The role of CYP2C19 genotyping to guide antiplatelet therapy following ischemic stroke or transient ischemic attack.

INTRODUCTION: Clopidogrel is an antiplatelet agent recommended for secondary prevention of ischemic stroke (IS) and transient ischemic attack (TIA). Conversion of clopidogrel to its active metabolite by hepatic cytochrome P450-2C19 (CYP2C19) is essential for the inhibition of the P2Y12 receptor and subsequent platelet aggregation to prevent thrombotic events. CYP2C19 is highly polymorphic, with over 30 loss of function (LoF) alleles. This review considers whether there is sufficient data to support genotype guided antiplatelet therapy after stroke. AREAS COVERED: A systematic literature review retrieved articles, which describe the interaction between CYP2C19 genotype and clinical outcomes following IS or TIA when treated with clopidogrel. The review documents efforts to identify optimal antiplatelet regimens and explores the value genotype guided antiplatelet therapy. The work outlines the contemporary understanding of clopidogrel metabolism and appraises evidence linking CYP2C19 LoF variants with attenuated platelet inhibition and poorer outcomes. EXPERT OPINION: There is good evidence that CYP2C19 LoF allele carriers of Han-Chinese ancestry have increased risk for further vascular events following TIA or IS when treated with clopidogrel. The evidence base is less certain in other populations. The expansion of pharmacogenetics into routine clinical practice will facilitate further research and help tailor other aspects of secondary prevention.

Fluid management knowledge in hospital physicians: 'Greenshoots' of improvement but still a cause for concern.

Fluid management is an essential competency for hospital doctors, but previous studies suggest junior clinicians lack the necessary 'knowledge' and 'prescription skills' to complete this task, resulting in preventable morbidity and mortality. In this study, preregistration (n=146), core (n=66) and specialty (n=133) medical trainees and general medical consultants (n=11) completed a structured questionnaire exploring fluid management training, confidence, serious adverse event experience and a 20-item fluid management 'knowledge' test. Results were compared with those of intensive care consultants (n=20). Most clinicians reported limited training and extensive 'unreported' serious adverse events experience. Knowledge about fluid and electrolyte requirements, fluid composition and chloride toxicity had improved compared to historical reports but overall test scores (median (interquartile range (IQR)): with a maximum score of 20) were low. Foundation year trainees scored 7 (IQR 5-8), core medical trainees scored 9 (IQR 6-10), specialist registrars scored 8 (IQR 6-10) and general medical consultants scored 8 (IQR 6-12) compared with the intensive care consultant score of 16 (IQR 14-16). Although weakly correlated, fluid management 'confidence' appeared higher than 'knowledge' tests would justify. These results suggest that physicians' fluid management knowledge is inadequate, including that of senior colleagues, compounded by poor training and failure to learn from serious adverse events.

Outcomes and quality of care in acute myeloid leukemia over 40 years.

BACKGROUND: Acute myeloid leukemia (AML) is associated with a poor prognosis, particularly in older patients. To the authors' knowledge, few population-based studies of AML treatment patterns and outcomes exist to date. METHODS: The authors used the Ontario Cancer Registry to identify all patients diagnosed with AML between 1965 and 2003. Referral to specialized cancer centers (SCCs) and receipt of chemotherapy were examined as quality of care indicators. Survival outcomes were examined using logistic regression at 30 days, 1 year, and 3 years. RESULTS: A total of 9365 patients (mean age, 58.1 years; range, 0 to 103 years) developed AML between 1965 and 2003. Overall, 75.1%, 32.9%, and 17.3% of patients survived to 30 days, 1 year, and 3 years, respectively. Although survival improved over time among patients aged 19 to 59 years, similar improvements were not seen among older patients. The proportion of patients receiving chemotherapy declined with age (59.0% vs 29.3% among patients ages 19-59 vs > or =60 years). Fewer patients aged > or =60 years were referred to a SCC compared with younger patients (20.8% vs 29.9%). Younger age, less comorbidity, later year of diagnosis, receipt of chemotherapy, and being referred to a SCC were associated with better 30-day and long-term survival in multivariate models. CONCLUSIONS: Although the prognosis has improved over time among younger adults, it remains poor among those aged > or =60 years. Fewer older patients were referred to SCCs or treated with chemotherapy compared with younger patients, whereas both factors were associated with improved survival. Opportunities may exist to improve the quality of care and outcomes among older adults with AML.

