Cost-effectiveness of second-line antihyperglycemic therapy in patients with type 2 diabetes mellitus inadequately controlled on metformin

Background:

Metformin is widely accepted as first-line pharmacotherapy for patients with type 2 diabetes mellitus when glycemic control cannot be achieved by lifestyle interventions alone. However, uncertainty exists regarding the optimal second-line therapy for patients whose diabetes is inadequately controlled by metformin monotherapy. Increased use of newer, more costly agents, along with the rising incidence of type 2 diabetes, carries significant budgetary implications for health care systems. We conducted this analysis to determine the relative costs, benefits and cost-effectiveness of options for second-line treatment of type 2 diabetes.

Methods:

We used the United Kingdom Prospective Diabetes Study Outcomes Model to forecast diabetes-related complications, quality-adjusted life-years and costs of alternative second-line therapies available in Canada for adults with type 2 diabetes inadequately controlled by metformin. We obtained clinical data from a systematic review and mixed treatment comparison meta-analysis, and we obtained information on costs and utilities from published sources. We performed extensive sensitivity analyses to test the robustness of results to variation in inputs and assumptions.

Results:

Sulphonylureas, when added to metformin, were associated with the most favourable cost-effectiveness estimate, with an incremental cost of $12 757 per quality-adjusted life-year gained, relative to continued metformin monotherapy. Treatment with other agents, including thiazolidinediones and dipeptidyl peptidase-4 inhibitors, had unfavourable cost-effectiveness estimates compared with sulphonylureas. These results were robust to extensive sensitivity analyses.

Interpretation:

For most patients with type 2 diabetes that is inadequately controlled with metformin monotherapy, the addition of a sulphonylurea represents the most cost-effective second-line therapy.Type 2 diabetes mellitus is a progressive disease typically treated in a stepwise fashion, beginning with lifestyle modification, followed by the addition of one or more oral antihyperglycemic drugs and, finally, administration of exogenous insulin. Metformin monotherapy is widely recommended as first-line pharmacotherapy,^1,2 given its favourable effects in controlling blood glucose and body weight, low risk of hypoglycemia, low cost and association with mortality benefit.³ Multiple second-line treatment strategies are available for patients in whom glycemic control has become inadequate. These approaches are typically used in addition to continued metformin therapy.^4,5 Numerous second-line agents are available in Canada, including older oral agents, such as sulphonylureas, and more recently introduced agents, such as thiazolidinediones and dipeptidyl peptidase-4 inhibitors.The large number of choices for second-line therapy has increased uncertainty regarding the optimal treatment pathway. Recent clinical practice guidelines, including those produced by the Canadian Diabetes Association¹ and by the American Diabetes Association and the European Association for the Study of Diabetes,² have suggested selecting from among several agents on the basis of their respective advantages and disadvantages. There has been a considerable increase in the use of newer, more costly oral antihyperglycemic agents, which has resulted in substantial increases in associated costs to patients and both public and private drug plans in Canada.⁴ In light of current therapeutic uncertainty, the large proportion of patients requiring second-line therapy over time^3,6 and the increasing prevalence of type 2 diabetes,⁷ the utilization and cost of second-line therapy are likely to continue to grow.Informed decisions regarding optimal prescribing and reimbursement of second-line agents by public and private health care payers requires information about clinical benefits, costs and cost-effectiveness.⁸ As part of a larger initiative to determine optimal prescribing of antihyperglycemic agents, we sought to determine the incremental cost-effectiveness of treatment with alternative second-line agents added to metformin in patients with type 2 diabetes no longer adequately controlled by metformin monotherapy.     

Cost-effectiveness of the use of low- and high-potency statins in people at low cardiovascular risk

Background:

Although statins have been shown to reduce the risk of cardiovascular events in patients at low cardiovascular risk, their absolute benefit is small in the short term, which may adversely affect cost-effectiveness. We sought to determine the long-term cost-effectiveness (beyond the duration of clinical trials) of low- and high-potency statins in patients at low cardiovascular risk and to estimate the impact on Canada’s publicly funded health care system.

Methods:

Using Markov modelling, we performed a cost-utility analysis in which we compared low-potency statins (fluvastatin, lovastatin, pravastatin and simvastatin) and high-potency statins (atorvastatin and rosuvastatin) with no statins in a simulated cohort of low-risk patients over a lifetime horizon. Model outcomes included costs (in 2010 Canadian dollars), quality-adjusted life-years (QALYs) gained and the cost per QALY gained.

Results:

Over a lifetime horizon, the cost of managing a patient at low cardiovascular risk was estimated to be about $10 100 without statins, $15 200 with low-potency statins and $16 400 with high-potency statins. The cost per QALY gained with high-potency statins (v. no statins) was $21 300; the use of low-potency statins was not considered economically attractive. These results were robust to sensitivity analyses, although their use became economically unattractive when the duration of benefit from statin use was assumed to be less than 10 years.

Interpretation:

Use of high-potency statins in patients at low cardiovascular risk was associated with a cost per QALY gained that was economically attractive by current standards, assuming that the benefit from statin use would continue for at least 10 years. However, the overall expenditure on statins would be substantial, and the ramifications of this practice should be carefully considered by policy-makers.Although statins improve survival and reduce the risk of cardiovascular events in populations at high and moderate risk,¹ their effectiveness and cost-effectiveness in low-risk populations is less certain.² This uncertainly is due in part to low-risk patients being less likely to have cardiovascular events over the short term. For instance, in the recent Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study³ — a large randomized trial comparing cardiovascular outcomes in low-risk patients randomly assigned to receive either rosuvastatin or placebo — the risk of death or nonfatal myocardial infarction over three years was 2.5% in the rosuvastatin group and 3.5% in the placebo group, which represented a large relative, but small absolute, risk reduction in cardiovascular events.Other cholesterol-lowering interventions are available, such as diet, exercise and the use of other hypolipidemic agents, but the use of statins is the only such intervention known to reduce cardiovascular risk in people with low and high blood cholesterol levels.^4–7 Thus, statins are now primarily indicated for the reduction of cardiovascular risk instead of being used mainly for the management of hypercholesterolemia.⁸With this broadening indication for use, expenditures on statins have increased and represent about 13% of total expenditures by provincial formularies in Canada.⁹ The absolute number of people at low cardiovascular risk who are taking statins has increased substantially over the last decade, driven by the large number of low-risk people in the general population.¹⁰ In addition, statins that are more effective in lowering low-density lipoprotein (LDL) cholesterol levels have become available.^3,11 These high-potency statins (atorvastatin and rosuvastatin) are substantially more expensive than low-potency statins available as generics (pravastatin, simvastatin, fluvastatin and lovastatin), although atorvastatin has recently become available as a generic in Canada.¹² Increasing costs and concerns over the absolute benefit of statins in people at low cardiovascular risk has raised concerns about the cost-effectiveness of statins in this group.We performed an incremental cost-utility analysis comparing low- and high-potency statins with no statins in patients at low cardiovascular risk in a Canadian setting. We used findings from our group’s recent systematic review of the efficacy of statins for primary prevention in low-risk people¹³ as well as observational data from a large provincial registry of patients documenting existing statin use. Our objective was to determine which strategy represents the best use of health care resources for the publicly funded health care system, and what investment would be required to fund statins.     

