Sulfonylurea in combination with insulin is associated with increased mortality compared with a combination of insulin and metformin in a retrospective Danish nationwide study.

AIMS/HYPOTHESIS: Individual sulfonylureas (SUs) and metformin have, in some studies, been associated with unequal hypoglycaemic, cardiovascular and mortality risks when used as monotherapy in type 2 diabetes. We investigated the outcomes in patients treated with different combinations of SUs and insulin vs a combination of metformin and insulin in a retrospective nationwide study. METHODS: All Danish individuals using dual therapy with SU + insulin or metformin + insulin without prior myocardial infarction (MI) or stroke were followed from 1 January 1997 to 31 December 2009 in nationwide registries. Risks of all-cause mortality, cardiovascular death, hypoglycaemia and a composite endpoint of MI, stroke and cardiovascular death were compared. Rate ratios (RR) [95% CIs] were calculated using time-dependent multivariable Poisson regression analysis. RESULTS: A total of 11,081 patients used SU + insulin and 16,910 used metformin + insulin. Patients receiving metformin + insulin were younger and had less comorbidity and a longer history of glucose-lowering treatment. SU + insulin was associated with higher mortality rates compared with metformin + insulin (76-126 vs 23 per 1,000 person-years). In adjusted analyses, SU + insulin was associated with increased all-cause mortality (RR 1.81 [1.63, 2.01]), cardiovascular death (RR 1.35 [1.14, 1.60]) and the composite endpoint (RR 1.25 [1.09, 1.42]) compared with metformin + insulin. Hypoglycaemia was more frequent with SU + insulin than with metformin + insulin (17-23 vs six events per 1,000 person-years) and was associated with increased mortality (RR 2.13 [1.97, 2.37]). There were no significant differences in risk between individual SUs in combination with insulin. CONCLUSIONS/INTERPRETATION: In combination with insulin, the use of SUs was associated with increased mortality compared with metformin. There were no significant risk differences between SUs.

Differences between out-of-hospital cardiac arrest in residential and public locations and implications for public-access defibrillation.

BACKGROUND: The majority of out-of-hospital cardiac arrests (OHCAs) occur in residential locations, but knowledge about strategic placement of automated external defibrillators in residential areas is lacking. We examined whether residential OHCA areas suitable for placement of automated external defibrillators could be identified on the basis of demographic characteristics and characterized individuals with OHCA in residential locations. METHODS AND RESULTS: We studied 4828 OHCAs in Copenhagen between 1994 and 2005. The incidence and characteristics of OHCA were examined in every 100 x 100-m (109.4 x 109.4-yd) residential area according to its underlying demographic characteristics. By combining > or =2 demographic characteristics, it was possible to identify 100 x 100-m (109.4 x 109.4-yd) areas with at least 1 arrest every 5.6 years (characterized by >300 persons per area and lowest income) to 1 arrest every 4.3 years (characterized by >300 persons per area, lowest income, low education, and highest age). These areas covered 9.0% and 0.8% of all residential OHCAs, respectively. Individuals with OHCA in residential locations differed from public ones in that the patients were older (70.6 versus 60.6 years; P<0.0001), the ambulance response interval was longer (6.0 versus 5.0 minutes; P<0.0001), arrests occurred more often at night (21.2% versus 11.2%; P<0.0001), the patients had ventricular fibrillation less often (12.8% versus 38.1%; P<0.0001), and the patients had a worse 30-day survival rate (3.2% versus 13.9%; P<0.0001). CONCLUSIONS: On the basis of simple demographic characteristics of a city center, we could identify residential areas suitable for automated external defibrillator placement. Individuals with OHCA in residential locations were more likely to have characteristics associated with poor outcome compared with public arrests.

Temporal trends in the initiation of glucose-lowering medications after a first-time myocardial infarction - a nationwide study between 1997 and 2006.

