Su-Jung Chen

Statins, risk of diabetes, and implications on outcomes in the general population.

OBJECTIVES This study aimed to evaluate the association of statin exposure and incident diabetes, and subsequent outcomes in the general population. BACKGROUND Cardiovascular events as consequences of atherosclerosis and diabetes are reduced by statins. However, statins are associated with excessive risk of diabetes occurrence according to clinical trial analyses. From daily-practice perspectives, it remains unclear whether statin use increases risk; prognoses of diabetes after exposure require further clarification. METHODS From Taiwan National Health Insurance beneficiaries age ≥45 years (men) and ≥55 years (women) before 2004, subjects continuously treated with statins ≥30 days during 2000 to 2003 and nonusers before 2004 were identified. Among nondiabetic individuals at the cohort entry, controls were matched to statin users on a 4:1 ratio by age, sex, atherosclerotic comorbidities, and year of their entry. Outcomes as diabetes, major adverse cardiovascular events (MACE, the composite of myocardial infarction and ischemic stroke), and in-hospital deaths were assessed. RESULTS Over a median of 7.2 years, annual rates of diabetes were significantly higher in statin users (2.4% vs. 2.1%, p < 0.001), whereas MACE (hazard ratio [HR]: 0.82; 95% confidence interval [CI]: 0.68 to 0.98 for myocardial infarction; HR: 0.94; 95% CI: 0.86 to 1.03 for ischemic stroke; HR: 0.91; 95% CI: 0.84 to 0.99 for MACE]) and in-hospital mortality (HR: 0.61; 95% CI: 0.55 to 0.67]) were less. The risk-benefit analyses suggested that statin treatment was favorable in high-risk (HR: 0.89; 95% CI: 0.83 to 0.95) and secondary prevention (HR: 0.89; 95% CI: 0.83 to 0.96) populations. Among diabetic patients, prior statin use was associated with fewer MACE (HR: 0.75; 95% CI: 0.59 to 0.97). In-hospital deaths were similar in statin-related diabetes among high-risk (HR: 1.11; 95% CI: 0.83 to 1.49) and secondary prevention (HR: 1.08; 95% CI: 0.79 to 1.47) subjects compared with nondiabetic controls. CONCLUSIONS Risk of diabetes was increased after statins, but outcomes were favorable.

Rate-Control Treatment and Mortality in Atrial Fibrillation

Background— Current American and European guidelines emphasize the importance of rate-control treatments in treating atrial fibrillation with a Class I recommendation, although data on the survival benefits of rate control are lacking. The goal of the present study was to investigate whether patients receiving rate-control drugs had a better prognosis compared with those without rate-control treatment. Methods and Results— This study used the National Health Insurance Research Database in Taiwan. There were 43 879, 18 466, and 38 898 patients with atrial fibrillation enrolled in the groups receiving &bgr;-blockers, calcium channel blockers, and digoxin, respectively. The reference group consisted of 168 678 subjects who did not receive any rate-control drug. The clinical end point was all-cause mortality. During a follow-up of 4.9±3.7 years, mortality occurred in 88 263 patients (32.7%). After adjustment for baseline differences, the risk of mortality was lower in patients receiving &bgr;-blockers (adjusted hazard ratio=0.76; 95% confidence interval=0.74–0.78) and calcium channel blockers (adjusted hazard ratio=0.93; 95% confidence interval=0.90–0.96) compared with those who did not receive rate-control medications. On the contrary, the digoxin group had a higher risk of mortality with an adjusted hazard ratio of 1.12 (95% confidence interval=1.10–1.14). The results were observed consistently in subgroup analyses and among the cohorts after propensity matching. Conclusions— In this nationwide atrial fibrillation cohort, the risk of mortality was lower for patients receiving rate-control treatment with &bgr;-blockers or calcium channel blockers, and the use of &bgr;-blockers was associated with the largest risk reduction. Digoxin use was associated with greater mortality. Prospective, randomized trials are necessary to confirm these findings.

Atrial fibrillation and the risk of ischemic stroke: does it still matter in patients with a CHA2DS2-VASc score of 0 or 1?