A qualitative investigation of smoke-free policies on hospital property

Background:

Many hospitals have adopted smoke-free policies on their property. We examined the consequences of such polices at two Canadian tertiary acute-care hospitals.

Methods:

We conducted a qualitative study using ethnographic techniques over a six-month period. Participants (n = 186) shared their perspectives on and experiences with tobacco dependence and managing the use of tobacco, as well as their impressions of the smoke-free policy. We interviewed inpatients individually from eight wards (n = 82), key policy-makers (n = 9) and support staff (n = 14) and held 16 focus groups with health care providers and ward staff (n = 81). We also reviewed ward documents relating to tobacco dependence and looked at smoking-related activities on hospital property.

Results:

Noncompliance with the policy and exposure to secondhand smoke were ongoing concerns. Peoples’ impressions of the use of tobacco varied, including divergent opinions as to whether such use was a bad habit or an addiction. Treatment for tobacco dependence and the management of symptoms of withdrawal were offered inconsistently. Participants voiced concerns over patient safety and leaving the ward to smoke.

Interpretation:

Policies mandating smoke-free hospital property have important consequences beyond noncompliance, including concerns over patient safety and disruptions to care. Without adequately available and accessible support for withdrawal from tobacco, patients will continue to face personal risk when they leave hospital property to smoke.Canadian cities and provinces have passed smoking bans with the goal of reducing people’s exposure to secondhand smoke in workplaces, public spaces and on the property adjacent to public buildings.^1,2 In response, Canadian health authorities and hospitals began implementing policies mandating smoke-free hospital property, with the goals of reducing the exposure of workers, patients and visitors to tobacco smoke while delivering a public health message about the dangers of smoking.^2–5 An additional anticipated outcome was the reduced use of tobacco among patients and staff. The impetuses for adopting smoke-free policies include public support for such legislation and the potential for litigation for exposure to second-hand smoke.^2,4Tobacco use is a modifiable risk factor associated with a variety of cancers, cardiovascular diseases and respiratory conditions.^6–11 Patients in hospital who use tobacco tend to have more surgical complications and exacerbations of acute and chronic health conditions than patients who do not use tobacco.^6–11 Any policy aimed at reducing exposure to tobacco in hospitals is well supported by evidence, as is the integration of interventions targetting tobacco dependence.¹² Unfortunately, most of the nearly five million Canadians who smoke will receive suboptimal treatment,¹³ as the routine provision of interventions for tobacco dependence in hospital settings is not a practice norm.^14–16 In smoke-free hospitals, two studies suggest minimal support is offered for withdrawal, ^17,18 and one reports an increased use of nicotine-replacement therapy after the implementation of the smoke-free policy.¹⁹Assessments of the effectiveness of smoke-free policies for hospital property tend to focus on noncompliance and related issues of enforcement.^17,20,21 Although evidence of noncompliance and litter on hospital property^2,17,20 implies ongoing exposure to tobacco smoke, half of the participating hospital sites in one study reported less exposure to tobacco smoke within hospital buildings and on the property.¹⁸ In addition, there is evidence to suggest some decline in smoking among staff.^18,19,21,22We sought to determine the consequences of policies mandating smoke-free hospital property in two Canadian acute-care hospitals by eliciting lived experiences of the people faced with enacting the policies: patients and health care providers. In addition, we elicited stories from hospital support staff and administrators regarding the policies.     

Telehealthcare for asthma: a Cochrane review

Background:

Telehealthcare has the potential to provide care for long-term conditions that are increasingly prevalent, such as asthma. We conducted a systematic review of studies of telehealthcare interventions used for the treatment of asthma to determine whether such approaches to care are effective.

Methods:

We searched the Cochrane Airways Group Specialised Register of Trials, which is derived from systematic searches of bibliographic databases including CENTRAL (the Cochrane Central Register of Controlled Trials), MEDLINE, Embase, CINAHL (Cumulative Index to Nursing and Allied Health Literature) and PsycINFO, as well as other electronic resources. We also searched registers of ongoing and unpublished trials. We were interested in studies that measured the following outcomes: quality of life, number of visits to the emergency department and number of admissions to hospital. Two reviewers identified studies for inclusion in our meta-analysis. We extracted data and used fixedeffect modelling for the meta-analyses.

Results:

We identified 21 randomized controlled trials for inclusion in our analysis. The methods of telehealthcare intervention these studies investigated were the telephone and video- and Internet-based models of care. Meta-analysis did not show a clinically important improvement in patients’ quality of life, and there was no significant change in the number of visits to the emergency department over 12 months. There was a significant reduction in the number of patients admitted to hospital once or more over 12 months (risk ratio 0.25 [95% confidence interval 0.09 to 0.66]).

Interpretation:

We found no evidence of a clinically important impact on patients’ quality of life, but telehealthcare interventions do appear to have the potential to reduce the risk of admission to hospital, particularly for patients with severe asthma. Further research is required to clarify the cost-effectiveness of models of care based on telehealthcare.There has been an increase in the prevalence of asthma in recent decades,^1–3 and the Global Initiative for Asthma estimates that 300 million people worldwide now have the disease.⁴ The highest prevalence rates (30%) are seen in economically developed countries.^5–8 There has also been an increase in the prevalence of asthma affecting both children and adults in many economically developing and transition countries.^9–11Asthma’s high burden of disease requires improvements in access to treatments.^7,12,13 Patterns of help-seeking behaviour are also relevant: delayed reporting is associated with morbidity and the need for emergency care.It is widely believed that telehealthcare interventions may help address some of the challenges posed by asthma by enabling remote delivery of care, facilitating timely access to health advice, supporting self-monitoring and medication concordance, and educating patients on avoiding triggers.^14–16 The precise role of these technologies in the management of care for people with long-term respiratory conditions needs to be established.¹⁷The objective of this study was to systematically review the effectiveness of telehealthcare interventions among people with asthma in terms of quality of life, number of visits to the emergency department and admissions to hospital for exacerbations of asthma.     

Association of practice size and pay-for-performance incentives with the quality of diabetes management in primary care

Background:

Not enough is known about the association between practice size and clinical outcomes in primary care. We examined this association between 1997 and 2005, in addition to the impact of the Quality and Outcomes Framework, a pay-for-performance incentive scheme introduced in the United Kingdom in 2004, on diabetes management.

Methods:

We conducted a retrospective open-cohort study using data from the General Practice Research Database. We enrolled 422 general practices providing care for 154 945 patients with diabetes. Our primary outcome measures were the achievement of national treatment targets for blood pressure, glycated hemoglobin (HbA_1c) levels and total cholesterol.

Results:

We saw improvements in the recording of process of care measures, prescribing and achieving intermediate outcomes in all practice sizes during the study period. We saw improvement in reaching national targets after the introduction of the Quality and Outcomes Framework. These improvements significantly exceeded the underlying trends in all practice sizes for achieving targets for cholesterol level and blood pressure, but not for HbA_1c level. In 1997 and 2005, there were no significant differences between the smallest and largest practices in achieving targets for blood pressure (1997 odds ratio [OR] 0.98, 95% confidence interval [CI] 0.82 to 1.16; 2005 OR 0.92, 95% CI 0.80 to 1.06 in 2005), cholesterol level (1997 OR 0.94, 95% CI 0.76 to 1.16; 2005 OR 1.1, 95% CI 0.97 to 1.40) and glycated hemoglobin level (1997 OR 0.79, 95% CI 0.55 to 1.14; 2005 OR 1.05, 95% CI 0.93 to 1.19).

