Soko Setoguchi

Comparison of Cardiovascular Outcomes in Elderly Patients With Diabetes Who Initiated Rosiglitazone vs Pioglitazone Therapy

BACKGROUND Recent meta-analyses have raised the possibility that rosiglitazone maleate may increase the risk of ischemic cardiovascular events, whereas pioglitazone hydrochloride could not be linked to such a risk. We compared cardiovascular outcomes and mortality between patients initiating pioglitazone vs rosiglitazone therapy. METHODS We assembled an inception cohort of Medicare beneficiaries older than 65 years with state-sponsored prescription drug benefits who had diabetes mellitus and initiated treatment with rosiglitazone or pioglitazone between January 1, 2000, and December 31, 2005. The study outcomes included all-cause mortality, myocardial infarction, stroke, and hospitalization for congestive heart failure. RESULTS Of 28 361 patients selected, 50.3% initiated treatment with pioglitazone and 49.7% with rosiglitazone. Most baseline characteristics were similar between the groups. As preferred in drug safety research, we censored patients at crossover or at 60 days after discontinuation of therapy with their study drug; during 29 060 person-years of follow-up, 1869 patients died. After adjustment for a large number of patient characteristics, Cox regression models revealed 15% greater mortality among patients who initiated therapy with rosiglitazone compared with pioglitazone (95% confidence interval, 5%-26%). Use of rosiglitazone was also associated with a 13% greater risk of congestive heart failure (95% confidence interval, 1%-26%). No differences between the 2 drugs were found in their rates of myocardial infarction or stroke. CONCLUSIONS Our findings from a large population-based cohort of US seniors are compatible with an increased risk of all-cause mortality and congestive heart failure in patients initiating therapy with rosiglitazone compared with similar patients initiating therapy with pioglitazone. Limitations of this study include residual confounding due to its nonrandomized nature.

Patterns of cardiovascular risk in rheumatoid arthritis

Background: Although it is known that rheumatoid arthritis is associated with an increased risk of cardiovascular disease (CVD), the pattern of this risk is not clear. This study investigated the relative risk of myocardial infarction, stroke and CVD mortality in adults with rheumatoid arthritis compared with adults without rheumatoid arthritis across age groups, sex and prior CVD event status. Methods: We conducted a cohort study among all residents aged ⩾18 years residing in British Columbia between 1999 and 2003. Residents who had visited the doctor at least thrice for rheumatoid arthritis (International Classification of Disease = 714) were considered to have rheumatoid arthritis. A non-rheumatoid arthritis cohort was matched to the rheumatoid arthritis cohort by age, sex and start of follow-up. The primary composite end point was a hospital admission for myocardial infarction, stroke or CVD mortality. Results: 25 385 adults who had at least three diagnoses for rheumatoid arthritis during the study period were identified. During the 5-year study period, 375 patients with rheumatoid arthritis had a hospital admission for myocardial infarction, 363 had a hospitalisation for stroke, 437 died from cardiovascular causes and 1042 had one of these outcomes. The rate ratio for a CVD event in patients with rheumatoid arthritis was 1.6 (95% confidence interval (CI) 1.5 to 1.7), and the rate difference was 5.7 (95% CI 4.9 to 6.4) per 1000 person-years. The rate ratio decreased with age, from 3.3 in patients aged 18–39 years to 1.6 in those aged ⩾75 years. However, the rate difference was 1.2 per 1000 person-years in the youngest age group and increased to 19.7 per 1000 person-years in those aged ⩾75 years. Among patients with a prior CVD event, the rate ratios and rate differences were not increased in rheumatoid arthritis. Conclusions: This study confirms that rheumatoid arthritis is a risk factor for CVD events and shows that the rate ratio for CVD events among subjects with rheumatoid arthritis is highest in young adults and those without known prior CVD events. However, in absolute terms, the difference in event rates is highest in older adults.

Risk of death associated with the use of conventional versus atypical antipsychotic drugs among elderly patients

