozen embryos, for which we had no data. Therefore, we do not know the effect of frozen embryo transfers on the CE. WIDER IMPLICATIONS OF THE FINDINGS: The duration of infertility at which IVF becomes cost-effective depends, firstly, on the level of society's willingness to pay for one extra live birth, and secondly, given a certain level of willingness to pay, on the woman's age and the diagnostic category. In current guidelines, the chances of a natural conception should always be taken into account before deciding whether to start IVF treatment and at which time. STUDY FUNDING/COMPETING INTEREST(S): Supported by Netherlands Organisation for Health Research and Development (ZonMW, grant 945-12-013). ZonMW had no role in designing the study, data collection, analysis and interpretation of data or writing of the report. Competing interests: none.

Advance notification letters increase adherence in colorectal cancer screening: a population-based randomized trial.

OBJECTIVE: The population benefit of screening depends not only on the effectiveness of the test, but also on adherence, which, for colorectal cancer (CRC) screening remains low. An advance notification letter may increase adherence, however, no population-based randomized trials have been conducted to provide evidence of this. METHOD: In 2008, a representative sample of the Dutch population (aged 50-74 years) was randomized. All 2493 invitees in group A were sent an advance notification letter, followed two weeks later by a standard invitation. The 2507 invitees in group B only received the standard invitation. Non-respondents in both groups were sent a reminder 6 weeks after the invitation. RESULTS: The advance notification letters resulted in a significantly higher adherence (64.4% versus 61.1%, p-value 0.019). Multivariate logistic regression analysis showed no significant interactions between group and age, sex, or socio-economic status. Cost analysis showed that the incremental cost per additional detected advanced neoplasia due to sending an advance notification letter was € 957. CONCLUSION: This population-based randomized trial demonstrates that sending an advance notification letter significantly increases adherence by 3.3%. The incremental cost per additional detected advanced neoplasia is acceptable. We therefore recommend that such letters are incorporated within the standard CRC-screening invitation process.

Screening for colorectal cancer: comparison of perceived test burden of guaiac-based faecal occult blood test, faecal immunochemical test and flexible sigmoidoscopy.

BACKGROUND: Perceived burden of colorectal cancer (CRC) screening is an important determinant of participation in subsequent screening rounds and therefore crucial for the effectiveness of a screening programme. This study determined differences in perceived burden and willingness to return for a second screening round among participants of a randomised population-based trial comparing a guaiac-based faecal occult blood test (gFOBT), a faecal immunochemical test (FIT) and flexible sigmoidoscopy (FS) screening. METHODS: A representative sample of the Dutch population (aged 50-74years) was randomised to be invited for gFOBT, FIT and FS screening. A random sample of participants of each group was asked to complete a questionnaire about test burden and willingness to return for CRC screening. RESULTS: In total 402/481 (84%) gFOBT, 530/659 (80%) FIT and 852/1124 (76%) FS screenees returned the questionnaire. The test was reported as burdensome by 2.5% of gFOBT, 1.4% of FIT and 12.9% of FS screenees (comparing gFOBT versus FIT p=0.05; versus FS p<0.001). In total 94.1% of gFOBT, 94.0% of FIT and 83.8% of FS screenees were willing to attend successive screening rounds (comparing gFOBT versus FIT p=0.84; versus FS p<0.001). Women reported more burden during FS screening than men (18.2% versus 7.7%; p<0.001). CONCLUSIONS: FIT slightly outperforms gFOBT with a lower level of reported discomfort and overall burden. Both FOBTs are better accepted than FS screening. All three tests have a high level of acceptance, which may affect uptake of subsequent screening rounds and should be taken into consideration before implementing a CRC screening programme.

The impact of healthcare costs in the last year of life and in all life years gained on the cost-effectiveness of cancer screening.