Interpretation:

We found no evidence that size of practice is associated with the quality of diabetes management in primary care. Pay-for-performance programs appear to benefit both large and small practices to a similar extent.There is a well-established body of literature showing positive associations between volume of patients and clinical outcomes in health care, which has been documented by a systematic review.¹ However, this association has usually been examined in a limited number of discrete procedures, and most studies have involved hospital-based services rather than primary care settings.^2–5Improving our understanding of the association between volume of patients and outcomes in primary care is important for several reasons. First, most contacts with health systems occur in primary care settings, and optimizing the delivery of these services has the potential to improve the health of the population.⁶ Second, over the past decade, primary care has assumed greater responsibility for managing the growing burden of chronic disease.^7,8 Larger providers may be better resourced, through the employment of additional support staff and greater use of information technology, to deliver the systematic, structured care necessary for the effective management of chronic disease.^6,9 Third, larger providers may have been more responsive to nonfinancial and financial incentives, including pay for performance, implemented by payers aimed at improving the quality of care.^7,10 Fourth, in many countries, primary care is based around a predominance of small practices.^6,11,12 In 2006, 53% of practices in England and Wales had three or fewer family physicians.¹¹ In the same year in the United States, 30.3% of family physicians were in solo practice; 9.4% were in two-physician practices.¹²Despite the limited data available, concerns have been raised about the standards of care delivered by smaller family practices.¹³ In the United Kingdom and Canada, this has resulted in an explicit policy objective of encouraging smaller practices to amalgamate.^13,14Our study examines the associations between the size of practice and the quality of diabetes management in UK primary care settings between 1997 and 2005. We tested the hypotheses that patients attending larger family practices receive better care for diabetes and that the quality gap between larger and smaller practices has increased over the past decade. We also hypothesized that larger practices derived more benefit from the Quality and Outcomes Framework, a major pay-for-performance program in primary care introduced in 2004.     

Development of guidelines for recently arrived immigrants and refugees to Canada: Delphi consensus on selecting preventable and treatable conditions

Background:

Setting priorities is critical to ensure guidelines are relevant and acceptable to users, and that time, resources and expertise are used cost-effectively in their development. Stakeholder engagement and the use of an explicit procedure for developing recommendations are critical components in this process.

Methods:

We used a modified Delphi consensus process to select 20 high-priority conditions for guideline development. Canadian primary care practitioners who care for immigrants and refugees used criteria that emphasize inequities in health to identify clinical care gaps.

Results:

Nine infectious diseases were selected, as well as four mental health conditions, three maternal and child health issues, caries and periodontal disease, iron-deficiency anemia, diabetes and vision screening.

Interpretation:

Immigrant and refugee medicine covers the full spectrum of primary care, and although infectious disease continues to be an important area of concern, we are now seeing mental health and chronic diseases as key considerations for recently arriving immigrants and refugees.Canada consistently receives more than 239 000 immigrants yearly, up to 35 000 of whom are refugees.¹ Many arrive with similar or better self-reported health than the general Canadian population reports, a phenomenon described as the “healthy immigrant effect.”^2–6 However, subgroups of immigrants, for example refugees, face health disparities and often a greater burden of infectious diseases.^7,8 These health issues sometimes differ from the general population because of differing disease exposures, vulnerabilities, social determinants of health and access to health services before, during and after migration. Cultural and linguistic differences combined with lack of evidence-based guidelines can contribute to poor delivery of services.^9,10Community-based primary health care practitioners see most of the immigrants and refugees who arrive in Canada. This is not only because Canada’s health system centres on primary care practice, but also because people with lower socioeconomic status, language barriers and less familiarity with the system are much less likely to receive specialist care.¹¹Guideline development can be costly in terms of time, resources and expertise.¹² Setting priorities is critical, particularly when dealing with complex situations and limited resources.¹³ There is no standard algorithm on who should and how they should determine top priorities for guidelines, although burden of illness, feasibility and economic considerations are all important.¹⁴ Stakeholder engagement to ensure relevance and acceptability, and the use of an explicit procedure for developing recommendations are critical in guideline development.^15–17 We chose primary care practitioners, particularly those who care for immigrants and refugees, to help the guideline committee select conditions for clinical preventive guidelines for immigrants and refugees with a focus on the first five years of settlement.     

Hypertriglyceridemic-waist phenotype and glucose intolerance among Canadian Inuit: the International Polar Year Inuit Health Survey for Adults 2007�C2008

Background

Inuit have not experienced an epidemic in type 2 diabetes mellitus, and it has been speculated that they may be protected from obesity’s metabolic consequences. We conducted a population-based screening for diabetes among Inuit in the Canadian Arctic and evaluated the association of visceral adiposity with diabetes.

Methods

A total of 36 communities participated in the International Polar Year Inuit Health Survey. Of the 2796 Inuit households approached, 1901 (68%) participated, with 2595 participants. Households were randomly selected, and adult residents were invited to participate. Assessments included anthropometry and fasting plasma lipids and glucose, and, because of survey logistics, only 32% of participants underwent a 75 g oral glucose tolerance test. We calculated weighted prevalence estimates of metabolic risk factors for all participants.

Results

Participants’ mean age was 43.3 years; 35% were obese, 43.8% had an at-risk waist, and 25% had an elevated triglyceride level. Diabetes was identified in 12.2% of participants aged 50 years and older and in 1.9% of those younger than 50 years. A hypertriglyceridemic-waist phenotype was a strong predictor of diabetes (odds ratio [OR] 8.6, 95% confidence interval [CI] 2.1–34.6) in analyses adjusted for age, sex, region, family history of diabetes, education and use of lipid-lowering medications.

Interpretation

Metabolic risk factors were prevalent among Inuit. Our results suggest that Inuit are not protected from the metabolic consequences of obesity, and that their rate of diabetes prevalence is now comparable to that observed in the general Canadian population. Assessment of waist circumference and fasting triglyceride levels could represent an efficient means for identifying Inuit at high risk for diabetes.Indigenous people across the Arctic continue to undergo cultural transitions that affect all dimensions of life, with implications for emerging obesity and changes in patterns of disease burden.^1–3 A high prevalence of obesity among Canadian Inuit has been noted,^3,4 and yet studies have suggested that the metabolic consequences of obesity may not be as severe among Inuit as they are in predominantly Caucasian or First Nations populations.^4–6 Conversely, the prevalence of type 2 diabetes mellitus, which was noted to be rare among Inuit in early studies,^7,8 now matches or exceeds that of predominately Caucasian comparison populations in Alaska and Greenland.^9–11 However, in Canada, available reports suggest that diabetes prevalence among Inuit remains below that of the general Canadian population.^3,12Given the rapid changes in the Arctic and a lack of comprehensive and uniform screening assessments, we used the International Polar Year Inuit Health Survey for Adults 2007–2008 to assess the current prevalence of glycemia and the toll of age and adiposity on glycemia in this population. However, adiposity is heterogeneous, and simple measures of body mass index (BMI) in kg/m² and waist circumference do not measure visceral adiposity (or intra-abdominal adipose tissue), which is considered more deleterious than subcutaneous fat.¹³ Therefore, we evaluated the “hypertriglyceridemic-waist” phenotype (i.e., the presence of both an at-risk waist circumference and an elevated triglyceride level) as a proxy indicator of visceral fat.^13–15     

Higher risk of venous thrombosis associated with drospirenone-containing oral contraceptives: a population-based cohort study

Background:

Combined oral contraceptives are a common method of contraception, but they carry a risk of venous and arterial thrombosis. We assessed whether use of drospirenone was associated with an increase in thrombotic risk relative to third-generation combined oral contraceptives.

