The association of active smoking with multiple cancers: national census-cancer registry cohorts with quantitative bias analysis.

PURPOSES: (1) Determine the association of multiple cancers with smoking, focusing on cancers with an uncertain association; and (2) illustrate quantitative bias analysis as applied to registry data, to adjust for misclassification of smoking and residual confounding by alcohol and obesity. METHODS: New Zealand 1981 and 1996 censuses, including smoking questions, were linked to cancer registry data giving 14.8 million person-years of follow-up. Rate ratios (RR) for current versus never smokers, adjusting for age, sex, ethnicity and socioeconomic factors were calculated and then subjected to quantitative bias analysis. RESULTS: RR estimates for lung, larynx (including ear and nasosinus), and bladder cancers adjusted for measured confounders and exposure misclassification were 9.28 (95 % uncertainty interval 8.31-10.4), 6.14 (4.55-8.30), and 2.22 (1.94-2.55), respectively. Moderate associations were found for cervical (1.82; 1.51-2.20), kidney (1.29; 1.07-1.56), liver cancer (1.75; 1.37-2.24; European only), esophageal (2.14; 1.73-2.65), oropharyngeal (2.30; 1.94-2.72), pancreatic (1.68; 1.44-1.96), and stomach cancers (1.42; 1.22-1.66). Protective associations were found for endometrial (0.67; 0.56-0.79) and melanoma (0.72; 0.65-0.81), and borderline association for thyroid (0.76; 0.58-1.00), colon (0.89; 0.81-0.98), and CML (0.66; 0.44-0.99). Remaining cancers had near null associations. Adjustment for residual confounding suggested little impact, except the RRs for endometrial, kidney, and esophageal cancers were slightly increased, and the oropharyngeal and liver (European/other) RRs were decreased. CONCLUSIONS: Our large study confirms the strong association of smoking with many cancers and strengthens the evidence for protective associations with thyroid cancer and melanoma. With large data sets, considering and adjusting for residual systematic error is as important as quantifying random error.

Prioritizing risk factors to identify preventive interventions for economic assessment.

OBJECTIVE: To explore a risk factor approach for identifying preventive interventions that require more in-depth economic assessment, including cost-effectiveness analyses. METHODS: A three-step approach was employed to: (i) identify the risk factors that contribute most substantially to disability-adjusted life years (DALYs); (ii) re-rank these risk factors based on the availability of effective preventive interventions warranting further cost-effectiveness analysis (and in some instances on evidence from existing cost-effectiveness analyses); and (iii) re-rank these risk factors in accordance with their relative contribution to health inequalities. Health inequalities between the Maori and non-Maori populations in New Zealand were used by way of illustration. FINDINGS: Seven of the top 10 risk factors prioritized for research on preventive interventions in New Zealand were also among the 10 risk factors most highly ranked as contributing to DALYs in high-income countries of the World Health Organization's Western Pacific Region. The final list of priority risk factors included tobacco use; alcohol use; high blood pressure; high blood cholesterol; overweight/obesity, and physical inactivity. All of these factors contributed to health inequalities. Effective interventions for preventing all of them are available, and for each risk factor there is at least one documented cost-saving preventive intervention. CONCLUSION: The straightforward approach to prioritizing risk factors described in this paper may be applicable in many countries, and even in those countries that lack the capacity to perform additional cost-effectiveness analyses, this approach will still make it possible to determine which cost-effective interventions should be implemented in the short run.

Pregabalin: in the treatment of generalised anxiety disorder.

Pregabalin, the pharmacologically active S-enantiomer of 3-aminomethyl-5-methyl-hexanoic acid, is a structural analogue of GABA, although it is not active at GABA receptors, nor does it acutely alter GABA uptake or degradation.black triangle Pregabalin binds with high affinity to the alpha2-delta subunit protein of voltage-gated calcium channels in CNS tissues and acts as a presynaptic modulator of the excessive release, in hyperexcited neurons, of various excitatory neurotransmitters. Binding of pregabalin to the alpha2-delta subunit appears necessary for its demonstrable anxiolytic, analgesic and anticonvulsant activities in animal models.black triangle Oral pregabalin, typically at dosages of 300-600 mg/day, was superior to placebo and similar to lorazepam 6 mg/day, alprazolam 1.5 mg/day and venlafaxine 75 mg/day in improving anxiety and depressive symptoms in patients with moderate-to-severe generalised anxiety disorder (GAD). Pregabalin had a rapid onset of anxiolytic activity relative to alprazolam and venlafaxine, which was evident after 1 week. Additionally, pregabalin (initial dosage 450 mg/day) was effective for the prevention of relapse of GAD over 34 weeks. Pregabalin was well tolerated during dosage escalation to fixed dosages (maximum 600 mg/day) over 7 days. Dizziness and somnolence, usually of mild to moderate severity, were the most common adverse events.black triangle The drug was not associated with a clinically significant medication withdrawal syndrome during a 1-week taper following 4 or 6 weeks' double-blind treatment.

