Hassan Behlouli

Warfarin Use and the Risk for Stroke and Bleeding in Patients With Atrial Fibrillation Undergoing Dialysis

Background— Current observational studies on warfarin use and the risk for stroke and bleeding in patients with atrial fibrillation (AF) undergoing dialysis found conflicting results. Methods and Results— We conducted a population-based retrospective cohort study of patients aged ≥65 years admitted to a hospital with a primary or secondary diagnosis of AF, in Quebec and Ontario, Canada from 1998 to 2007. The AF cohort was grouped into dialysis (hemodialysis and peritoneal dialysis) and nondialysis patients and into warfarin and no-warfarin users according to the first prescription filled for warfarin within 30 days after AF hospital discharge. We determined the association between warfarin use and the risk for stroke and bleeding in dialysis and nondialysis patients. The cohort comprised 1626 dialysis patients and 204 210 nondialysis patients. Among dialysis patients, 46% (756/1626) patients were prescribed warfarin. Among dialysis patients, warfarin users had more congestive heart failure and diabetes mellitus, but fewer prior bleeding events in comparison with the no-warfarin users. Among dialysis patients, warfarin use, in comparison with no-warfarin use, was not associated with a lower risk for stroke (adjusted hazard ratio, 1.14; 95% confidence interval, 0.78–1.67) but was associated with a 44% higher risk for bleeding (adjusted hazard ratio, 1.44; 95% confidence interval, 1.13–1.85) after adjusting for potential confounders. Propensity score–adjusted analyses yielded similar results. Conclusions— Our results suggest that warfarin use is not beneficial in reducing stroke risk, but it is associated with a higher bleeding risk in patients with AF undergoing dialysis.

Utility of PSA doubling time in follow-up of untreated patients with localized prostate cancer

OBJECTIVESnTo evaluate the prostate-specific antigen (PSA) changes and the ability of PSA doubling time (PSADT) to predict disease progression in untreated patients with clinically localized prostate cancer.nnnMETHODSnA total of 104 patients with localized prostate cancer were followed up expectantly with serial PSA measurements and digital rectal examination (DRE). PSADT was calculated by linear regression analysis for the 94 patients who had a minimum of three PSA measurements and 12 months of follow-up. The median follow-up was 33 months. Of the 94 patients, 45 underwent repeat prostate biopsy to evaluate whether tumor progression occurred during the observation period.nnnRESULTSnTwenty-seven percent of patients had rapid PSADTs (less than 48 months). Only the presence of palpable disease on DRE correlated with a PSADT of less than 48 months (P <0.05). However, a PSADT of less than 120 months consistently correlated with disease progression on DRE and on repeat biopsy, as well as with the presence of clinically significant cancer. PSADT did not correlate with the Gleason score. Furthermore, patients with a PSADT of less than 48 months did not differ significantly from those with a PSADT of 48 to 120 months with regard to Gleason score, disease progression on DRE or on repeat biopsy, and the presence of significant cancer.nnnCONCLUSIONSnA PSADT of less than 120 months correlates with disease progression. However, its clinical utility remains limited to identify patients at risk of disease progression reliably.

Rhythm Versus Rate Control Therapy and Subsequent Stroke or Transient Ischemic Attack in Patients With Atrial Fibrillation