Methods:

Using computerized records of the largest health care provider in Israel, we identified all women aged 12 to 50 years for whom combined oral contraceptives had been dispensed between Jan. 1, 2002, and Dec. 31, 2008. We followed the cohort until 2009. We used Poisson regression models to estimate the crude and adjusted rate ratios for risk factors for venous thrombotic events (specifically deep vein thrombosis and pulmonary embolism) and arterial thromboic events (specifically transient ischemic attack and cerebrovascular accident). We performed multivariable analyses to compare types of contraceptives, with adjustment for the various risk factors.

Results:

We identified a total of 1017 (0.24%) venous and arterial thrombotic events among 431 223 use episodes during 819 749 woman-years of follow-up (6.33 venous events and 6.10 arterial events per 10 000 woman-years). In a multivariable model, use of drospirenone carried an increased risk of venous thrombotic events, relative to both third-generation combined oral contraceptives (rate ratio [RR] 1.43, 95% confidence interval [CI] 1.15–1.78) and second-generation combined oral contraceptives (RR 1.65, 95% CI 1.02–2.65). There was no increase in the risk of arterial thrombosis with drospirenone.

Interpretation:

Use of drospirenone-containing oral contraceptives was associated with an increased risk of deep vein thrombosis and pulmonary embolism, but not transient ischemic attack or cerebrovascular attack, relative to second- and third-generation combined oral contraceptives.Oral hormonal therapy is the preferred method of contraception, especially among young women. In the United States in 2002, 12 million women were using “the pill.”¹ In a survey of households in Great Britain conducted in 2005 and 2006, one-quarter of women aged 16 to 49 years of age were using this form of contraception.² A large variety of combined oral contraceptive preparations are available, differing in terms of estrogen dose and in terms of the dose and type of the progestin component. Among preparations currently in use, the estrogen dose ranges from 15 to 35 μg, and the progestins are second-generation, third-generation or newer. The second-generation progestins (levonorgestrel and norgestrel), which are derivatives of testosterone, have differing degrees of androgenic and estrogenic activities. The structure of these agents was modified to reduce the androgenic activity, thus producing the third-generation progestins (desogestrel, gestodene and norgestimate). Newer progestins are chlormadinone acetate, a derivative of progesterone, and drospirenone, an analogue of the aldosterone antagonist spironolactone having antimineralo-corticoid and antiandrogenic activities. Drospirenone is promoted as causing less weight gain and edema than other forms of oral contraceptives, but few well-designed studies have compared the minor adverse effects of these drugs.³The use of oral contraceptives has been reported to confer an increased risk of venous and arterial thrombotic events,^4–7 specifically an absolute risk of venous thrombosis of 6.29 per 10 000 woman-years, compared with 3.01 per 10 000 woman-years among nonusers.⁸ It has long been accepted that there is a dose–response relationship between estrogen and the risk of venous thrombotic events. Reducing the estrogen dose from 50 μg to 20–30 μg has reduced the risk.⁹ Studies published since the mid-1990s have suggested a greater risk of venous thrombotic events with third-generation oral contraceptives than with second-generation formulations,^10–13 indicating that the risk is also progestin-dependent. The pathophysiological mechanism of the risk with different progestins is unknown. A twofold increase in the risk of arterial events (specifically ischemic stroke^6,14 and myocardial infarction⁷) has been observed in case–control studies for users of second-generation pills and possibly also third-generation preparations.^7,14Conflicting information is available regarding the risk of venous and arterial thrombotic events associated with drospirenone. An increased risk of venous thromboembolism, relative to second-generation pills, has been reported recently,^8,15,16 whereas two manufacturer-sponsored studies claimed no increase in risk.^17,18 In the study reported here, we investigated the risk of venous and arterial thrombotic events among users of various oral contraceptives in a large population-based cohort.     

San Francisco Syncope Rule to predict short-term serious outcomes: a systematic review

Background:

The San Francisco Syncope Rule has been proposed as a clinical decision rule for risk stratification of patients presenting to the emergency department with syncope. It has been validated across various populations and settings. We undertook a systematic review of its accuracy in predicting short-term serious outcomes.

Methods:

We identified studies by means of systematic searches in seven electronic databases from inception to January 2011. We extracted study data in duplicate and used a bivariate random-effects model to assess the predictive accuracy and test characteristics.

Results:

We included 12 studies with a total of 5316 patients, of whom 596 (11%) experienced a serious outcome. The prevalence of serious outcomes across the studies varied between 5% and 26%. The pooled estimate of sensitivity of the San Francisco Syncope Rule was 0.87 (95% confidence interval [CI] 0.79–0.93), and the pooled estimate of specificity was 0.52 (95% CI 0.43–0.62). There was substantial between-study heterogeneity (resulting in a 95% prediction interval for sensitivity of 0.55–0.98). The probability of a serious outcome given a negative score with the San Francisco Syncope Rule was 5% or lower, and the probability was 2% or lower when the rule was applied only to patients for whom no cause of syncope was identified after initial evaluation in the emergency department. The most common cause of false-negative classification for a serious outcome was cardiac arrhythmia.

Interpretation:

The San Francisco Syncope Rule should be applied only for patients in whom no cause of syncope is evident after initial evaluation in the emergency department. Consideration of all available electrocardiograms, as well as arrhythmia monitoring, should be included in application of the San Francisco Syncope Rule. Between-study heterogeneity was likely due to inconsistent classification of arrhythmia.Syncope is defined as sudden, transient loss of consciousness with the inability to maintain postural tone, followed by spontaneous recovery and return to pre-existing neurologic function.^1–5 It represents a common clinical problem, accounting for 1%–3% of visits to the emergency department and up to 6% of admissions to acute care hospitals.^6,7Assessment of syncope in patients presenting to the emergency department is challenging because of the heterogeneity of underlying pathophysiologic processes and diseases. Although many underlying causes of syncope are benign, others are associated with substantial morbidity or mortality, including cardiac arrhythmia, myocardial infarction, pulmonary embolism and occult hemorrhage.^4,8–10 Consequently, a considerable proportion of patients with benign causes of syncope are admitted for inpatient evaluation.^11,12 Therefore, risk stratification that allows for the safe discharge of patients at low risk of a serious outcome is important for efficient management of patients in emergency departments and for reduction of costs associated with unnecessary diagnostic workup.^12,13In recent years, various prediction rules based on the probability of an adverse outcome after an episode of syncope have been proposed.^3,14–16 However, the San Francisco Syncope Rule, derived by Quinn and colleagues in 2004,³ is the only prediction rule for serious outcomes that has been validated in a variety of populations and settings. This simple, five-step clinical decision rule is intended to identify patients at low risk of short-term serious outcomes^3,17 (Box 1).