It is under debate whether healthcare costs related to death and in life years gained (LysG) due to life saving interventions should be included in economic evaluations. We estimated the impact of including these costs on cost-effectiveness of cancer screening. We obtained health insurance, home care, nursing homes, and mortality data for 2.1 million inhabitants in the Netherlands in 1998-1999. Costs related to death were approximated by the healthcare costs in the last year of life (LastYL), by cause and age of death. Costs in LYsG were estimated by calculating the healthcare costs in any life year. We calculated the change in cost-effectiveness ratios (CERs) if unrelated healthcare costs in the LastYL or in LYsG would be included. Costs in the LastYL were on average 33% higher for persons dying from cancer than from any cause. Including costs in LysG increased the CER by 4040 euro in women, and by 4100 euro in men. Of these, 660 euro in women, and 890 euro in men, were costs in the LastYL. Including unrelated healthcare costs in the LastYL or in LYsG will change the comparative cost-effectiveness of healthcare programmes. The CERs of cancer screening programmes will clearly increase, with approximately 4000 euro. However, because of the favourable CER's, including unrelated healthcare costs will in general have limited policy implications.

[Insufficient basis for the inclusion of Human papillomavirus vaccination in the National Immunisation Programme in The Netherlands]. / Onvoldoende gronden voor opname van vaccinatie tegen Humaan papillomavirus in het Rijksvaccinatieprogramma.

The Dutch Minister of Health, Welfare and Sportintends to implement Human papillomavirus (HPV) vaccination for 12-year-old girls and catch-up vaccination for 13- 16-year-old girls, as part of the National Immunisation Programme from September 2009 onwards. However, due to a well-organised screening programme, cervical cancer is not an important public health problem in the Netherlands any more, which limits the possible impact of HPV vaccination. Vaccine trials thus far have involved a relatively small number ofparticipants with limited follow-up, so the efficacy of the vaccine in preventing cervical cancer is not yet known. There are no data on frequency and severity of possible adverse events and the vaccine has not yet been tested in the intention-to-vaccinate group of 12-year-old girls. Even when we assume that HPV16/18-related cervical cancer is prevented on a lifelong basis, the cost-effectiveness ratio of HPV vaccination is estimated not to be favourable. In conclusion, HPV vaccination does not seem to be urgent in the Netherlands. Therefore we advise studying the safety in 12-year-old girls first while at the same time waiting for the longer follow-up results of ongoing trials.

Cost-effectiveness of a mild compared with a standard strategy for IVF: a randomized comparison using cumulative term live birth as the primary endpoint.

BACKGROUND Conventional ovarian stimulation and the transfer of two embryos in IVF exhibits an inherent high probability of multiple pregnancies, resulting in high costs. We evaluated the cost-effectiveness of a mild compared with a conventional strategy for IVF. METHODS Four hundred and four patients were randomly assigned to undergo either mild ovarian stimulation/GnRH antagonist co-treatment combined with single embryo transfer, or standard stimulation/GnRH agonist long protocol and the transfer of two embryos. The main outcome measures are total costs of treatment within a 12 months period after randomization, and the relationship between total costs and proportion of cumulative pregnancies resulting in term live birth within 1 year of randomization. RESULTS Despite a significantly increased average number of IVF cycles (2.3 versus 1.7; P < 0.001), lower average total costs over a 12-month period (8333 versus euro10 745; P = 0.006) were observed using the mild strategy. This was mainly due to higher costs of the obstetric and post-natal period for the standard strategy, related to multiple pregnancies. The costs per pregnancy leading to term live birth were euro19 156 in the mild strategy and euro24 038 in the standard. The incremental cost-effectiveness ratio of the standard strategy compared with the mild strategy was euro185 000 per extra pregnancy leading to term live birth. CONCLUSIONS Despite an increased mean number of IVF cycles within 1 year, from an economic perspective, the mild treatment strategy is more advantageous per term live birth. It is unlikely, over a wide range of society's willingness-to-pay, that the standard treatment strategy is cost-effective, compared with the mild strategy.

[The 1996 revision of the Dutch cervical cancer screening programme: increased coverage, fewer repeat smears and less opportunistic screening]. / Herziening bevolkingsonderzoek op baarmoederhalskanker 1996: hogere dekkingsgraad, minder herhalingsuitstrijkjes en minder opportunistische screening.