Management of decreased bone mineral density in men starting androgen-deprivation therapy for prostate cancer.

OBJECTIVE: To determine whether clinicians discuss bone-specific side-effects with patients on androgen-deprivation therapy (ADT) for prostate cancer, or prescribe lifestyle and pharmacological interventions for low bone mineral density (BMD), as decreased BMD is a common side-effect of ADT, leading to increased risk of fracture. PATIENTS AND METHODS: Sixty-six men (mean age 70.6 years) with non-metastatic prostate cancer and starting continuous ADT were enrolled in a prospective longitudinal study. BMD was determined by dual X-ray absorptiometry (DXA) at baseline. Patients were interviewed to obtain their medical histories, and charts were reviewed to determine whether clinicians documented potential bone side-effects in clinic notes, and made lifestyle and/or medication recommendations. Both were done at the start of ADT, and 3 and 6 months later. Patients were classified based on DXA T-score as having normal BMD, as osteopenic, or osteoporotic. RESULTS: At baseline, 53% of patients had osteopenia and 5% had osteoporosis. Within 6 months of starting ADT, general side-effects and bone-specific side-effects of ADT were documented as being discussed with 26% and 15%, respectively. Clinicians recommended lifestyle interventions to 11% of patients. Pharmacological interventions (calcium, vitamin D, and/or bisphosphonates) were recommended to 18% of all patients within 6 months of starting ADT, and to 26% and 67% of osteopenic and osteoporotic patients, respectively. CONCLUSIONS: A minority of patients is being informed of bone-specific side-effects of ADT. Lifestyle and drug interventions to prevent declines in BMD were recommended uncommonly. Practices around bone health for men starting ADT are suboptimal.

Major 30-day complications after radical radiotherapy: a population-based analysis and comparison with surgery.

BACKGROUND: Radiotherapy (RT) is used commonly to treat localized prostate cancer, particularly among older men and men with comorbid illnesses. Few population-based studies have reported on the rates of major short-term complications that lead to hospitalization after radiotherapy. METHODS: In this study, the authors identified all men with nonmetastatic prostate cancer who received RT between 1990 and 1999 in Ontario, Canada. Patients who underwent a prior prostate-directed surgery were excluded. Mortality and complications after RT were examined by using administrative data. A comprehensive list of 7 categories of complications was developed by combining published lists from radical prostatectomy series with input from experts. Logistic regression was used to analyze the relations between complications (that occurred within 30 days of RT) and clinical factors. A similar analysis was performed among men who underwent radical prostatectomy during the same period. RESULTS: There were 7661 men (mean age, 69 years) identified who received RT. Nine patients (0.1%) died within 30 days of RT. Any complication within 30 days of RT was experienced by 6.5% of patients. In analyses that were adjusted for year of treatment, increasing age was associated with any, respiratory, bleeding, genitourinary, and miscellaneous medical complications (P<.02) but not with cardiac, vascular, or bowel complications. Over time, any, cardiac, vascular, and genitourinary complications decreased, but the other 4 categories of complications did not decrease. Despite being older and having more comorbidity, men who received RT had lower complication rates in each category compared with 11,010 men who underwent radical prostatectomy. CONCLUSIONS: Short-term complications that required hospital-based management were relatively uncommon after RT, commonly increased with patient age, and generally declined over time.

Quality of life beyond 6 months after diagnosis in older adults with acute myeloid leukemia.

Although intensive chemotherapy may improve survival in older people with acute myeloid leukemia (AML) without adverse cytogenetics, its impact on quality of life (QOL) is mixed and most patients complain of fatigue up to 6 months after diagnosis. Little information is available on longer-term QOL outcomes. We prospectively followed 20 patients age 60 or older with AML who provided QOL data more than 6 months after diagnosis. Over the first 6 months, there were clinically important improvements in global health, role function, social function, and emotional function. Physical function and cognitive function were stable over time. Over the next 6 months, social function and fatigue improved, and other domains remained stable. Achievement of complete remission appeared to be associated with improvements in global health, physical function, and role function without negatively affecting other health domains. This information may aid discussions with patients about treatment.