Background and Purpose— Atrial fibrillation (AF) is an independent risk factor for stroke. Recent studies have demonstrated that the CHA2DS2-VASc scheme is useful for selecting patients who are truly at low risk. The goal of the present study was to compare the risk of ischemic stroke among AF patients with a CHA2DS2-VASc score of 0 (male) or 1 (female) with those without AF. Methods— The study enrolled 509 males (CHA2DS2-VASc score=0) and 320 females (CHA2DS2-VASc score=1) with AF who did not receive any antithrombotic therapy. Patients were selected from the National Health Insurance Research Database in Taiwan. For each study patient, 10 age-matched and sex-matched subjects without AF and without any comorbidity from the CHA2DS2-VASc scheme were selected as controls. The clinical end point was the occurrence of ischemic stroke. Results— During a follow-up of 57.4±35.7 months, 128 patients (1.4%) experienced ischemic stroke. The event rate did not differ between groups with and without AF for male patients (1.6% vs 1.6%; P=0.920). In contrast, AF was a significant risk factor for ischemic stroke among females (hazard ratio, 7.77), with event rates of 4.4% and 0.7% for female patients with and without AF (P<0.001). Conclusions— AF males with a CHA2DS2-VASc score of 0 were at true low risk for stroke, which was similar to that of non-AF patients. However, AF females with a score of 1 were still at higher risk for ischemic events than non-AF patients.

Sitagliptin and the risk of hospitalization for heart failure: A population-based study

BACKGROUND Saxagliptin was associated with an increased risk of hospitalization for heart failure (HHF) in diabetic patients with high cardiovascular risk. This study assessed the risk of HHF during an exposure to sitagliptin in general diabetic patients. METHODS In Taiwan National Health Insurance research database, a study of the beneficiaries aged ≥ 45 years with diabetes treated with or without sitagliptin between March 2009 and July 2011 was conducted. Patients treated with sitagliptin were matched to patients never exposed to a dipeptidyl peptidase-4 (DPP-4) inhibitor by the propensity score methodology. The outcome measures were the first and the total number of HHF, and mortality for heart failure or all causes. RESULTS A total of 8288 matched pairs of patients were analyzed. During a median of 1.5 years, the first event of HHF occurred in 339 patients with sitagliptin and 275 patients never exposed to a DPP-4 inhibitor (hazard ratio: 1.21, 95% confidence interval: 1.04-1.42, P = 0.017); all-cause mortality was similar (hazard ratio: 0.87, 95% confidence interval: 0.74-1.03, P = 0.109). The risk for HHF was proportional to exposure (hazard ratio: 1.09, 95% confidence interval: 1.06-1.11, P < 0.001 for every 10% increase in adherence to sitagliptin). Overall, there were 935 events of HHF, in which the association between the number of HHF and the adherence to sitagliptin was linear. The greatest total number of HHF occurred in the patients with the highest adherence. CONCLUSIONS The use of sitagliptin was associated with a higher risk of HHF but no excessive risk for mortality was observed.

The Use of Benzodiazepine Receptor Agonists and Risk of Respiratory Failure in Patients with Chronic Obstructive Pulmonary Disease: A Nationwide Population-Based Case-Control Study

STUDY OBJECTIVES Insomnia is prevalent in patients with chronic obstructive pulmonary disease (COPD), and benzodiazepine receptor agonists (BZRAs) are the most commonly used drugs despite their adverse effects on respiratory function. The aim of this study was to investigate whether the use of BZRAs was associated with an increased risk of respiratory failure (RF) in COPD patients. DESIGN Matched case-control study. SETTING National Health Insurance Research Database (NHIRD) in Taiwan. PARTICIPANTS The case group consisted of 2,434 COPD patients with RF, and the control group consisted of 2,434 COPD patients without RF, matched for age, sex, and date of enrollment. MEASUREMENTS AND RESULTS Exposure to BZRAs during the 180-day period preceding the index date was analyzed and compared in the case and control groups. Conditional logistic regression was performed, and the use of BZRAs was associated with an increased risk of RF (adjusted odds ratio [aOR] 1.56, 95% confidence interval [CI] 1.14-2.13). In subgroup analysis, we found that the benzodiazepine (BZD) users had a higher risk of RF (aOR 1.58, 95% CI 1.14-2.20), whereas the risk in non-benzodiazepine (non-BZD) users was insignificant (aOR 0.85, 95% CI 0.51-1.44). A greater than 2-fold increase in risk was found in those who received two or more kinds of BZRAs and those using a combination of BZD and non-BZD medications. CONCLUSIONS The use of benzodiazepine receptor agonists was a significant risk factor for respiratory failure in patients with chronic obstructive pulmonary disease (COPD). Compared to benzodiazepine, the prescription of non-benzodiazepine may be safer for the management of insomnia in COPD patients.