Pregabalin: in the treatment of postherpetic neuralgia.

Pregabalin, the pharmacologically active S-enantiomer of 3-aminomethyl-5-methyl-hexanoic acid, has a similar pharmacological profile to that of its developmental predecessor gabapentin, but showed greater analgesic activity in rodent models of neuropathic pain. The exact mechanism of action of pregabalin is unclear, although it may reduce excitatory neurotransmitter release by binding to the alpha2-delta protein subunit of voltage-gated calcium channels. Oral pregabalin 150-600 mg/day, administered twice or three times daily, was superior to placebo in relieving pain and improving pain-related sleep interference in three randomised, double-blind, placebo-controlled, multicentre studies of 8-13 weeks' duration in a total of 776 evaluable patients with postherpetic neuralgia (PHN). Weekly mean pain scores (primary endpoint; assessed in all three studies) and weekly mean sleep interference scores (assessed in two studies) were significantly improved at 1 week. In two studies, significant improvements in daily mean pain scores were apparent on the first or second day of treatment with pregabalin administered three times daily. Pregabalin was generally well tolerated when force-titrated over 1 week to fixed dosages (maximum 600 mg/day) in clinical trials that enrolled most elderly PHN patients. Dizziness, somnolence and peripheral oedema of mild-to-moderate intensity were the most common adverse events.

Rizatriptan: a pharmacoeconomic review of its use in the acute treatment of migraine.

Rizatriptan (Maxalt; Maxalt-MLT; Maxalt-Melt) is an oral serotonin 5-HT(1B/1D) receptor agonist (triptan) used in the acute treatment of migraine with or without aura in adults. Rizatriptan 5 mg and 10 mg are effective in relieving the symptoms of migraine and the 10 mg dose provided faster pain relief than sumatriptan 50 mg, naratriptan 2.5 mg, ergotamine/caffeine 2 mg/200 mg and possibly zolmitriptan 2.5 mg, while displaying similar tolerability. Two cost-utility analyses performed from a societal perspective indicated that rizatriptan 10 mg was dominant over ergotamine/caffeine 2 mg/200 mg, sumatriptan 50 mg or 100 mg, naratriptan 2.5 mg, zolmitriptan 2.5 mg and analgesic-based usual care in the acute treatment of migraine. In one analysis also performed from the perspective of a healthcare payer, rizatriptan was still dominant over naratriptan, sumatriptan and zolmitriptan. Rizatriptan was cost effective compared with usual care with an incremental cost per quality-adjusted life-year (QALY) gained of 31,845 Can dollars (2002 values) and an incremental cost per additional attack aborted of 49.82 Can dollars. A modelled cost-effectiveness analysis conducted from a healthcare payer's perspective indicated that almotriptan 12.5 mg was more cost effective than rizatriptan 10 mg as a result of better tolerability. The incremental cost per additional successfully treated patient (defined as being sustained pain free without adverse events) with almotriptan was 6.94 US dollars (1999 values). In other nonmodelled cost-effectiveness analyses, rizatriptan 10 mg, eletriptan 40 mg and almotriptan 12.5 mg most consistently displayed the greatest cost effectiveness in different analyses using different clinical endpoints. A modelled analysis of the costs of migraine-related productivity losses in US corporations indicated that the use of rizatriptan rather than usual care to treat migraines could result in annual cost offsets of approximately 84-118 US dollars (2000 values) per employee in lost productivity avoided. An intervention study in Spanish postal service workers demonstrated that replacement of usual care with rizatriptan reduced the mean per-patient cost of lost productivity per migraine attack from 34.47 euros (2001/2002 values) before the intervention to 13.94 euros and 4.59 euros for the first and second post-intervention migraine attacks. In conclusion, rizatriptan is one of the more clinically effective and therefore cost-effective oral triptans available for the acute treatment of migraine. The available data from cost-utility analyses suggest that rizatriptan is more cost effective than ergotamine/caffeine, simple analgesics, naratriptan, zolmitriptan and sumatriptan. The economic value of rizatriptan depends on the payer's perspective, as the greatest savings can be expected to be achieved in terms of reduced migraine-related loss of work productivity compared with less effective treatments. For healthcare payers, the high acquisition cost appears to be at least partly offset by reduced migraine-related healthcare resource use when compared with usual care. The comparative cost effectiveness of the newer triptans requires further elucidation from comprehensive direct comparisons.