Box 1:

San Francisco Syncope Rule³

AimPrediction of short-term (within 30 days) serious outcomes in patients presenting to the emergency department with syncope.DefinitionsSyncope: Transient loss of consciousness with return to baseline neurologic function. Trauma-associated and alcohol- or drug-related loss of consciousness excluded, as is definite seizure or altered mental status.Serious outcome: Death, myocardial infarction, arrhythmia, pulmonary embolism, stroke, subarachnoid hemorrhage, significant hemorrhage or any condition causing or likely to cause a return visit to the emergency department and admission to hospital for a related event.Selection of predictors in multivariable analysis: Fifty predictor variables were evaluated for significant associations with a serious outcome and combined to create a minimal set of predictors that are highly sensitive and specific for prediction of a serious outcome.Clinical decision ruleFive risk factors, indicated by the mnemonic “CHESS,” were identified to predict patients at high risk of a serious outcome:

• C – History of congestive heart failure
• H – Hematocrit < 30%
• E – Abnormal findings on 12-lead ECG or cardiac monitoring¹⁷ (new changes or nonsinus rhythm)
• S – History of shortness of breath
• S – Systolic blood pressure < 90 mm Hg at triage

Note: ECG = electrocardiogram.The aim of this study was to conduct a systematic review and meta-analysis of the accuracy of the San Francisco Syncope Rule in predicting short-term serious outcome for patients presenting to the emergency department with syncope.     

Risk of herpes zoster among patients with chronic obstructive pulmonary disease: a population-based study

Background

Systemic inflammation and dysregulated immune function in chronic obstructive pulmonary disease (COPD) is hypothesized to predispose patients to development of herpes zoster. However, the risk of herpes zoster among patients with COPD is undocumented. We therefore aimed to investigate the risk of herpes zoster among patients with COPD.

Methods

We conducted a cohort study using data from the Taiwan Longitudinal Health Insurance Database. We performed Cox regressions to compare the hazard ratio (HR) of herpes zoster in the COPD cohort and in an age- and sex-matched comparison cohort. We divided the patients with COPD into three groups according to use of steroid medications and performed a further analysis to examine the risk of herpes zoster.

Results

The study included 8486 patients with COPD and 33 944 matched control patients. After adjustment for potential confounding factors, patients with COPD were more likely to have incidents of herpes zoster (adjusted HR 1.68, 95% confidence interval [CI] 1.45–1.95). When compared with the comparison cohort, the adjusted HR of herpes zoster was 1.67 (95% CI 1.43–1.96) for patients with COPD not taking steroid medications. The adjusted HR of herpes zoster was slightly greater for patients with COPD using inhaled corticosteroids only (adjusted HR 2.09, 95% CI 1.38–3.16) and was greatest for patients with COPD using oral steroids (adjusted HR 3.00, 95% CI 2.40–3.75).

Interpretation

Patients with COPD were at increased risk of herpes zoster relative to the general population. The relative risk of herpes zoster was greatest for patients with COPD using oral steroids.Herpes zoster is caused by a reactivation of latent varicella-zoster virus residing in sensory ganglia after an earlier episode of varicella.¹ Herpes zoster is characterized by a painful vesicular dermatomal rash. It is commonly complicated with chronic pain (postherpetic neuralgia), resulting in reduced quality of life and functional disability to a degree comparable to that experienced by patients with congestive heart failure, diabetes mellitus and major depression.^1,2 Patients with herpes zoster experience more substantial role limitations resulting from emotional and physical problems than do patients with congestive heart failure or diabetes.³ Pain scores for postherpetic neuralgia have been shown to be as high as those for chronic pain from osteoarthritis and rheumatoid arthritis.³ Although aging is the most well-known risk factor for herpes zoster, people with diseases associated with impaired immunity, such as malignancy, HIV infection, diabetes and rheumatic diseases, are also at higher risk for herpes zoster.^4,5Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation that is associated with an abnormal inflammatory response by the small airways and alveoli to inhaled particles and pollutants.⁶ Disruption of local defence systems (e.g., damage to the innate immune system, impaired mucociliary clearance) predispose patients with COPD to respiratory tract infections. Each infection can cause exacerbation of COPD and further deterioration of lung function, which in turn increase predisposition to infection.^7,8There is increasing evidence that COPD is an autoimmune disease, with chronic systemic inflammation involving more than just the airways and lungs.⁶ Given that various immune-mediated diseases (e.g., rheumatoid arthritis, inflammatory bowel disease) have been reported to be associated with an increased risk of herpes zoster,^4,9,10 it is reasonable to hypothesize that the immune dysregulation found in COPD may put patients at higher risk of developing herpes zoster. In addition, inhaled or systemic corticosteroids used for management of COPD can increase susceptibility to herpes zoster by suppressing normal immune function.¹¹ However, data are limited regarding the risk of herpes zoster among patients with COPD.The goal of our study was to investigate whether patients with COPD have a higher incidence of herpes zoster than the general population. In addition, we aimed to examine the risk for herpes zoster with and without steroid therapy among patients with COPD relative to the general population.     

The potential economic impact of restricted access to angiotensin-receptor blockers

Background

The use of angiotensin-receptor blockers increased by more than 4000% in Canada from 1996 to 2006. The benefit of these medications over angiotensin-converting-enzyme (ACE) inhibitors has not been proven aside from a reduction in dry cough. We estimated the potential cost savings that might have been achieved had access to angiotensin-receptor blockers been restricted.

Methods

We performed a cost-minimization analysis with a decision-tree model using a societal perspective over a one-year period. Sources of data for model parameters included IMS Health Canada data collected from one-third of all retail pharmacies for the cost and use of angiotensin-receptor blockers and ACE inhibitors in each province, as well as published studies for administrative costs and incidence of dry cough. We used Monte Carlo simulations with 10 000 iterations to test the impact of several model parameters (e.g., drug prices, administrative costs and the incidence of dry cough). All data are in 2006 Canadian dollars.

Results

A policy that would have restricted access to angiotensin-receptor blockers might have saved more than $77 million in Canada in 2006. The simulations yielded similar savings for the year (mean $58.3 million, 95% confidence interval $29.3 million to $90.8 million). Every simulation showed a cost savings.

Interpretation

Had access to angiotensin-receptor blockers been restricted, the potential cost savings to the Canadian health care system might have been more than $77 million in 2006, likely without any adverse effect on cardiovascular health.Costs of cardiovascular drugs in Canada increased by more than 200% from 1996 to 2006. The use of angiotensin-receptor blockers grew at an especially high rate, rising by more than 4000% during that period.¹ Such an increase in the use of these agents is not strongly supported by evidence.¹ Although angiotensin-receptor blockers were effective in reducing mortality and morbidity associated with hypertension in one large trial, patients in the control group were not given an angiotensin-converting-enzyme (ACE) inhibitor.² Instead, they received atenolol, a β-blocker, a drug class whose use is increasingly being questioned in the management of high blood pressure uncomplicated by prior myocardial infarction, heart failure or tachyarrhythmia.^3,4 Although angiotensin-receptor blockers are not associated with dry cough, a side effect reported by 5%–35% of patients taking ACE inhibitors,⁵ this side effect is benign and fully reversible once the drug is stopped. Meta-analyses that included several randomized trials failed to show superiority of angiotensin-receptor blockers over ACE inhibitors for the treatment of hypertension,⁶ heart failure⁷ or the secondary prevention of coronary artery disease.⁸Innovative policies are needed to offset the ever-increasing costs of cardiovascular drugs in Canada. Currently, British Columbia is the only province that restricts access to angiotensin-receptor blockers. Given that these agents can safely be substituted by ACE inhibitors and still yield similar clinical outcomes,^6–8 restricting their access is expected to lead to cost savings without adversely affecting patient heath. We estimated the potential cost savings that might have been achieved had access to angiotensin-receptor blockers been restricted in Canada in 2006.     