Background: Public health advisories have warned that the use of atypical antipsychotic medications increases the risk of death among elderly patients. We assessed the short-term mortality in a population-based cohort of elderly people in British Columbia who were prescribed conventional and atypical antipsychotic medications. Methods: We used linked health care utilization data of all BC residents to identify a cohort of people aged 65 years and older who began taking antipsychotic medications between January 1996 and December 2004 and were free of cancer. We compared the 180-day all-cause mortality between residents taking conventional antipsychotic medications and those taking atypical antipsychotic medications. Results: Of 37 241 elderly people in the study cohort, 12 882 were prescribed a conventional antipsychotic medication and 24 359 an atypical formulation. Within the first 180 days of use, 1822 patients (14.1%) in the conventional drug group died, compared with 2337 (9.6%) in the atypical drug group (mortality ratio 1.47, 95% confidence interval [CI] 1.39–1.56). Multivariable adjustment resulted in a 180-day mortality ratio of 1.32 (1.23–1.42). In comparison with risperidone, haloperidol was associated with the greatest increase in mortality (mortality ratio 2.14, 95% CI 1.86–2.45) and loxapine the lowest (mortality ratio 1.29, 95% CI 1.19–1.40). The greatest increase in mortality occurred among people taking higher (above median) doses of conventional antipsychotic medications (mortality ratio 1.67, 95% CI 1.50–1.86) and during the first 40 days after the start of drug therapy (mortality ratio 1.60, 95% CI 1.42–1.80). Results were confirmed in propensity score analyses and instrumental variable estimation, minimizing residual confounding. Interpretation: Among elderly patients, the risk of death associated with conventional antipsychotic medications is comparable to and possibly greater than the risk of death associated with atypical antipsychotic medications. Until further evidence is available, physicians should consider all antipsychotic medications to be equally risky in elderly patients.

Tumour necrosis factor antagonist use and associated risk reduction of cardiovascular events among patients with rheumatoid arthritis

Objective To examine the association of cardiovascular events with tumour necrosis factor (TNF) α antagonist use compared with non-biological disease-modifying antirheumatic drug (DMARD) utilisation in patients with rheumatoid arthritis (RA). Methods The study population included 10 156 patients enrolled in the Consortium of Rheumatology Researchers of North America RA registry. Three study cohorts were defined based on three mutually exclusive drug use categories, including TNF antagonists, methotrexate and other non-biological DMARDs. HR were calculated adjusting for cardiovascular risk factors, RA disease characteristics and prednisone use. The primary study outcome was a composite of non-fatal myocardial infarction (MI), transient ischaemic attack (TIA) or stroke and cardiovascular-related death. Results There were 88 cardiovascular events, including 26 MI, 45 TIA/strokes and 17 cardiovascular-related deaths. After adjusting for age, gender, cardiovascular risk factors and RA disease characteristics, patients using a TNF antagonist experienced a reduced risk of the primary composite cardiovascular endpoint (HR 0.39, 95% CI 0.19 to 0.82) compared with users of non-biological DMARDs. Methotrexate was not associated with a reduced risk (HR 0.94, 95% CI 0.49 to 1.80). Prednisone use was associated with a dose-dependent increased risk (p=0.04). The risk reduction associated with TNF antagonists was also observed for non-fatal cardiovascular events (HR 0.35, 95% CI 0.16 to 0.74). Conclusion TNF antagonist use was associated with a reduced risk of cardiovascular events in patients with RA.

Explaining the cardiovascular risk associated with rheumatoid arthritis: traditional risk factors versus markers of rheumatoid arthritis severity

Background Cardiovascular (CV) disease has a major impact on patients with rheumatoid arthritis (RA), however, the relative contributions of traditional CV risk factors and markers of RA severity are unclear. The authors examined the relative importance of traditional CV risk factors and RA markers in predicting CV events. Methods A prospective longitudinal cohort study was conducted in the setting of the CORRONA registry in the USA. Baseline data from subjects with RA enrolled in the CORRONA registry were examined to determine predictors of CV outcomes, including myocardial infarction, stroke or transient ischemic attack. Possible predictors were of two types: traditional CV risk factors and markers of RA severity. The discriminatory value of these variables was assessed by calculating the area under the receiver operating characteristic curve (c-statistic) in logistic regression. The authors then assessed the incidence rate for CV events among subjects with an increasing number of traditional CV risk factors and/or RA severity markers. Results The cohort consisted of 10 156 patients with RA followed for a median of 22 months. The authors observed 76 primary CV events during follow-up for a composite event rate of 3.98 (95% CI 3.08 to 4.88) per 1000 patient-years. The c-statistic improved from 0.57 for models with only CV risk factors to 0.67 for models with CV risk factors plus age and gender. The c-statistic improved further to 0.71 when markers of RA severity were also added. The incidence rate for CV events was 0 (95% CI 0 to 5.98) for persons without any CV risk factors or markers of RA severity, while in the group with two or more CV risk factors and three or more markers of RA severity the incidence was 7.47 (95% CI 4.21 to 10.73) per 1000 person-years. Conclusions Traditional CV risk factors and markers of RA severity both contribute to models predicting CV events. Increasing numbers of both types of factors are associated with greater risk.