Drotrecogin alfa (activated): a pharmacoeconomic review of its use in severe sepsis.

Drotrecogin alfa (activated) [Xigris] (DAA), the recombinant form of human activated protein C, is approved as an adjunctive therapy for patients with severe sepsis (sepsis associated with > or = 1 organ system failure [OSF]). In the international, randomised, double-blind, placebo-controlled PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) study, the absolute reduction in 28-day all-cause mortality with intravenous DAA 24 micro g/kg/h for 96 hours plus conventional care versus conventional care alone was 6.1%. Although lacking statistical power, a prospectively planned subgroup analysis of this study suggested that the absolute reduction in mortality increased in patients with a baseline APACHE (Acute Physiology and Chronic Health Evaluation) II score of > or = 25 or > or = 2 OSFs, with no clear treatment effect in patients with an APACHE II score of < or = 24 or 1 OSF. Three fully published cost-effectiveness/cost-utility models of DAA plus conventional care relative to conventional care alone adopted a national healthcare payer's and/or societal perspective in North America. The base-case (baseline) discounted incremental cost per life-year gained (LYG) with DAA for all patients with severe sepsis was $US15,801-33,300 (year of costing 2000-2002). The results were more favourable for patients with an APACHE II score of > or = 25 ($US10,833-19,723 per LYG), but considerably worse for patients with an APACHE II score of < or = 24 based on a post hoc reanalysis by the US FDA. Among several fully or partly published cost-effectiveness/cost-utility models that adopted a national healthcare payer's perspective in continental Western European countries, the base-case (baseline) undiscounted incremental cost per LYG was broadly similar and more favourable for patients with > or = 2 OSFs (9660-11,300 euros; year of costing/publication 1998/1999, 2000, 2002 or 2003) than for all patients with severe sepsis (13,436-15,071 euros) in those studies that reported both analyses. The DAA acquisition cost accounts for up to 95% of the additional cost of using the drug. In conclusion, DAA is a major advance in the treatment of severe sepsis, based on the significant mortality reduction observed in the PROWESS study. From a hospital/hospital pharmacy perspective, the drug is associated with a high acquisition cost and a small increase in other short-term costs. From a societal or national healthcare payer's perspective, however, its administration to patients who meet the PROWESS study inclusion criteria, especially individuals with more severe disease (e.g APACHE II score of > or =25 and/or > or = 2 OSFs), has a lifetime cost-effectiveness profile that compares well to that of many widely accepted therapies.

Infliximab: a pharmacoeconomic review of its use in rheumatoid arthritis.

Infliximab (Remicade), a biological disease-modifying antirheumatic drug (DMARD), binds to and inhibits the activity of tumour necrosis factor-alpha, which is thought to play an important role in the pathophysiology of rheumatoid arthritis. Intravenous infliximab plus methotrexate is recommended in patients with rheumatoid arthritis who have not achieved satisfactory disease control with adequate courses of other DMARDs. Pharmacoeconomic analyses have been based on efficacy data from the pivotal placebo-controlled Anti-Tumour Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT) trial in patients with active, refractory rheumatoid arthritis. Infliximab every 8 weeks plus methotrexate demonstrated rapid and sustainable improvements in clinical response, delayed radiographic progression, and/or improved functional status and health-related QOL compared with placebo plus methotrexate at weeks 30, 54 and 102. In cost-utility analyses of infliximab plus methotrexate conducted from a healthcare payer and/or societal perspective in the US, Europe, Portugal, Sweden and the UK, infliximab 3 mg/kg every 8 weeks plus methotrexate was associated with acceptable (<$US50,000 per discounted QALY gained) cost-utility ratios relative to methotrexate alone in patients with active, refractory rheumatoid arthritis. When only direct costs were considered, the lifetime incremental cost per discounted QALY gained with infliximab plus methotrexate relative to methotrexate alone was $US30,500-38,700 (year of costing 1998 or not reported; treatment duration 54 or 102 weeks or lifelong) in the US and Europe analyses, and euro39 500 (year of costing not reported; lifelong treatment) in the Portuguese analysis. The cost-utility ratios were more favourable when lost productivity costs or the additional benefit of infliximab on radiographic stabilisation were considered. In the Swedish and UK analyses with a 10-year time horizon, infliximab plus methotrexate for 1 or 2 years was associated with cost-utility ratios of euro28 600-56 100 (year of costing not reported) when direct costs were considered, and euro3440-48 200 when direct costs plus loss-of-productivity costs were considered. In conclusion, cost-utility analyses, which were based on modelling of data from the pivotal clinical trial of infliximab plus methotrexate, indicate that infliximab plus methotrexate is associated with acceptable cost-effectiveness ratios (<$US50,000 per discounted QALY gained) relative to methotrexate monotherapy in patients with active rheumatoid arthritis who have not responded to previous methotrexate or other DMARD therapy. The cost effectiveness of infliximab versus other DMARDs is at present unclear, but will be clarified when appropriate data from directly comparative clinical and/or pharmacoeconomic studies become available. In patients in whom adequate courses of other DMARDs have failed to achieve satisfactory disease control, infliximab plus methotrexate may prevent or delay disability, which may produce reductions in nondrug costs that can help offset its acquisition cost.