OBJECTIVE: Comparison of the indicators of effectiveness and efficiency of the Dutch national cervical cancerscreening programme in 2003 and 1994, the last year before implementation of important changes in the medical and organisational guidelines. DESIGN: Descriptive. METHOD: Data on all Pap smears made in 1994 and 2003 were retrieved from the Pathologic Anatomical National Automated Archive (PALGA), together with the matching cytological and histological follow-up until April 2004. In order to calculate the 5-year coverage, the number of women that had had a smear taken was placed in the numerator and divided by the number of women that had been invited for the screening programme during those 5 years. RESULTS: The 5-year coverage in the age range 30-64 years increased from 69 in 1994 to 77% in 2003. The percentage of smears resulting in a recommendation for a repeat smear decreased from 10 to 2. The percentage of timely compliance with recommendations for a repeat smear increased from 47 to 86, while that of smears with an immediate referral recommendation remained the same (about go). There was a sharp decrease in screening outside of the target-age range and screening with too short an interval. As a consequence, despite the higher coverage, the total number of smears decreased. CONCLUSION: The changes in the Dutch cervical cancerscreening programme in 1996 with regard to participation, the number of and compliance with recommendations for repeat smears, and screening activity outside of the target group were accompanied by significant improvements in agreement with the goals of the revision. The potential consequences for the effectiveness of the screening programme (reduction of cervical cancer mortality) will become apparent in the years to come.

Population screening for colorectal cancer: faeces, endoscopes or X-rays?

Colorectal carcinoma (CRC) is a common cancer and the second most common cause of death. The therapeutic costs for this disease will continue to rise due to an increasing incidence and the introduction of new chemotherapeutic modalities. Colorectal carcinoma is preceded by precursor lesions, which can be used as a target for early detection and therapy. Biennial population screening with faecal occult blood tests (FOBT) lowers CRC mortality with 14-18%. Five year screening with flexible sigmoidoscopy is a cost-effective alternative, which yields a higher preventive effect when similar participation rates are achieved. Screening colonoscopy has the advantage of examination of the complete colon but disadvantages are the high participant burden and the higher demand for endoscopic personnel and endoscopy units. Future screening modalities like faecal DNA markers and CT colonography are promising but need further improvement. In Europe, faecal occult blood testing and flexible sigmoidoscopy are currently the most suitable screening modalities for colorectal cancer screening.

Spinal cord stimulation is not cost-effective for non-surgical management of critical limb ischaemia.

OBJECTIVE: To quantify the costs of treatment in critical limb ischaemia (CLI) and to compare costs and effectiveness of two treatment strategies: spinal cord stimulation (SCS) and best medical treatment. METHODS: One hundred and twenty patients with CLI not suitable for vascular reconstruction were randomised to either SCS in addition to best medical treatment or best medical treatment alone. Primary outcomes were mortality, amputation and cost. Cost analysis was based on resources used by patients for 2 years after randomisation. Both medical and non-medical costs were included. RESULTS: Patient and limb survival were similar in the two treatment groups. Costs of in-hospital-stay and institutional rehabilitation constituted the predominant part (+/-70%) of the total costs of medical care in CLI. Cost of SCS-implantation and complications (7950 euro per patient) exceeded by far cost due to amputation procedures (410 euro per patient). The total costs of treatment were 36,600 euro per patient over 2 years for the SCS-group vs. 28,700 euro for best medical treatment alone (28% higher for SCS-group, p=0.009). CONCLUSIONS: Total costs of treatment in CLI are high. Major components are hospital and rehabilitation costs. In contrast to recent reviews, there were no long-term benefits of SCS-treatment. Therefore, cost-effectiveness is reduced to cost-minimisation and SCS-treatment is considerably more expensive than best medical treatment.

Comparison of different treatment strategies in IVF with cumulative live birth over a given period of time as the primary end-point: methodological considerations on a randomized controlled non-inferiority trial.

BACKGROUND: We discuss methodological considerations related to a study in IVF, which compares the effectiveness, health economics and patient discomfort of two treatment strategies that differ in both ovarian stimulation and embryo transfer policies. METHODS: This was a randomized controlled clinical trial in two large Dutch IVF centres. The tested treatment strategies are: mild ovarian stimulation [including gonadotrophin-releasing hormone (GnRH) antagonist co-treatment] together with the transfer of one embryo, versus conventional stimulation (with GnRH agonist long protocol co-treatment) and the transfer of two embryos. Outcome measures are: (i) pregnancies resulting in term live birth; (ii) total costs per term live birth; and (iii) patient stress/discomfort per started IVF treatment, over a 12 month period. Power considerations for this study were an overall cumulative live birth rate of 45% for the conventional treatment strategy, with non-inferiority of the mild treatment strategy defined as a live birth rate no more than 12.5% lower compared with the conventional study arm. For a power of 80% and alpha of 0.05, 400 subjects are required. RESULTS: As planned, from February 2002 until February 2004, 410 patients were enrolled. CONCLUSIONS: This effectiveness study applies an integrated medical, health economics and psychological approach with term live birth over a given period of time after starting IVF as the end-point. Complete and timely patient enrolment vindicates many of the design decisions.

