Fracture types and risk factors in men with prostate cancer on androgen deprivation therapy: a matched cohort study of 19,079 men.

PURPOSE: Accumulating evidence shows that androgen deprivation therapy is associated with osteoporosis and fragility fractures of the spine, hip and wrist. One study suggested that androgen deprivation therapy may also be associated with nonfragility fractures in older men. Whether other clinical risk factors independently increase the risk of fractures is not certain. MATERIALS AND METHODS: Using linked administrative databases in Ontario, Canada, we matched 19,079 men 66 years old or older with prostate cancer with at least 6 months of continuous androgen deprivation therapy or bilateral orchiectomy with men with prostate cancer who had never received androgen deprivation. Matching variables were age, prior cancer treatment, diagnosis year, comorbidity, medication, prior fractures and socioeconomic variables. Primary outcomes were a typical fragility fracture of the spine, hip or wrist and any fracture. Independent predictors of fracture outcomes were assessed with Cox proportional hazards models. RESULTS: At a mean 6.47-year followup androgen deprivation therapy was associated with an increased risk of fragility fracture (HR 1.65, 95% CI 1.53-1.78) and any fracture (HR 1.46, 95% CI 1.39-1.54). Independent predictors of fragility and any fracture were increasing age, prior bone thinning medications, chronic kidney disease, prior dementia, prior fragility fracture and prior osteoporosis diagnosis or treatment (p <0.05). CONCLUSIONS: Continuous androgen deprivation therapy for at least 6 months is associated with an increased risk of fracture. Increasing age, prior osteoporotic fracture and dementia are important clinical factors that may warrant greater consideration of anti-osteoporotic therapy in these men.

Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study.

OBJECTIVE: To characterise whether some selective serotonin reuptake inhibitor (SSRI) antidepressants reduce tamoxifen's effectiveness by inhibiting its bioactivation by cytochrome P450 2D6 (CYP2D6). DESIGN: Population based cohort study. PARTICIPANTS: Women living in Ontario aged 66 years or older treated with tamoxifen for breast cancer between 1993 and 2005 who had overlapping treatment with a single SSRI. MAIN OUTCOME MEASURES: Risk of death from breast cancer after completion of tamoxifen treatment, as a function of the proportion of time on tamoxifen during which each SSRI had been co-prescribed. RESULTS: Of 2430 women treated with tamoxifen and a single SSRI, 374 (15.4%) died of breast cancer during follow-up (mean follow-up 2.38 years, SD 2.59). After adjustment for age, duration of tamoxifen treatment, and other potential confounders, absolute increases of 25%, 50%, and 75% in the proportion of time on tamoxifen with overlapping use of paroxetine (an irreversible inhibitor of CYP2D6) were associated with 24%, 54%, and 91% increases in the risk of death from breast cancer, respectively (P<0.05 for each comparison). By contrast, no such risk was seen with other antidepressants. We estimate that use of paroxetine for 41% of tamoxifen treatment (the median overlap in our sample) would result in one additional breast cancer death within five years of cessation of tamoxifen for every 19.7 (95% confidence interval 12.5 to 46.3) patients so treated; the risk with more extensive overlap would be greater. CONCLUSION: Paroxetine use during tamoxifen treatment is associated with an increased risk of death from breast cancer, supporting the hypothesis that paroxetine can reduce or abolish the benefit of tamoxifen in women with breast cancer.

Impact of androgen deprivation therapy on cardiovascular disease and diabetes.

PURPOSE Use of androgen deprivation therapy (ADT) may be associated with an increased risk of diabetes mellitus but the risk of both acute myocardial infarction (AMI) and cardiovascular mortality remain controversial because few outcomes and conflicting findings have been reported. We sought to clarify whether ADT is associated with these outcomes in a large, representative cohort. METHODS Using linked administrative databases in Ontario, Canada, men age 66 years or older with prostate cancer given continuous ADT for at least 6 months or who underwent bilateral orchiectomy (n = 19,079) were matched with men with prostate cancer who had never received ADT. Treated and untreated groups were matched 1:1 (ie, hard-matched) on age, prior cancer treatment, and year of diagnosis and propensity-matched on comorbidities, medications, cardiovascular risk factors, prior fractures, and socioeconomic variables. Primary outcomes were development of AMI, sudden cardiac death, and diabetes. Fragility fracture was also examined. Results The cohort was observed for a mean of 6.47 years. In time-to-event analyses, ADT use was associated with an increased risk of diabetes (hazard ratio [HR], 1.16; 95% CI, 1.11 to 1.21) and fragility fracture (HR, 1.65; 95% CI, 1.53 to 1.77) but not with AMI (HR, 0.91; 95% CI, 0.84 to 1.00) or sudden cardiac death (HR, 0.96; 95% CI, 0.83 to 1.10). Increasing duration of ADT was associated with an excess risk of fragility fractures and diabetes but not cardiac outcomes. CONCLUSION Continuous ADT use for at least 6 months in older men is associated with an increased risk of diabetes and fragility fracture but not AMI or sudden cardiac death.