Impact of hospital and surgeon volume on mortality and complications after prostatectomy.

PURPOSE: It remains controversial whether short-term surgical complications after radical prostatectomy can be decreased by increasing surgeon or hospital procedural volume. We determined whether hospital or surgeon volumes impacted various short-term surgical complications. MATERIALS AND METHODS: We examined in-hospital mortality and complications following radical prostatectomy in all 25,404 men who underwent this surgery across 8 provinces in Canada between 1990 and 2001. Bayesian multilevel logistic regression models were used, adjusting for patient age, comorbidity, surgery year, and hospital and surgeon volume, while accounting for clustering by surgeon and hospital. RESULTS: Overall 50 men (0.2%) died and 5,087 (20.0%) had 1 or more in-hospital complications following surgery. In models adjusted for age, comorbidity and surgery year hospital volume was associated with in-hospital mortality (p = 0.037). In adjusted models doubling hospital volume was associated with a decreased risk of any, cardiac, respiratory, vascular, genitourinary, miscellaneous medical and miscellaneous surgical complications (each p <0.001), although not wound/bleeding complications (p = 0.40). Similarly doubling surgical volume was associated with a decreased risk of any, respiratory, wound/bleeding, genitourinary, miscellaneous medical and miscellaneous surgical complications (each p <0.01), although not cardiac and vascular complications (p = 0.58 and 0.17, respectively). Adjustment for clustering led to nonsignificant effects of hospital volume on miscellaneous surgical complications, and of surgeon volume on miscellaneous medical and miscellaneous surgical complications. However, this did not alter other findings. CONCLUSIONS: Increasing hospital and surgeon volume are associated with a decreased risk of most complications after radical prostatectomy even after adjusting for the effects of clustering.

Is there an optimal comorbidity index for prostate cancer?

BACKGROUND: Comorbidity is an important consideration in oncology practice, particularly among older patients. Although a variety of comorbidity indices have been employed in research studies, it is unclear whether any one index is preferred. METHODS: An age-stratified random sample of 345 men (mean age of 69 years) who were newly diagnosed with prostate cancer were identified from a cancer registry in Ontario, Canada. Comorbidity and treatment information were obtained from chart review. Four comorbidity indices were utilized: Charlson Index, Diagnosis Count, Index of Coexistent Disease (ICED), and number of medications. Logistic regression analysis was used to compare the performance of comorbidity measures with respect to predicting receipt of curative treatment (radical prostatectomy or radiotherapy) and overall 6-year survival. Multivariable model performance including each of the comorbidity measures was compared by calculating the area under the receiver operating characteristic curve (AUROC). RESULTS: Among men with localized disease (n = 231), in models adjusted for age, Gleason score, and prostate-specific antigen level, only the Charlson Index was found to be a statistically significant predictor of receipt of curative treatment (P < .05), although all comorbidity indices had similar AUROC in adjusted models. After a median follow-up of 6.5 years, 116 of 345 men (33.6%) had died. In adjusted models, all 4 comorbidity indices performed similarly in predicting overall survival. CONCLUSIONS: Although comorbidity is an important predictor of both curative treatment and overall survival in prostate cancer, the optimal comorbidity index for use in research remains unclear. Selecting the optimal comorbidity index may depend on both the specific patient population and the outcome being considered.

The impact of acute myeloid leukemia and its treatment on quality of life and functional status in older adults.

Although intensive chemotherapy (IC) may modestly improve survival compared to supportive care in older people with acute myeloid leukemia (AML), treatment may worsen quality of life (QOL) and functional status. We assessed QOL and functional status at baseline, 1 month, 4 months, and 6 months in 65 consecutive, English-speaking, patients age 60 or older with newly diagnosed AML. At baseline, functional status was high but QOL was negatively affected in global health and most QOL domains. Over time, QOL remained stable or improved in most patients and was generally similar between IC and non-IC groups. Basic activities of daily living (ADL) scores did not change over time, whereas instrumental ADL scores declined slightly regardless of treatment. Receiving IC does not appear to lead to worse QOL or functional status than more palliative approaches. This information may aid treatment discussions in older patients with AML.