Background— Stroke is a debilitating condition with an increased risk in patients with atrial fibrillation. Although data from clinical trials suggest that both rate and rhythm control are acceptable approaches with comparable rates of mortality in the short term, it is unclear whether stroke rates differ between patients who filled prescriptions for rhythm or rate control therapy. Methods and Results— We conducted a population-based observational study of Quebec patients ≥65 years with a diagnosis of atrial fibrillation during the period 1999 to 2007 with the use of linked administrative data from hospital discharge and prescription drug claims databases. We compared rates of stroke or transient ischemic attack (TIA) among patients using rhythm (class Ia, Ic, and III antiarrhythmics), versus rate control (&bgr;-blockers, calcium channel blockers, and digoxin) treatment strategies (either current or new users). The cohort consisted of 16 325 patients who filled a prescription for rhythm control therapy (with or without rate control therapy) and 41 193 patients who filled a prescription for rate control therapy, with a mean follow-up of 2.8 years (maximum 8.2 years). A lower proportion of patients on rhythm control therapy than on rate control therapy had a CHADS2 (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, and previous stroke or TIA) score of ≥2 (58.1% versus 67.0%, P<0.001). Treatment with any antithrombotic drug was comparable in the 2 groups (76.8% in rhythm control versus 77.8% in rate control group). Crude stroke/TIA incidence rate was lower in patients treated with rhythm control in comparison with rate control therapy (1.74 versus 2.49, per 100 person-years, P<0.001). This association was more marked in patients in the moderate- and high-risk groups for stroke according to the CHADS2 risk score. In multivariable Cox regression analysis, rhythm control therapy was associated with a lower risk of stroke/TIA in comparison with rate control therapy (adjusted hazard ratio, 0.80; 95% confidence interval, 0.74, 0.87). The lower stroke/TIA rate was confirmed in a propensity score–matched cohort. Conclusions— In comparison with rate control therapy, the use of rhythm control therapy was associated with lower rates of stroke/TIA among patients with atrial fibrillation, in particular, among those with moderate and high risk of stroke.

Comparative evaluation of total PSA, free/total PSA, and complexed PSA in prostate cancer detection

OBJECTIVESnTo compare the performance of prostate-specific antigen (PSA), the free/total PSA (F/T PSA) ratio, and complexed PSA (cPSA) in prostate cancer detection.nnnMETHODSnFive hundred thirty-five patients evaluated at the UROMED prostate cancer detection clinic had total PSA, free PSA, and cPSA measured before undergoing transrectal ultrasonography and sextant prostate biopsies. A direct comparison was performed between the different PSA assays to evaluate their ability to detect prostate cancer.nnnRESULTSnOf the 535 patients evaluated, 38.1% had prostate cancer detected. The mean age of the entire population was 63.6 years (range 35 to 86). Abnormal digital rectal examination findings were present in 33.4% of the patients. The mean and median values of PSA and cPSA were significantly higher and the F/T PSA ratio was lower in patients with prostate cancer. The F/T PSA ratio performed better than either cPSA or total PSA. A higher specificity was observed with the F/T PSA ratio than with cPSA using either the entire patient population or subsets of patients with PSA levels between 4.0 and 10 ng/mL or 4.0 to 6.0 ng/mL.nnnCONCLUSIONSnThe use of the F/T PSA ratio offers improved prostate cancer detection compared with either cPSA or total PSA.

Relation of Digoxin Use in Atrial Fibrillation and the Risk of All-Cause Mortality in Patients ‡65 Years of Age With Versus Without Heart Failure

Previous studies on digoxin use in patients with atrial fibrillation (AF) and the risk of all-cause mortality found conflicting results. We conducted a population-based, retrospective, cohort study of patients aged ≥65xa0years admitted to a hospital with a primary or secondary diagnosis of AF, in Quebec province, Canada, from 1998 to 2012. The AF cohort was grouped into patients with and without heart failure (HF) and into digoxin and no-digoxin users according to the first prescription filled for digoxin within 30xa0days after AF hospital discharge. We derived propensity score-matched digoxin and no-digoxin treatment groups for the groups of patients with and without HF, respectively, and conducted multivariable Cox proportional hazards regression analyses to determine association between digoxin use and all-cause mortality. The AF propensity score-matched cohorts of patients with and without HF were well balanced on baseline characteristics. In the propensity score-matched HF group, digoxin use was associated with a 14% greater risk of all-cause mortality (adjusted hazard ratio 1.14, 95% confidence interval 1.10 to 1.17). In the propensity score-matched no-HF group, digoxin use was associated with a 17% greater risk of all-cause mortality (adjusted hazard ratio 1.17, 95% confidence interval 1.14 to 1.19). In conclusion, our retrospective analyses found that digoxin use was associated with a greater risk for all-cause mortality in patients aged ≥65xa0years with AF regardless of concomitant HF. Large, multicenter, randomized controlled trials or prospective cohort studies are required to clarify this issue.