Angiotensin inhibition in renovascular disease: a population-based cohort study.

BACKGROUND: Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers effectively reduce blood pressure in patients with renovascular disease (RVD); yet, randomized cardiovascular prevention trials of these drugs typically exclude individuals with this condition. PATIENTS AND METHODS: We studied the association of renin-angiotensin system inhibition with prognosis in a population-based cohort comprising 3,570 patients with RVD in Ontario, Canada; slightly more than half (n = 1,857, 53%) were prescribed angiotensin inhibitors. The primary outcome was the composite of death, myocardial infarction, or stroke. Secondary outcomes included individual cardiovascular and renal events. RESULTS: Patients receiving angiotensin inhibitors had a significantly lower risk for the primary outcome during follow-up (10.0 vs 13.0 events per 100 patient-years at risk, multivariable adjusted hazard ratio [HR] 0.70, 95% CI 0.59-0.82). In addition, hospitalization for congestive heart failure (HR 0.69, 95% CI 0.53-0.90), chronic dialysis initiation (HR 0.62, 95% CI 0.42-0.92), and mortality (HR 0.56, 95% CI 0.47-0.68) was lower in treated patients. Conversely, patients receiving angiotensin inhibitors were significantly more likely to be hospitalized for acute renal failure during follow-up (HR 1.87, 95% CI 1.05-3.33; 1.2 vs 0.6 events per 100 patient-years at risk). CONCLUSIONS: These data emphasize the high vascular risk of RVD and suggest that angiotensin inhibitors may improve prognosis in this setting at the expense of acute renal toxicity. If the latter are selected in the management of RVD, renal function parameters should be assiduously followed.

Pergolide associated cardiac valvulopathy based on Ontario administrative data.

INTRODUCTION: Pergolide is an ergot derived dopamine agonist that is widely used for the treatment of Parkinson's disease. Studies have found an association between pergolide and valvular heart abnormalities although there is still much to be learned about the clinical significance of the valvular changes, who is at risk, and whether there is duration of exposure effect. OBJECTIVE: To assess the long term risk of hospital admissions for valvular heart disease (VHD) or congestive heart failure (CHF, a clinically overt outcome of VHD) in new users of pergolide compared to new users of levodopa. The secondary objective was to assess whether there are any characteristics that can predict who is at higher risk of developing this outcome. DESIGN: Retrospective, population-based cohort study. SETTING: Ontario, Canada. SUBJECTS: Ontario residents aged 66 and older, newly started on treatment with either pergolide or levodopa. OUTCOMES: Admission to hospital with the most responsible diagnosis of congestive heart failure or valvular heart disease. RESULTS: The risk for admission for valvular heart disease or congestive heart failure were higher in those with 1-4 years exposure to pergolide compared with no exposure to pergolide (VHD: hazard ratio 2.4, p = 0.04; CHF: hazard ratio 1.6, p = 0.02). No such pattern was found with exposure to levodopa. CONCLUSION: Our study demonstrates that treatment with pergolide is associated with a higher risk of hospital admission for valvular heart disease or congestive heart failure and that this risk is greater in those with 1-4 years exposure than in those with less exposure. We did not find an increased risk beyond four years.

Polytherapy with two or more antihypertensive drugs to lower blood pressure in elderly Ontarians. Room for improvement.

BACKGROUND: Although guidelines now recommend polytherapy to achieve blood pressure targets, little is know about which antihypertensive drugs are combined in clinical practice. OBJECTIVE: To examine current practices for the coprescribing of antihypertensive agents. METHODS: A population-based cohort study was performed using linked administrative databases on all Ontario residents 66 years of age or older who were newly treated for hypertension between July 1, 1994, and March 31, 2002, and did not have diabetes or other relevant comorbidities. All patients were followed for two years to determine which antihypertensives were prescribed concurrently. RESULTS: Of the 166,018 patients in the described cohort, 1819 (1%) were prescribed a combination therapy tablet as their first-line therapy. The number of patients prescribed antihypertensive polytherapy within the first two years of diagnosis increased from 2071 (21%) of the 9825 hypertensive patients starting treatment in the second half of 1994 to 2578 (37%) of the 6988 hypertensive patients beginning treatment in the first quarter of 2002 (P<0.0001). Overall, 11,003 (27%) of polytherapy prescriptions were for drugs without additive hypotensive effects when combined and this proportion did not change over time. CONCLUSIONS: Although there has been an increase in the use of polytherapy in elderly hypertensive patients without comorbidities in Ontario over the past decade, more than one-quarter of the two drugs prescribed together have not been proven to have additive hypotensive effects. Because this likely contributes to suboptimal blood pressure control rates, future guidelines and educational programs should devote increased attention to the choice of optimal polytherapy combinations.