Review of the evidence for the potential impact and feasibility of substituting saturated fat in the New Zealand diet.

OBJECTIVE: To estimate the potential impact on cardiovascular health of modifying dietary intake of saturated fat across the New Zealand population, and whether this would be appropriate and feasible. METHODS: First, a literature review of meta-analyses was conducted to estimate the magnitude of reduction in risk for cardiovascular events in response to a reduction in dietary saturated fat intake (with or without substitution with other macronutrients). Second, data from the New Zealand Adult Nutrition Survey 2008/09 were used to determine whether a change to the population's dietary fat intake would be warranted and feasible. RESULTS: Five relevant meta-analyses were identified. No significant association between saturated fat intake alone and cardiovascular disease was found. However, the incidence of cardiovascular disease events was less when dietary saturated fats were replaced with polyunsaturated fats, reducing the risk of cardiovascular events by about 10%. Compared with nutritional guidelines, New Zealanders' current saturated fat intake is excessive while polyunsaturated fat intake is inadequate; both would be corrected by a substitution of 5% of daily energy intake. CONCLUSIONS: Replacing 5% of daily energy consumed as saturated fat with polyunsaturated fats would be expected to reduce cardiovascular events by about 10%. IMPLICATIONS: In order to achieve the population-wide dietary fat modifications needed to improve cardiovascular health for New Zealanders, a public health strategy (e.g. fiscal, regulatory and/or educational interventions) must be implemented. Further work is needed to establish the cost-effectiveness of the various strategies.

The feasibility of achieving low-sodium intake in diets that are also nutritious, low-cost, and have familiar meal components.

OBJECTIVE: Given the importance of high sodium diets as a risk factor for disease burden (ranked 11(th) in importance in the Global Burden of Disease Study 2010), we aimed to determine the feasibility of low-sodium diets that were also low-cost, nutritious and (for some scenarios) included familiar meals. METHODS: The mathematical technique of "linear programming" was used to model eight optimized daily diets (some with uncertainty), including some diets that contained "familiar meals" for New Zealanders or were Mediterranean-, Asian- and Pacific-style diets. Data inputs included nutrients in foods, food prices and food wastage. FINDINGS: Using nutrient recommendations for men and a cost constraint of

Cancer care coordinators: what are they and what will they cost?

Health care resources are scarce, and future funding increases are less likely than in the past; reorientation of health services to more efficient and effective delivery is as timely as ever. In this light, we consider the recent funding decision by the Government to provide $16 million over the next 4 years for cancer coordination nurses. While the intricacies of the role are still being defined, it is likely that cancer care coordinators could benefit patients in terms of access to and timeliness of care, and patient satisfaction. Our research into the role shows that many coordinating activities for cancer patients are already being done, but often in an ad hoc manner by a number of different personnel. Thus, we estimate that the likely 'true' incremental cost of cancer care coordinators is in fact relatively low when considered in opportunity cost terms because the cancer care coordinator will be able to free up time for other staff enabling them to provide care elsewhere in the health system and reduce tasks being unnecessarily repeated. The funding of cancer care coordinators is a great opportunity to improve the timeliness of care and improve the experience of patients through their cancer journey, but the success of these roles depends on the leadership provided, peer support, continual appraisal and the resources available.

Seasonal patterns of mortality in relation to social factors.