Recent epidemiologic trends of diabetes mellitus among status Aboriginal adults

Background:

Little is known about longitudinal trends in diabetes mellitus among Aboriginal people in Canada. We compared the incidence and prevalence of diabetes, and its impact on mortality, among status Aboriginal adults and adults in the general population between 1995 and 2007.

Methods:

We examined de-identified data from Alberta Health and Wellness administrative databases for status Aboriginal people (First Nations and Inuit people with treaty status) and members of the general public aged 20 years and older who received a diagnosis of diabetes mellitus from Apr. 1, 1995, to Mar. 31, 2007. We calculated the incidence and prevalence of diabetes and mortality rate ratios by sex and ethnicity in 2007. We examined the average relative changes per year for longitudinal trends.

Results:

The average relative change per year in the prevalence of diabetes showed a smaller increase over time in the Aboriginal population than in the general population (2.39 v. 4.09, p < 0.001). A similar finding was observed for the incidence of diabetes. In the Aboriginal population, we found that the increase in the average relative change per year was greater among men than among women (3.13 v. 1.88 for prevalence, p < 0.001; 2.60 v. 0.02 for incidence, p = 0.001). Mortality among people with diabetes decreased over time to a similar extent in both populations. Among people without diabetes, mortality decreased in the general population but was unchanged in the Aboriginal population (−1.92 v. 0.11, p = 0.04). Overall, mortality was higher in the Aboriginal population than in the general population regardless of diabetes status.

Interpretation:

The increases in the incidence and prevalence of diabetes over the study period appeared to be slower in the status Aboriginal population than in the general population in Alberta, although the overall rates were higher in the Aboriginal population. Mortality decreased among people with diabetes in both populations but was higher overall in the Aboriginal population regardless of diabetes status.The health of Aboriginal people in Canada is generally poorer than their non-Aboriginal counterparts, and diabetes mellitus is a significant contributor.^1,2 Studies have shown that type 2 diabetes and its complications occur at rates two to five times higher in Canada’s Aboriginal population than in the general population.^3–7 In response, diverse diabetes programs have materialized, including various community-based prevention and screening projects.^8–10 The federally funded Aboriginal Diabetes Initiative was created to emphasize health promotion and diabetes prevention.¹¹ In addition, numerous Aboriginal communities have established their own diabetes and health programs.¹²Accurate diabetes surveillance data are essential for governments and health care organizations to plan health care delivery and translate knowledge into policy and funding decisions. However, research into the longitudinal trends of diabetes in Aboriginal populations is scarce. For the most part, data have come from small, community-based studies and self-reported surveys. Population-based studies of primary data are few and have been conducted only for limited periods. Even less is known about outcomes, mortality in particular, among Aboriginal individuals with diabetes.The use of administrative data is becoming more common for tracking diabetes in Canada.¹³ The National Diabetes Surveillance System uses administrative health data to document the burden of the disease, but it has little information on Aboriginal people. Dyck and colleagues recently used the methodology of the National Diabetes Surveillance System to examine the incidence and prevalence of diabetes among Aboriginal people in the province of Saskatchewan,¹⁴ and similar analyses were conducted in Manitoba and Ontario.^15,16As part of the Alberta Diabetes Surveillance System, we conducted this study to compare the incidence and prevalence of diabetes among people 20 years and older in the status Aboriginal population (First Nations and Inuit people with treaty status) and the general population in the province of Alberta between 1995 and 2007. We also compared trends in mortality in the two populations among people with and without diabetes.     

Tobacco, alcohol and illicit drug use among Aboriginal youth living off-reserve: results from the Youth Smoking Survey

Background

Despite the high prevalence of smoking among Aboriginal youth, there is a paucity of research related to tobacco use and other risk behaviours among Aboriginal youth living off-reserve in Canada. We used data from the national Youth Smoking Survey to characterize non-traditional tobacco use, exposure to second-hand smoke, and alcohol and drug use among Aboriginal youth living off-reserve. We examined whether these youth were at increased health risk compared with non-Aboriginal youth.

Methods

We examined cigarette smoking behaviour, use of other tobacco products, use of alcohol and other drugs, and exposure to second-hand smoke among 2620 Aboriginal youth living off-reserve and 26 223 non-Aboriginal youth in grades 9 to 12 who participated in the 2008/09 Youth Smoking Survey.

Results

The prevalence of current smoking among the Aboriginal youth was more than double that among non-Aboriginal youth (24.9% v. 10.4%). Aboriginal youth also had a higher prevalence of regular exposure to second-hand smoke at home (37.3% v. 19.7%) and in cars (51.0% v. 30.3%). Aboriginal youth were more likely than non-Aboriginal youth to be current smokers, to be regularly exposed to second-hand smoke, to have tried marijuana and other illicit drugs, and to engage in binge drinking. They were less likely than non-Aboriginal youth to have tried to quit smoking.

Interpretation

Current national estimates of smoking, and alcohol and illicit drug use among youth underestimate the prevalence of these behaviours among Aboriginal youth living off-reserve. Our findings highlight the need for culturally appropriate prevention and cessation policies and programs for this at-risk population.Compared with the general population in Canada, Aboriginal youth start smoking earlier¹ and have a higher prevalence of smoking,^1–3 with female Aboriginals at greatest risk.¹ Research has also shown that Aboriginal youth have high rates of binge drinking¹ and are more likely than non-Aboriginal youth to use marijuana.⁴Despite the high prevalence of smoking among Aboriginal youth in Canada, there is a paucity of research related to their patterns of tobacco use, especially among Aboriginals living off-reserve.⁵ Most Aboriginals in Canada live off-reserve,⁶ and those 15 years of age and older are more likely than non-Aboriginals to have chronic health conditions, to drink heavily and to smoke.⁷ Given that the Canadian Tobacco Control Strategy emphasizes targeting youth, young adults, First Nations, Inuit and other Aboriginal groups,⁸ a better understanding of tobacco use among Aboriginal youth living off-reserve is required.We conducted this study to examine patterns of tobacco use, exposure to second-hand smoke and the prevalence of alcohol and other drug use among Aboriginal youth living off-reserve. We compared these data with those for non-Aboriginal youth using nationally representative data from the 2008/09 Youth Smoking Survey.     

The cost-effectiveness of screening for colorectal cancer

Background

Published decision analyses show that screening for colorectal cancer is cost-effective. However, because of the number of tests available, the optimal screening strategy in Canada is unknown. We estimated the incremental cost-effectiveness of 10 strategies for colorectal cancer screening, as well as no screening, incorporating quality of life, noncompliance and data on the costs and benefits of chemotherapy.