Effectiveness and Safety of Warfarin Initiation in Older Hemodialysis Patients with Incident Atrial Fibrillation

BACKGROUND AND OBJECTIVES Although generally recommended in atrial fibrillation (AF) patients, the effectiveness and safety of oral anticoagulation in dialysis patients with AF is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We assembled a cohort of older hemodialysis patients who initiated dialysis without prior record of AF and who had prescription drug benefits through three state-administered programs. The index event was a first hospitalization with diagnosed AF; patients with any recorded prior warfarin use were excluded. Eligible patients survived ≥30 days from discharge, and new warfarin use was recorded from prescription records during that 30-day window. Propensity-matched warfarin users and nonusers were compared using Cox regression. Outcomes included ischemic stroke, hemorrhagic stroke, and mortality. RESULTS Among 2313 patients with new AF who survived 30 days from discharge, 249 (10.8%) filled a prescription for warfarin. Comparing 237 warfarin users and 948 propensity-matched nonusers over 2287 person-years of follow-up, the occurrence of ischemic stroke was similar (HR = 0.92; 95% CI, 0.61 to 1.37), whereas warfarin users experienced twice the risk of hemorrhagic stroke (HR = 2.38; 95% CI, 1.15 to 4.96). The risks of stroke, gastrointestinal hemorrhage, and mortality did not differ between groups. As-treated analyses yielded similar findings, as did analyses restricted to patients with CHADS(2) scores ≥2. CONCLUSIONS Although we confirmed association between warfarin use and hemorrhagic stroke in dialysis patients with AF, we found no association between warfarin use and ischemic stroke. Adequately powered randomized trials are required to conclusively determine the risks and benefits of the studied warfarin indication in hemodialysis patients.

Association Between the Choice of IV Crystalloid and In-Hospital Mortality Among Critically Ill Adults With Sepsis*

Objective:Isotonic saline is the most commonly used crystalloid in the ICU, but recent evidence suggests that balanced fluids like Lactated Ringer’s solution may be preferable. We examined the association between choice of crystalloids and in-hospital mortality during the resuscitation of critically ill adults with sepsis. Design:A retrospective cohort study of patients admitted with sepsis, not undergoing any surgical procedures, and treated in an ICU by hospital day 2. We used propensity score matching to control for confounding and compared the following outcomes after resuscitation with balanced versus with no-balanced fluids: in-hospital mortality, acute renal failure with and without dialysis, and hospital and ICU lengths of stay. We also estimated the dose-response relationship between receipt of increasing proportions of balanced fluids and in-hospital mortality. Setting:Three hundred sixty U.S. hospitals that were members of the Premier Healthcare alliance between November 2005 and December 2010. Patients:A total of 53,448 patients with sepsis, treated with vasopressors and crystalloids in an ICU by hospital day 2 including 3,396 (6.4%) that received balanced fluids. Interventions:None. Measurements and Main Results:Patients treated with balanced fluids were younger and less likely to have heart or chronic renal failure, but they were more likely to receive mechanical ventilation, invasive monitoring, colloids, steroids, and larger crystalloid volumes (median 7 vs 5 L). Among 6,730 patients in a propensity-matched cohort, receipt of balanced fluids was associated with lower in-hospital mortality (19.6% vs 22.8%; relative risk, 0.86; 95% CI, 0.78, 0.94). Mortality was progressively lower among patients receiving larger proportions of balanced fluids. There were no significant differences in the prevalence of acute renal failure (with and without dialysis) or in-hospital and ICU lengths of stay. Conclusions:Among critically ill adults with sepsis, resuscitation with balanced fluids was associated with a lower risk of in-hospital mortality. If confirmed in randomized trials, this finding could have significant public health implications, as crystalloid resuscitation is nearly universal in sepsis.

Improvements in long-term mortality after myocardial infarction and increased use of cardiovascular drugs after discharge: a 10-year trend analysis.