Incidence and risk factors for new-onset atrial fibrillation among patients with end-stage renal disease undergoing renal replacement therapy

Atrial fibrillation (AF) is prevalent in end-stage renal disease (ESRD) patients and negatively impacts patient outcomes. We explored the incidence and risk factors for new-onset AF among patients with ESRD undergoing renal replacement therapy, without a prior history of AF, retrieved from Taiwans National Health Insurance Research Database (NHIRD). For each of 134,901 patients with ESRD, one age- and gender-matched control and one similarly matched patient with chronic kidney disease (CKD), a total of 404,703 patients, were selected from the NHIRD. The study endpoint was the occurrence of new-onset AF and patients were followed an average of 5.1 years. The incidence rates of AF were 12.1, 7.3, and 5.0 per 1000 person-years for ESRD, CKD, and control patients, respectively. Among patients with ESRD, age, hypertension, heart failure, coronary artery disease, peripheral arterial occlusive disease, and chronic obstructive pulmonary disease were significant risk factors for new-onset AF. Thus, patients with ESRD had a significantly higher risk of new-onset AF. The presence of multiple risk factors was associated with a higher possibility of AF occurrence.

Does digoxin increase the risk of ischemic stroke and mortality in atrial fibrillation? A nationwide population-based cohort study.

BACKGROUND Digoxin and related cardiac glycosides have been used for almost 100 years in atrial fibrillation (AF). However, 2 recent analyses of the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) trial showed inconsistent results regarding the risk of mortality associated with digoxin use. The goal of the present study was to investigate the relationship between digoxin and the risk of ischemic stroke and mortality in Asians. METHODS This study used the National Health Insurance Research Database (NHIRD) in Taiwan. A total of 4781 patients with AF who did not receive any antithrombotic therapy were selected as the study population. Among the study population, 829 participants (17.3%) received the digoxin treatment. The risk of ischemic stroke and mortality in patients who received digoxin and those who did not was compared. RESULTS The use of digoxin was associated with an increased risk of clinical events, with an adjusted hazard ratio of 1.41 (95% confidence interval [CI], 1.17-1.70) for ischemic stroke and 1.21 (95% CI, 1.01-1.44) for all-cause mortality. In the subgroup analysis based on coexistence with heart failure or not, digoxin was a risk factor for adverse events in patients without heart failure but not in those with heart failure (interaction P < 0.001 for either end point). Among patients with AF without heart failure, the use of β-blockers was associated with better survival, with an adjusted hazard ratio of 0.48 (95% CI, 0.34-0.68). CONCLUSIONS Digoxin should be avoided for patients with AF without heart failure because it was associated with an increased risk of clinical events. β-Blockers may be a better choice for controlling ventricular rate in these patients.

The association between the use of non-steroidal anti-inflammatory drugs and atrial fibrillation: A nationwide case–control study

BACKGROUND Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. The goal of the present study was to investigate whether exposure to non-steroidal anti-inflammatory drugs (NSAIDs) was a risk factor for AF, and to discern which patients were at the highest risk for AF due to NSAID use. METHODS A total of 7280 patients with newly diagnosed AF from 2000 to 2009 were identified from the National Health Insurance Research Database. On the same date of enrollment, 10 patients without AF, who were matched for age, sex, and underlying disease for each study patient, were selected to be the control group. The relationship between NSAID exposure before enrollment and AF risk was analyzed. RESULTS The NSAID use was associated with an increased AF risk, especially for new users (odds ratio [OR]=1.651). Among new users, subgroup analysis revealed that patients with heart failure were at the highest risk for AF (OR=1.920). For patients who were only exposed to selective cyclooxygenase 2 (COX2) inhibitors, no significant associations were found between AF and selective COX2 inhibitor use, except for patients with chronic kidney or pulmonary disease (OR=1.656 and 1.707, respectively). CONCLUSIONS New NSAID use may predispose patients to AF, and the risk is almost doubled in heart failure patients. Use of selective COX2 inhibitors was not significantly related to AF occurrence, except in patients with chronic kidney or pulmonary disease.