Rethinking 30-day mortality risk after radical prostatectomy.

OBJECTIVES: Although radical prostatectomy (RP) is associated with greater 30-day mortality in older men, the magnitude of the excess risk in older age groups compared with younger ones has not been well characterized. METHODS: Using data from the Ontario Cancer Registry, we identified 11,010 men who underwent RP from 1990 to 1999 in Ontario, Canada and compared the 30-day mortality risk immediately after RP with the 1-month mortality risk in the same population of men 7 to 12 months after RP and that of an age-matched general population of men. RESULTS: Overall, 53 men (0.48%) died within 30 days of surgery. The absolute excess 30-day mortality risk associated with RP was 0.18%, 0.51%, and 0.59% for men aged 50 to 59, 60 to 69, and 70 to 79 years, respectively, and was similar for men aged 60 to 69 and 70 to 79 years (P >0.05). The relative mortality risk within 30 days of RP was approximately nine times the baseline risk (95% confidence interval 3 to 38) and was similar for men in all three age groups (P >0.05). CONCLUSIONS: The results of our study indicate that men aged 70 to 79 years do not have a greater absolute excess or relative risk of 30-day mortality after RP compared with men aged 60 to 69 years.

30-day mortality and major complications after radical prostatectomy: influence of age and comorbidity.

BACKGROUND: Radical prostatectomy is associated with excellent long-term disease control for localized prostate cancer. Prior studies have suggested an increased risk of short-term complications among older men who underwent radical prostatectomy, but these studies did not adjust for comorbidity. METHODS: We examined mortality and complications occurring within 30 days following radical prostatectomy among all 11,010 men who underwent this surgery in Ontario, Canada, between 1990 and 1999 using multivariable logistic regression modeling. We adjusted for comorbidity using two common comorbidity indices. Statistical tests were two-sided. RESULTS: Overall, 53 men (0.5%) died, and 2195 [corrected] (19.9%[corrected]) had one or more complications within 30 days of radical prostatectomy. In models adjusted for comorbidity and year of surgery, age was associated with an increased risk of 30-day mortality (odds ratio = 2.04 per decade of age, 95% confidence interval [CI] = 1.23 to 3.39). However, the absolute 30-day mortality risk was low, even in older men, at 0.66% (95% CI = 0.2 to 1.1%) for men aged 70-79 years. In adjusted models, age was associated with an increased risk of cardiac (Ptrend < .001), respiratory (Ptrend = .01), and miscellaneous medical (Ptrend = .058) complications. Similarly, increasing comorbidity was associated with a higher risk of all categories of complications. CONCLUSIONS: Increasing comorbidity is a stronger predictor than age of almost all categories of early complications after radical prostatectomy. The risk of postoperative mortality after radical prostatectomy is relatively low for otherwise healthy older men up to age 79.

Examining the location and cause of death within 30 days of radical prostatectomy.

OBJECTIVES: To better characterize the cause and location of death after radical prostatectomy (RP), as early mortality is relatively uncommon after RP, with little known about the cause of death among men who die within 30 days of RP, and the trend toward earlier discharge after surgery means that a greater proportion of early mortality after RP may occur out of hospital. PATIENTS AND METHODS: Using the Ontario Cancer Registry, we identified 11,010 men (mean age 68 years) who had a RP in the province of Ontario between 1990 and 1999. We identified the occurrence and location of all deaths within 30 days of RP. The cause of death was obtained from death certificate information. Logistic regression was used to examine factors (age, comorbidity, year of surgery) associated with the location of death. RESULTS: Of the 11,010 men, 53 died within 30 days of RP (0.5%); of these 53 men, 28 (53%) died in hospital. Neither age, comorbidity nor year of surgery were significantly associated with location of death (P > 0.05). Major causes of death included cardiovascular disease (38%) and pulmonary embolism (13%). More than half of the patients who died out of hospital had an unknown cause of death. CONCLUSIONS: Almost half of all deaths within 30 days of RP occur out of hospital; the two most common causes of death are potentially preventable. More detailed cause-of-death information may help to identify opportunities for prevention.