OBJECTIVES We sought to assess the relationship between increasing use of cardiovascular medications and trends in long-term prognosis after myocardial infarction (MI) in the elderly. BACKGROUND During the past decade, statins, beta-blockers (BBs), angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin-II receptor blockers (ARBs) have been increasingly used after MI. However, little is known about the relationship between increasing use of these medications and improvements in prognosis after MI. METHODS Using data from pharmacy assistance programs and Medicare in 2 states (1995 to 2004), we identified patients with MI who survived >or=30 days after discharge. We assessed age, gender, race, comorbidities, and coronary interventions during the MI hospitalization and recorded filled prescriptions for statins, BBs, ACEIs/ARBs, or antiplatelet agents within 30 days after discharge. All patients were tracked until they died or until the end of the eligibility/study period. We built multivariate Cox proportional hazards regression models to assess trends in long-term mortality and the contribution to increasing medication use after MI. RESULTS Of 21,484 patients identified, 12,142 died during 74,982 person-years of follow-up. After adjusting for demographics and comorbidities, we found that mortality after MI decreased significantly from 1995 to 2004 (hazard ratio for annual trend 0.97; 95% confidence interval 0.97 to 0.98), a 3% reduction in mortality each year. Adjusting for the use of statins, BBs, ACEIs/ARBs, and antiplatelet drugs after discharge completely eliminated the association between time trend and mortality (hazard ratio 1.00; 95% confidence interval 0.99 to 1.01). CONCLUSIONS The observed improvement in long-term mortality in elderly patients with MI may be mainly due to increased use of cardiovascular medications after discharge.

The Increasing Prevalence of Atrial Fibrillation among Hemodialysis Patients

A half million Americans have ESRD, which puts them at high risk for cardiovascular disease and poor outcomes. Little is known about the epidemiology of atrial fibrillation among patients with ESRD. We analyzed data from annual cohorts (1992 to 2006) of prevalent hemodialysis patients from the United States Renal Data System. In each cohort, we searched 1 year of medical claims for relevant diagnosis codes to determine the prevalence of atrial fibrillation. Among 2.5 million patient observations, 7.7% had atrial fibrillation, with the prevalence increasing 3-fold from 3.5% (1992) to 10.7% (2006). The number of affected patients increased from 3620 to 23,893 (6.6-fold) during this period. Older age, male gender, and several comorbid conditions were associated with increased risk for atrial fibrillation. Compared with otherwise similar Caucasians, the prevalence of atrial fibrillation rates was substantially lower for blacks, Asians, and Native Americans. One-year mortality was twice as high among hemodialysis patients with atrial fibrillation compared with those without (39% versus 19%), and this increased risk was constant during the 15 years of the study. In conclusion, the prevalence of diagnosed atrial fibrillation among patients receiving hemodialysis in the United States is increasing, varies by race, and remains associated with substantially increased mortality. Identifying potentially modifiable risk factors for incident atrial fibrillation requires further investigation.

Antidepressant Use in Pregnancy and the Risk of Cardiac Defects

BACKGROUND Whether the use of selective serotonin-reuptake inhibitors (SSRIs) and other antidepressants during pregnancy is associated with an increased risk of congenital cardiac defects is uncertain. In particular, there are concerns about a possible association between paroxetine use and right ventricular outflow tract obstruction and between sertraline use and ventricular septal defects. METHODS We performed a cohort study nested in the nationwide Medicaid Analytic eXtract for the period 2000 through 2007. The study included 949,504 pregnant women who were enrolled in Medicaid during the period from 3 months before the last menstrual period through 1 month after delivery and their liveborn infants. We compared the risk of major cardiac defects among infants born to women who took antidepressants during the first trimester with the risk among infants born to women who did not use antidepressants, with an unadjusted analysis and analyses that restricted the cohort to women with depression and that used propensity-score adjustment to control for depression severity and other potential confounders. RESULTS A total of 64,389 women (6.8%) used antidepressants during the first trimester. Overall, 6403 infants who were not exposed to antidepressants were born with a cardiac defect (72.3 infants with a cardiac defect per 10,000 infants), as compared with 580 infants with exposure (90.1 per 10,000 infants). Associations between antidepressant use and cardiac defects were attenuated with increasing levels of adjustment for confounding. The relative risks of any cardiac defect with the use of SSRIs were 1.25 (95% confidence interval [CI], 1.13 to 1.38) in the unadjusted analysis, 1.12 (95% CI, 1.00 to 1.26) in the analysis restricted to women with depression, and 1.06 (95% CI, 0.93 to 1.22) in the fully adjusted analysis restricted to women with depression. We found no significant association between the use of paroxetine and right ventricular outflow tract obstruction (relative risk, 1.07; 95% CI, 0.59 to 1.93) or between the use of sertraline and ventricular septal defects (relative risk, 1.04; 95% CI, 0.76 to 1.41). CONCLUSIONS The results of this large, population-based cohort study suggested no substantial increase in the risk of cardiac malformations attributable to antidepressant use during the first trimester. (Funded by the Agency for Healthcare Research and Quality and the National Institutes of Health.).