Methods

We used a probabilistic Markov model to estimate the costs and quality-adjusted life expectancy of 50-year-old average-risk Canadians without screening and with screening by each test. We populated the model with data from the published literature. We calculated costs from the perspective of a third-party payer, with inflation to 2007 Canadian dollars.

Results

Of the 10 strategies considered, we focused on three tests currently being used for population screening in some Canadian provinces: low-sensitivity guaiac fecal occult blood test, performed annually; fecal immunochemical test, performed annually; and colonoscopy, performed every 10 years. These strategies reduced the incidence of colorectal cancer by 44%, 65% and 81%, and mortality by 55%, 74% and 83%, respectively, compared with no screening. These strategies generated incremental cost-effectiveness ratios of $9159, $611 and $6133 per quality-adjusted life year, respectively. The findings were robust to probabilistic sensitivity analysis. Colonoscopy every 10 years yielded the greatest net health benefit.

Interpretation

Screening for colorectal cancer is cost-effective over conventional levels of willingness to pay. Annual high-sensitivity fecal occult blood testing, such as a fecal immunochemical test, or colonoscopy every 10 years offer the best value for the money in Canada.Colorectal cancer is the fourth most common cancer diagnosed in North America and the second leading cause of cancer death.^1,2 An effective population-based screening program is likely to decrease mortality associated with colorectal cancer^3–6 through earlier detection and to decrease incidence by allowing removal of precursor colorectal adenomas.^7,8 Professional societies and government-sponsored committees have released guidelines for screening of average-risk individuals for colorectal cancer by means of several testing options.^9–12 These tests vary in sensitivity, specificity, risk, costs and availability. With no published studies designed to directly compare screening strategies, decision analysis is a useful technique for examining the relative cost-effectiveness of these strategies.^13–21 Previous studies have shown that screening for colorectal cancer is cost-effective at conventional levels of willingness to pay, but no single strategy has emerged as clinically superior or economically dominant.²² The interpretations of economic evaluations in this area have been limited because investigators have not simultaneously accounted for the positive effects of screening on quality of life, the effect of noncompliance with screening schedules, and the greater efficacy and cost of more modern chemotherapy regimens for colorectal cancer. Furthermore, no study has included all of the strategies recommended in the 2008 guidelines of the US Multi-Society Task Force on Colorectal Cancer.¹⁰Our objective was to estimate the incremental cost-effectiveness of 10 strategies for colorectal cancer screening, as well as the absence of a screening program. The current study is more complete than earlier studies because we included information on quality of life, noncompliance with screening and the efficacy observed in recent randomized trials of colorectal cancer treatments. The complete model is available in Appendix 1 (available at www.cmaj.ca/cgi/content/full/cmaj.090845/DC1). This article focuses on the comparison of no screening and three screening strategies:¹ low-sensitivity guaiac fecal occult blood test,² performed annually; fecal immunochemical test,³ performed annually; and colonoscopy, performed every 10 years. These three tests are currently being used or considered for population-based screening of average-risk individuals in some Canadian provinces.     

Cost-effectiveness of self-monitoring of blood glucose in patients with type 2 diabetes mellitus managed without insulin

Background

The benefits of self-monitoring blood glucose levels are unclear in patients with type 2 diabetes mellitus who do not use insulin, but there are considerable costs. We sought to determine the cost effectiveness of self-monitoring for patients with type 2 diabetes not using insulin.

Methods

We performed an incremental cost-effectiveness analysis of the self-monitoring of blood glucose in adults with type 2 diabetes not taking insulin. We used the United Kingdom Prospective Diabetes Study (UKPDS) model to forecast diabetes-related complications, corresponding quality-adjusted life years and costs. Clinical data were obtained from a systematic review comparing self-monitoring with no self-monitoring. Costs and utility decrements were derived from published sources. We performed sensitivity analyses to examine the robustness of the results.

Results

Based on a clinically modest reduction in hemoglobin A_1C of 0.25% (95% confidence interval 0.15–0.36) estimated from the systematic review, the UKPDS model predicted that self-monitoring performed 7 or more times per week reduced the lifetime incidence of diabetes-related complications compared with no self-monitoring, albeit at a higher cost (incremental cost per quality-adjusted life year $113 643). The results were largely unchanged in the sensitivity analysis, although the incremental cost per quality-adjusted life year fell within widely cited cost-effectiveness thresholds when testing frequency or the price per test strip was substantially reduced from the current levels.

Interpretation

For most patients with type 2 diabetes not using insulin, use of blood glucose test strips for frequent self-monitoring (≥ 7 times per week) is unlikely to represent efficient use of finite health care resources, although periodic testing (e.g., 1 or 2 times per week) may be cost-effective. Reduced test strip price would likely also improve cost-effectiveness.Self-monitoring of blood glucose in patients with diabetes who use insulin may contribute to improved glycemic control and reduced hypoglycemia by allowing for self-adjustments in insulin dose to be made based on meter readings.¹ Self-monitoring may also allow for appropriate changes in diet and physical activity to be made. However, the benefits of self-monitoring of blood glucose for patients not using insulin are less clear. Hypoglycemia is less frequent in this population² and is confined mainly to those taking secretagogues. The degree to which patients can adjust the dose of oral antidiabetes drugs in response to readings is limited.Nevertheless, self-monitoring of blood glucose is routinely recommended for patients who are not using insulin.¹ This results in major investments in this technology by patients and payers.³ In 2006, $250 million was spent on blood glucose test strips in 8 publicly funded drugs plans in Newfoundland and Labrador, Nova Scotia, Quebec, Ontario, Manitoba, Saskatchewan and British Columbia, while over $120 million was spent in privately funded drug plans in Canada.⁴ In some publicly funded drug plans in Canada, blood glucose test strips are among the top 5 classes in terms of total expenditure,⁵ with costs exceeding those for all oral antidiabetes drugs combined.^4,6 It is estimated that more than 50% of the total expenditure on blood glucose test strips is for patients with type 2 diabetes who are not using insulin.³ Costs related to test strips are expected to rise steadily^5,7 because of the increasing prevalence of type 2 diabetes.⁸Decisions about the prescribing and reimbursement of blood glucose test strips require consideration of information about the costs and clinical benefits.^9,10 As part of a larger initiative to determine the optimal use of this technology, we sought to determine the cost-effectiveness of self-monitoring of blood glucose for patients with type 2 diabetes who do not use insulin, based on data from our systematic review¹¹ of the available clinical evidence.     

Use of angiotensin-converting-enzyme inhibitors or angiotensin-receptor blockers and cancer risk: a meta-analysis of observational studies

Background:

Epidemiologic studies have reported inconsistent findings regarding the association between the use of angiotensin-converting-enzyme (ACE) inhibitors or angiotensin-receptor blockers and the risk of cancer. We performed a meta-analysis of observational studies to assess the association.

Methods:

We searched MEDLINE, EMBASE and the Cochrane Library to identify studies through January 2011. Two evaluators independently reviewed and selected articles of cohort and case–control studies on the basis of predetermined selection criteria.