Validation of a Modified CHA2DS2-VASc Score for Stroke Risk Stratification in Asian Patients With Atrial Fibrillation: A Nationwide Cohort Study.

Background and Purpose— The age threshold for an increased stroke risk for patients with atrial fibrillation may be different for Asians and non-Asians. We hypothesized that a modified CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75, diabetes mellitus, prior stroke or transient ischemic attack, vascular disease, age 65–74 years, female) scheme, mCHA2DS2-VASc, which assigned one point for patients aged 50 to 74 years, may perform better than CHA2DS2-VASc score for stroke risk stratification in Asians. Methods— This study used the Taiwan National Health Insurance Research Database, which included 224 866 newly diagnosed atrial fibrillation patients. The predictive accuracies of ischemic stroke of CHA2DS2-VASc and mCHA2DS2-VASc scores were compared among 124 271 patients without antithrombotic therapies. From the whole cohort, 15 948 patients had a CHA2DS2-VASc score 0 (males) or 1 (females), and 8654 patients had an mCHA2DS2-VASc score 1 (males) or 2 (females). The latter were categorized into 3 groups, that is, no treatment, antiplatelet therapy, and warfarin, and the risks of ischemic stroke and intracranial hemorrhage (ICH) were compared. Results— During a follow-up of 538 653 person-years, 21 008 patients experienced ischemic stroke. The mCHA2DS2-VASc performed better than CHA2DS2-VASc score in predicting ischemic stroke assessed by C indexes and net reclassification index. For 8654 patients having an mCHA2DS2-VASc score of 1 (males) or 2 (females) because of the resetting of the age threshold, use of warfarin was associated with a 30% lower risk of ischemic stroke and a similar risk of ICH compared with nontreatment. Net clinical benefit analyses also favored the use of warfarin in different weighted models. Conclusions— In this Asian atrial fibrillation cohort, the mCHA2DS2-VASc score performed better than the CHA2DS2-VASc and would further identify atrial fibrillation patients who may derive a positive net clinical benefit from oral anticoagulation.

Risk of New-Onset Diabetes Mellitus Versus Reduction in Cardiovascular Events With Statin Therapy

The Food and Drug Administration recently updated the safety warning concerning the association between statin therapy and new-onset diabetes mellitus (NODM). For prediabetes, little information is available for statins on cardiovascular outcome reduction and diabetogenic consequences. This study aimed to examine the risk of NODM and the reduction of cardiovascular events and death (MACE) after statin therapy in the prediabetic subjects. The medical and pharmacy claims of the prediabetic beneficiaries were retrieved from Taiwan National Health Insurance research database. The occurrence of NODM, MACE, and morbidity indexed by hospitalizations and emergency visits was ascertained by ambulatory and inpatient database. A propensity score-matched model was constructed for statin users and nonusers. During follow-up (4.1 ± 2.5 years), NODM and MACE occurred in 23.5% and 16.7%, respectively, of nonusers and 28.5% and 12.0%, respectively, of users. Statin therapy was associated with a greater risk of NODM (hazard ratio 1.20, 95% confidence interval 1.08 to 1.32) and less risk of MACE (hazard ratio 0.70, 95% confidence interval 0.61 to 0.80), both in dose-dependent fashions. The earlier and more persistent use correlated with the greater increase in risk of NODM offset by the proportionally larger reduction in MACE. Furthermore, the early persistent users had the lowest rate of hospitalizations and emergency visits. In conclusion, our findings suggested that the relation between NODM and therapeutic advantages of statins was parallel in the prediabetic population. Treatment benefits outweighed diabetic consequences in subjects receiving the earlier and more persistent treatment.