Class effects of statins in elderly patients with congestive heart failure: A population-based analysis

BACKGROUNDnLong-term treatment with statins reduces mortality in patients with congestive heart failure (CHF). Whether statin agents exert a class effect is unknown.nnnMETHODSnWe analyzed long-term mortality in Canadian patients aged > or = 65 years who were discharged from hospital with a diagnosis of CHF from January 1998 to December 2002. Administrative data from Quebec, Ontario, and British Columbia were merged. We compared patients prescribed with atorvastatin, simvastatin, pravastatin, and lovastatin.nnnRESULTSnA total of 15,368 patients hospitalized with a diagnosis of CHF fulfilled the inclusion criteria for this study. In this final dataset, 6670 (43.4%) filled a prescription for atorvastatin, 4261 (27.7%) for simvastatin, 3209 (20.9%) for pravastatin, and 1228 (8.0%) for lovastatin. Clinical characteristics and proportion of days covered with a statin prescription were similar across groups. Drug dosages were relatively low, with 82% of patients who received the agent at a dose of < or = 20 mg. Although controlling for time-dependent covariates representing current use and dosage, as well as for age, sex, coronary artery disease, and several other comorbidities, treatment with pravastatin (adjusted hazards ratio [HR] 0.94, 95% CI 0.83-1.07), lovastatin (adjusted HR 1.02, 95% CI 0.88-1.17), or simvastatin (adjusted HR 0.92, 95% CI 0.83-1.01) had a similar effectiveness to prevent mortality compared to atorvastatin (reference in this analysis) in this population with CHF. Time-dependent exposure to a statin was highly protective against mortality.nnnCONCLUSIONSnStatins exert a class effect in patients with CHF, when used at a relatively low dose. The favorable effects appear largely independent of drug dosage.

Population-Level Incidence and Risk Factors for Pulmonary Toxicity Associated With Amiodarone

Estimates from clinical trials and small observational studies of the incidence of pulmonary toxicity (PT) associated with amiodarone range from 1% to 10%. We report a unique study of the population-based incidence and potential predictors of PT in a real-world atrial fibrillation (AF) population. We conducted a retrospective cohort study of patients ≥65 years old discharged with AF using linked administrative databases from Quebec, Canada from 1999 to 2007. Users and nonusers of amiodarone were identified by prescriptions dispensed within 7 days after hospital discharge. PT was defined through International Classification of Diseases, Ninth Revision and Tenth Revision codes for pulmonary fibrosis, alveolar/interstitial lung disease, and adult respiratory distress syndrome. Potential risk factors for PT were identified using multivariable Cox regression. PT occurred in 250 of 6,460 amiodarone users (3.87%) and 676 of 50,993 nonusers (1.33%). Age-standardized PT incidences were 28.30 and 16.02 per 1,000 person-years in men and women users, respectively, and 14.05 and 8.82 per 1,000 person-years in nonusers, respectively. It was associated with amiodarone exposure at all doses (≤200 mg/day, hazard ratio 1.62, 1.35 to 1.96; >200 mg/day, 1.46, 1.22 to 1.75). Other predictors of PT included increasing age (1.01 per year, 1.00 to 1.02), male gender (1.37, 1.19 to 1.57), chronic obstructive pulmonary disease (2.53, 2.21 to 2.89), and renal disease (1.26, 1.06 to 1.50). In conclusion, the population-based incidence of amiodarone PT is in the lower range of what has been previously reported. However, patients with AF who use amiodarone have an approximately 50% higher risk of PT than nonusers. Clinicians may be able to use the present results to identify patients at higher risk for PT and implement strategies to increase monitoring or select alternative therapy.