Results:

Of 3970 screened articles, 12 cohort studies and 16 case–control studies were selected for analysis. We found no significant association between the use of ACE inhibitors or angiotensin-receptor blockers and the overall risk of cancer (relative risk [RR] 0.96, 95% confidence interval [CI] 0.90–1.03). We found a decreased risk of cancer associated with use of either medication when we restricted the analyses to cohort and nested case–control studies (RR 0.90, 95% CI 0.83–0.97) or to studies with long-term follow-up of more than five years (RR 0.89, 95% CI 0.83–0.96). In the subgroup meta-analyses by cancer site, a decreased risk was identified for esophageal cancer, whereas an increased risk was found for melanoma and kidney cancer.

Interpretation:

No significant association was found between the use of ACE inhibitors or angiotensin-receptor blockers and overall risk of cancer. A possible beneficial effect associated with use of either medication was suggested in sensitivity analyses, including those of studies with long-term follow-up. Large randomized controlled trials with long-term follow-up are needed to specifically test the effect of each of these medications on the risk of cancer.Recent meta-analyses have shown a possible increased risk of cancer associated with angiotensin-receptor blockers used alone or combined with angiotensin-converting-enzyme (ACE) inhibitors.^1,2 Despite the strong internal validity of randomized controlled trials (RCTs) used in prior meta-analyses, it is difficult to interpret these results because of the short duration of follow-up for cancer detection.³ A previous retrospective cohort study with a mean follow-up of 6.6 years showed that the use of ACE inhibitors was associated with a significantly decreased risk of overall cancer, and cancer of the lung, breast and female reproductive organs and smoking-related cancers.⁴ Despite the inconsistent results reported by previous observational studies regarding this issue,^4–35 we conducted a meta-analysis of cohort and case–control studies to assess the association between use of these medications and the risk of cancer.     

Incidence of bleeding from gastroduodenal ulcers in patients with end-stage renal disease receiving hemodialysis

Background:

Few large population-based studies have compared the incidence of bleeding of gastroduodenal ulcers between patients with and without end-stage renal disease. We investigated the association between ulcer bleeding and end-stage renal disease in patients receiving hemodialysis, and we sought to identify risk factors for ulcer bleeding.

Methods:

We performed a nationwide seven-year population study using data from the National Health Insurance Research Database in Taiwan. We identified 36 474 patients with end-stage renal disease who were receiving hemodialysis, 6320 patients with chronic kidney disease and 36 034 controls matched for age, sex and medication use. We performed log-rank testing to analyze differences in survival time without ulcer bleeding among the three groups. We performed Cox proportional hazard regressions to evaluate the risk factors for ulcer bleeding among the three groups and to identify risk factors in patients receiving hemodialysis.

Results:

Patients receiving hemodialysis and those with chronic kidney disease had a significantly higher incidence of ulcer bleeding than controls had (p < 0.001). Hemodialysis (hazard ratio [HR] 5.24, 95% confidence interval [CI] 4.67–5.86) and chronic kidney disease (HR 1.95, 95% CI 1.62–2.35) were independently associated with an increased risk of ulcer bleeding. Diabetes mellitus, coronary artery disease, cirrhosis and use of nonsteroidal anti-inflammatory drugs were risk factors for ulcer bleeding in patients with end-stage renal disease who were receiving hemodialysis

Interpretation:

Patients with end-stage renal disease who are receiving hemodialysis had a high risk of ulcer bleeding. Diabetes mellitus, coronary artery disease, cirrhosis and the use of nonsteroidal anti-inflammatory drugs were important risk factors for ulcer bleeding in these patients.Taiwan has the highest incidence and prevalence of end-stage renal disease in the world.¹ The approximately 40 000 patients with end-stage renal disease consume 7% (about NT$26 billion) of Taiwan’s health insurance budget for dialysis treatment, especially because 90% of these patients receive hemodialysis rather than peritoneal dialysis.² In Western and Asian countries, previous studies have suggested that the prevalence of peptic ulcer disease among patients with end-stage renal disease is not higher than in the general population;^3–5 however, recent reports show a higher prevalence among patients receiving long-term hemodialysis^6,7 and a higher rate of bleeding after the development of ulcers in these patients.⁸The pathogenesis and risk factors for ulcers or ulcer bleeding in patients with end-stage renal disease are unclear.^9–11 We performed a nationwide population-based cohort study to investigate the association between hemodialysis and bleeding of gastroduodeanl ulcers and to identify the risk factors for ulcer bleeding in patients with end-stage renal disease.     

Effectiveness of disease-management programs for improving diabetes care: a meta-analysis

Background

We conducted a meta-analysis of randomized controlled trials to assess the effectiveness of disease-management programs for improving glycemic control in adults with diabetes mellitus and to study which components of programs are associated with their effectiveness.

Methods

We searched several databases for studies published up to December 2009. We included randomized controlled trials involving adults with type 1 or 2 diabetes that evaluated the effect of disease-management programs on glycated hemoglobin (hemoglobin A_1C) concentrations. We performed a meta-regression analysis to determine the effective components of the programs.

Results

We included 41 randomized controlled trials in our review. Across these trials, disease-management programs resulted in a significant reduction in hemoglobin A_1C levels (pooled standardized mean difference between intervention and control groups −0.38 [95% confidence interval −0.47 to −0.29], which corresponds to an absolute mean difference of 0.51%). The finding was robust in the sensitivity analyses based on quality assessment. Programs in which the disease manager was able to start or modify treatment with or without prior approval from the primary care physician resulted in a greater improvement in hemoglobin A_1C levels (standardized mean difference −0.60 v. −0.28 in trials with no approval to do so; p < 0.001). Programs with a moderate or high frequency of contact reported a significant reduction in hemoglobin A_1C levels compared with usual care; nevertheless, only programs with a high frequency of contact led to a significantly greater reduction compared with low-frequency contact programs (standardized mean difference −0.56 v. −0.30, p = 0.03).

Interpretation

Disease-management programs had a clinically moderate but significant impact on hemoglobin A_1C levels among adults with diabetes. Effective components of programs were a high frequency of patient contact and the ability for disease managers to adjust treatment with or without prior physician approval.Despite well-established recommendations for diabetes care,^1–3 quality of care still needs to be improved. Although many nonpharmacologic strategies (patient education, psychological intervention, dietary education, self-monitoring and telemedicine) have been developed, their effectiveness is still unclear.^4–6 “Disease management” is a structured, multi-faceted intervention that includes several of the above-mentioned components. In two recent meta-analyses, disease management was associated with an improvement in glycemic control, as assessed by a mean reduction in hemoglobin A_1C concentration of 0.52% and 0.81%.^7,8 Disease management seems to be more effective than single strategies such as clinician education, patient education or promotion of self-management.⁷Because disease-management programs are heterogeneous, the effective components need to be identified to improve program implementation. Previous studies have evaluated the efficacy of some program components.^7,8 Independent medication changes by the disease manager appear to be particularly effective.⁷ However, other important factors such as the intensity of the intervention have not been previously evaluated.We conducted a meta-analysis of randomized controlled trials (RCTs) involving adults with type 1 or 2 diabetes mellitus that evaluated the effect of disease-management programs on hemoglobin A_1C levels. We determined the effective components of the programs, considering both the type of component and the intensity of the intervention.