BACKGROUND: New Zealand is a temperate country with substantial excess winter mortality. We investigated whether this excess winter mortality varies with social factors. METHODS: Records from New Zealand censuses in 1981, 1986, 1991, 1996 and 2001 were each anonymously and probabilistically linked to 3 years of subsequent mortality data creating five cohort studies of the New Zealand adult population (age 30-74 years at census) each with 3 years' follow-up. Logistic regression analysis was used to model the risk of dying in winter compared to summer with winter deaths classified '1' and summer deaths '0'. There were 75,138 eligible mortality records with complete data on social variables recorded for 58,683 (78%). RESULTS: Adjusting for age, sex, census year, ethnicity and tenure, those in the lowest tertile of income were at increased risk of winter death compared to those in the highest tertile: OR 1.13 (95% CI 1.08 to 1.19). Compared to home owners, people living in rented accommodation were at greater risk of winter death: OR 1.05 (95% CI 1.01 to 1.10). Urban dwellers were also at significantly increased risk. The strongest associations were seen for infectious diseases. CONCLUSIONS: There was an increased risk of dying in winter for most New Zealanders, but more so among low-income people, those living in rented accommodation and those living in cities. Exact causal mechanisms are not known but possibly include correlated poorer health status, low indoor temperatures and household crowding.

Do effects of price discounts and nutrition education on food purchases vary by ethnicity, income and education? Results from a randomised, controlled trial.

BACKGROUND: Reducing health inequalities requires interventions that work as well, if not better, among disadvantaged populations. The aim of this study was to determine if the effects of price discounts and tailored nutrition education on supermarket food purchases (percentage energy from saturated fat and healthy foods purchased) vary by ethnicity, household income and education. METHOD: A 2×2 factorial trial of 1104 New Zealand shoppers randomised to receive a 12.5% discount on healthier foods and/or tailored nutrition education (or no intervention) for 6 months. RESULTS: There was no overall association of price discounts or nutrition education with percentage energy from saturated fat, or nutrition education with healthy food purchasing. There was an association of price discounts with healthy food purchasing (0.79 kg/week increase; 95% CI 0.43 to 1.16) that varied by ethnicity (p=0.04): European/other 1.02 kg/week (n=755; 95% CI 0.60 to 1.43); Pacific 1.20 kg/week (n=101; 95% CI 0.06 to 2.34); Maori -0.15 kg/week (n=248; 95% CI -1.10 to 0.80). This association of price discounts with healthy food purchasing did not vary by household income or education. CONCLUSIONS: While a statistically significant variation by ethnicity in the effect of price discounts on food purchasing was found, the authors caution against a causal interpretation due to likely biases (eg, attrition) that differentially affected Maori and Pacific people. The study highlights the challenges in generating valid evidence by social groups for public health interventions. The null findings for tailored nutritional education across all social groups suggest that structural interventions (such as price) may be more effective.

Borage oil in the treatment of atopic dermatitis.

Nutritional supplementation with omega-6 essential fatty acids (omega-6 EFAs) is of potential interest in the treatment of atopic dermatitis. EFAs play a vital role in skin structure and physiology. EFA deficiency replicates the symptoms of atopic dermatitis, and patients with atopic dermatitis have been reported to have imbalances in EFA levels. Although direct proof is lacking, it has been hypothesized that patients with atopic dermatitis have impaired activity of the delta-6 desaturase enzyme, affecting metabolism of linoleic acid to gamma-linolenic acid (GLA). However, to date, studies of EFA supplementation in atopic dermatitis, most commonly using evening primrose oil, have produced conflicting results. Borage oil is of interest because it contains two to three times more GLA than evening primrose oil. This review identified 12 clinical trials of oral or topical borage oil for treatment of atopic dermatitis and one preventive trial. All studies were controlled and most were randomized and double-blind, but many were small and had other methodological limitations. The results of studies of borage oil for the treatment of atopic dermatitis were highly variable, with the effect reported to be significant in five studies, insignificant in five studies, and mixed in two studies. Borage oil given to at-risk neonates did not prevent development of atopic dermatitis. However, the majority of studies showed at least a small degree of efficacy or were not able to exclude the possibility that the oil produces a small benefit. Overall, the data suggest that nutritional supplementation with borage oil is unlikely to have a major clinical effect but may be useful in some individual patients with less severe atopic dermatitis who are seeking an alternative treatment. Which patients are likely to respond cannot yet be identified. Borage oil is well tolerated in the short term but no long-term tolerability data are available.