Antihypertensive medication prescribing in 27,822 elderly Canadians with diabetes over the past decade.

OBJECTIVE: The purpose of this study was to examine whether prescribing practices for elderly individuals with diabetes and hypertension changed over the past decade. RESEARCH DESIGN AND METHODS: We linked the Ontario Diabetes Database and four administrative databases in Ontario, Canada, to identify 27,822 patients >65 years of age who had diabetes and were newly treated for hypertension between 1 January 1995 and 31 December 2001. All patients were followed for 2 years after their initial antihypertensive medication prescription. RESULTS: The 27,822 patients in this study (mean age 72 years, 51% men) were treated with oral hypoglycemic agents alone (n = 17,128 patients, 62%), insulin alone (n = 2,346, 8%), both oral hypoglycemic agents and insulin (n = 2,205, 8%), or diet alone (n = 6,143, 22%). Management within the first 2 years of hypertension diagnosis consisted of antihypertensive monotherapy in 20,183 patients (73%), two antihypertensive drugs in 6,207 (22%), and three or more drugs in 1,432 (5%); the most frequently chosen antihypertensive drugs were ACE inhibitors (68%), thiazides (15%), and calcium channel blockers (9%). Between 1995 and 2001, physician prescribing practices changed: the population-adjusted rates of antihypertensive drug prescribing increased by 46% (95% CI 33-55%), the proportion of initial antihypertensive prescriptions for ACE inhibitors increased from 54 to 76% (P < 0.0001), and the use of multiple antihypertensive agents within the first 2 years of diagnosis increased from 21 to 32% (P < 0.0001). CONCLUSIONS: Antihypertensive prescribing patterns in elderly individuals with diabetes changed over the past decade in Ontario in directions consistent with the evolving evidence base.

The impact of the Canadian Hypertension Education Program on antihypertensive prescribing trends.

Although previous studies have shown that hypertension management has improved in Canada during the past decade, this study was designed to determine whether these changes were temporally related to initiation of the Canadian Hypertension Education Program in 1999. Antihypertensive prescription rates in Ontario were compared using time series analyses before and after 1999 in 2 Ontario cohorts: all hypertensives prescribed therapy (using the Intercontinental Medical Statistics CompuScript Database) and all elderly hypertensives without diabetes prescribed therapy (using linked administrative databases including the Ontario Drug Benefit Database). Between January 1998 and December 2003, &280 million prescriptions for antihypertensive agents were filled in Ontario, and total antihypertensive prescriptions increased by 58% annually; time series analyses confirmed that the prescribing rates for total antihypertensives, thiazide diuretics, beta-blockers, and calcium channel blockers increased significantly after 1999, even after adjustment for the temporal trends in the pre-1999 data. In the 166,018 nondiabetic individuals over age 65 who were newly treated for hypertension in Ontario between July 1994 and March 2002, changes in prescription rates for total antihypertensive drugs, angiotensin-converting enzyme inhibitors, beta blockers, and calcium channel blockers occurred in directions that were consistent with guideline recommendations and were statistically significantly related to the initiation of the Canadian Hypertension Education Program. The substantial changes in prescription rates for guideline-recommended antihypertensive drug classes in elderly Ontarians without diabetes and the general Ontario population seen in the past decade are temporally related to the initiation of the Canadian Hypertension Education Program.

Hypertension management in the elderly has improved: Ontario prescribing trends, 1994 to 2002.

To examine whether the treatment of elderly hypertensives had become more aggressive over the past decade, we evaluated: (1) the frequency of new prescriptions for hypertension treatment, adjusted by age and gender; (2) the frequency with which multiple antihypertensives were prescribed concurrently within 2 years of initial diagnosis; and (3) discontinuation rates for antihypertensive therapy. We linked 4 administrative databases and a province-wide clinical database in Ontario, Canada, to derive a cohort of patients > or =66 years of age who were newly started on an antihypertensive agent between July 1, 1994, and March 31, 2002, without another indication for the agent (all patients were followed for 2 years after their initial antihypertensive prescription). Our cohort consisted of 196 451 people newly started on antihypertensive therapy, 30 433 of whom also had diabetes mellitus. The population-adjusted rate of new antihypertensive prescriptions increased by 30% between 1994 and 2002. Whereas 21% of patients newly diagnosed with hypertension in 1994 were prescribed multiple antihypertensives concurrently within 2 years of diagnosis, this proportion had increased to 40% by 2002 (P<0.0001). In the cohort of patients first prescribed an antihypertensive in 1994, 36% were not taking any antihypertensive within 2 years; only 21% of patients first prescribed an antihypertensive in 2002 had discontinued all therapy within 2 years (P<0.0001). Our data provide evidence that the physician management of hypertension in elderly Canadians became more aggressive between 1994 and 2002.