Dynamic decision analysis to determine optimal treatment duration in chronic hepatitis C.

BACKGROUND: Current guidelines for stopping treatment of chronic hepatitis C are based on hepatitis C ribonucleic acid measurements at 12 and 24 weeks. AIM: To explore an alternative approach for making individualized recommendations about treatment duration, based on simple alanine aminotransferase tests and on cost-per-cure. METHODS: We analysed individual patient data from 13 randomized, controlled trials with interferon alone or combined with ribavirin. Using multiple logistic regression, we built a model that estimated the probability of sustained virological response for treatment durations of 24 and 48 weeks. Decisions to prolong treatment were based on an increase in probability of sustained virological response. If the increase was 10%, the cost-per-cure became decisive with a limit of 50,000. RESULTS: Noncirrhotics with genotype 2 or 3 did not benefit when treatment was continued beyond 24 weeks. Sustained virological response rates in cirrhotic patients increased by 14-47% if treatment was continued up to 48 weeks. In noncirrhotic genotype 1 or 4 patients who had elevated alanine aminotransferase levels at week 4, the probability of sustained virological response increased by <10% if treatment was continued up to 48 weeks; the cost-per-cure for these patients would exceed 50,000. CONCLUSION: The dynamics of alanine aminotransferase levels and cost-per-cure provides a useful alternative to determine the duration of therapy in chronic hepatitis C.

Measuring schistosomiasis case management of the health services in Ghana and Mali.

The World Health Organization recommends passive case detection by regular health services as a minimum strategy for schistosomiasis morbidity control. To evaluate preparedness of the health systems in Ghana and Mali, we presented four clinical scenarios, two with blood in urine (main early symptom of Schistosoma haematobium) and two with (bloody) diarrhoea (main early symptom of S. mansoni), to health workers. We requested the health personnel for an initial diagnosis and case management strategy without providing information about our primary interest in schistosomiasis. The information was used to determine the chance that a person reporting with symptoms that might have been caused by schistosomiasis would receive praziquantel. All selected health workers participated. Their initial diagnosis was frequently S. haematobium for both scenarios with blood in urine. For the two scenarios with (bloody) diarrhoea, only few mentioned S. mansoni. At health centre level, case management in Mali mainly consisted of direct prescription of medication, whereas in Ghana health workers often referred to a hospital or requested a diagnostic test. The ultimate probability of prescribing praziquantel was relatively high for the scenarios with blood in urine, 60% in Ghana and 75% in Mali, but very low for both scenarios with (bloody) diarrhoea (<20%). Of those health care facilities that would prescribe praziquantel, 60% (Ghana) and 80% (Mali) had it in stock. In conclusion, the clinical scenario study showed that patients reporting with blood in urine will be treated with praziquantel at approximately half of the health care facilities, whereas of those presenting with (bloody) diarrhoea only few would receive treatment with praziquantel. Considering these facts, it is questionable if passive case detection is a sufficient basis for effective schistosomiasis morbidity control, especially for S. mansoni infection.

The effect of HIV, behavioural change, and STD syndromic management on STD epidemiology in sub-Saharan Africa: simulations of Uganda.

An assessment was made of how the HIV epidemic may have influenced sexually transmitted disease (STD) epidemiology in Uganda, and how HIV would affect the effectiveness of syndromic STD treatment programmes during different stages of the epidemic. The dynamic transmission model STDSIM was used to simulate the spread of HIV and four bacterial and one viral STD. Model parameters were quantified using demographic, behavioural, and epidemiological data from rural Rakai and other Ugandan populations. The findings suggest that severe HIV epidemics can markedly alter STD epidemiology, especially if accompanied by a behavioural response. Likely declines in bacterial causes of genital ulcers should be considered in defining policies on syndromic STD management in severe HIV epidemics.