Population-Based Analysis of Class Effect of β Blockers in Heart Failure

The long-term use of β blockers has been shown to improve the outcomes of patients with heart failure (HF). However, it is still disputed whether this is a class effect, and, specifically, whether carvedilol or bisoprolol are superior to metoprolol. The present study was a comparative effectiveness study of β blockers for patients with HF in a population-based setting. We conducted an observational cohort study using the Quebec administrative databases to identify patients with HF who were prescribed a β blocker after the diagnosis of HF. We used descriptive statistics to characterize the patients by the type of β blocker prescribed at discharge. The unadjusted mortality for users of each β blocker was calculated using Kaplan-Meier curves and compared using the log-rank test. To account for differences in follow-up and to control for differences among patient characteristics, a multivariate Cox proportional hazards model was used to compare the mortality. Of the 26,787 patients with HF, with a median follow-up of 1.8 years per patient, the crude incidence of death was 47% with metoprolol, 40% with atenolol, 41% with carvedilol, 36% with bisoprolol, and 43% with acebutolol. After controlling for several different covariates, we found that carvedilol (hazard ratio [HR] 1.04, 95% confidence interval [CI] 0.97 to 1.12, p = 0.22) and bisoprolol (HR 0.96, 95% CI 0.91 to 1.01, p = 0.16) were not superior to metoprolol in improving survival. Atenolol (HR 0.82, 95% CI 0.77 to 0.87, p <0.0001) and acebutolol (HR 0.86, 95% CI 0.78 to 0.95, p = 0.004) were superior to metoprolol. In conclusion, we did not find evidence of a class effect for β blockers in patients with HF.

Treatment Discontinuation and Clinical Events in Type 2 Diabetes Patients Treated with Dipeptidyl Peptidase-4 Inhibitors or NPH Insulin as Third-Line Therapy

Objective To compare dipeptidyl peptidase-4 (DPP-4) inhibitors with neutral protamine Hagedorn (NPH) insulin, in terms of effectiveness and safety for the management of patients with type 2 diabetes mellitus (DM2) not controlled on metformin and sulfonylureas. Methods A retrospective cohort study of individuals with DM2 newly dispensed with either DPP-4 inhibitors or NPH as third-line therapy, after metformin and sulfonylurea. Treatment discontinuation, macrovascular outcomes, and hypoglycemia were compared using multivariable Cox regression models, adjusted for sex, age, year of cohort entry, place of residence, hypertension, past history of hypoglycemia, diabetic ketoacidosis, comorbidities, and number of visits to emergency departments, outpatient physician, and hospitalizations. Results Treatment discontinuation and hypoglycemia occurred more frequently with NPH than with DPP-4 inhibitor users. In the adjusted Cox model, the use of NPH compared to that of DPP-4 inhibitors was associated with a higher risk of discontinuation (HR: 1.33; 95% CI 1.27–1.40) and hypoglycemia (HR: 2.98; 95% CI 2.72–3.28). Risk of cardiovascular events was similar across groups. Conclusions This real-world analysis suggests that DM2 patients initiating third-line therapy with NPH have poorer control of diabetes when compared to DPP-4 inhibitor initiators.

Comparative effectiveness of antihypertensive drugs in nondiabetic patients with hypertension: A population‐based study

The authors compared the effectiveness of thiazide diuretic (TD), angiotensin‐converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), and calcium channel blocker (CCB) monotherapies for the treatment of nondiabetic hypertension using MarketScan Databases 2010–2014. Multivariable Cox regression models assessed whether the addition of a new antihypertensive drug, treatment discontinuation, or switch and major cardiovascular or cerebrovascular events varied across groups. A total of 565 009 patients started monotherapy with ACEIs (43.6%), CCBs (23.6%), TDs (18.8%), or ARBs (14.0%). Patients who took TDs had a higher risk for either drug addition or discontinuation than patients who took ACEIs (hazard ratio [HR], 0.69 [95% CI, 0.68–0.70] vs HR, 0.81 [95% CI, 0.80–0.81]), ARBs (HR, 0.67 [95% CI, 0.66–0.68] vs HR, 0.66 [95% CI, 0.65–0.67]), and CCBs (HR, 0.85 [95% CI, 0.84–0.87] vs HR, 0.94 [95% CI, 0.93–0.95]). Conversely, patients who took TDs experienced a lower risk of clinical events compared with patients who took ACEIs (HR, 1.24 [95% CI, 1.15–1.33]), ARBs (HR, 1.28 [95% CI, 1.18–1.39]), and CCBs (HR, 1.35 [95% CI, 1.25–1.46]). Our results provide a strong rationale for choosing TDs as first‐line monotherapy for the control of hypertension.