BACKGROUND: Type 2 diabetes is a well-established risk factor for cardiovascular disease and is common among patients with acute myocardial infarction (MI). The extent to which patients with first-time MI develop diabetes requiring glucose-lowering medications (GLM) is largely unknown. The aim of the study was to investigate temporal trends in the initiation of GLM among patients discharged after first-time MI. METHODS: All Danish residents aged ≥ 30 years without prior diabetes hospitalized with first-time MI between 1997 and 2006 were identified by individual-level-linkage of nationwide registers. Initiation of GLM during follow-up was assessed by claimed prescriptions from pharmacies. Temporal trends in initiation of GLM were assessed by incidence rate calculations in the MI population as in the general population. Multivariable Cox proportional-hazard models were used to investigate the likelihood of initiating GLM within a year post-MI. RESULTS: The population comprised 66,788 patients. Among these patients 3962 patients initiated GLM, of whom 1567 started within one year post-MI. An increase in incidence rates of GLM initiation in the MI population from 19.6 per 1000 person years in 1997 to approximately 27.6 in 2001 was demonstrated. After 2001 the incidence rates stabilized. A similar trend was observed in the general population where the incidence rates increased from 2.8 in 1997 to 4.0 in 2004 and then stabilized. CONCLUSION: Our study demonstrated an increase in incidence rates of GLM initiation within the first year post- MI. A similar trend was observed in the general population suggesting that the increase in GLM among MI patients was primarily the effect of a general increased awareness of diabetes. From a public heath perspective, this study underscores a continuous need for diagnostic and therapeutic improvement in the care of MI patients that develop diabetes.

Effects of oral glucose-lowering drugs on long term outcomes in patients with diabetes mellitus following myocardial infarction not treated with emergent percutaneous coronary intervention--a retrospective nationwide cohort study.

BACKGROUND: The optimum oral pharmacological treatment of diabetes mellitus to reduce cardiovascular disease and mortality following myocardial infarction has not been established. We therefore set out to investigate the association between individual oral glucose-lowering drugs and cardiovascular outcomes following myocardial infarction in patients with diabetes mellitus not treated with emergent percutaneous coronary intervention. MATERIALS AND METHODS: All patients aged 30 years or older receiving glucose-lowering drugs (GLDs) and admitted with myocardial infarction (MI) not treated with emergent percutaneous coronary intervention in Denmark during 1997-2006 were identified by individual-level linkage of nationwide registries of hospitalizations and drug dispensing from pharmacies. Multivariable Cox regression models adjusted for age, sex, calendar year, comorbidity, and concomitant pharmacotherapy were used to assess differences in the composite endpoint of non-fatal MI and cardiovascular mortality between individual GLDs, using metformin monotherapy as reference. RESULTS: The study comprised 9876 users of GLDs admitted with MI. The mean age was 72.3 years and 56.5% of patients were men. A total of 3649 received sulfonylureas and 711 received metformin at admission. The average length of follow-up was 2.2 (SD 2.6) years. A total of 6,171 patients experienced the composite study endpoint. The sulfonylureas glibenclamide, glimepiride, glipizide, and tolbutamide were associated with increased risk of cardiovascular mortality and/or nonfatal MI with hazard ratios [HRs] of 1.31 (95% confidence interval [CI] 1.17-1.46), 1.19 (1.06-1.32), 1.25 (1.11-1.42), and 1.18 (1.03-1.34), respectively, compared with metformin. Gliclazide was the only sulfonylurea not associated with increased risk compared with metformin (HR 1.03 [0.88-1.22]). CONCLUSIONS: In patients with diabetes mellitus admitted with MI not treated with emergent percutaneous coronary intervention, monotherapy treatment with the sulfonylureas glibenclamide, glimepiride, glipizide, and tolbutamide was associated with increased cardiovascular risk compared with metformin monotherapy.

Atrial fibrillation pharmacotherapy after hospital discharge between 1995 and 2004: a shift towards beta-blockers.

AIMS: To study evolvement in pharmacotherapy of atrial fibrillation from 1995 to 2004. METHODS AND RESULTS: All Danish patients were discharged following first-time atrial fibrillation and their pharmacotherapy was identified by individual-level-linkage of nationwide registers of hospitalization and drug dispensing from pharmacies. A total of 108 791 patients survived 30 days after discharge and were included. In 1995-1996, 7.4% of the patients received beta-blockers, increasing to 44.3% in 2003-2004. The corresponding figures for amiodarone were 2.9 and 5.4%. In contrast, use of nondihydropyridine calcium-channel blockers, digoxin, sotalol, and class 1C antiarrhythmics decreased from 20.6, 63.9, 21.3, and 4.0% in 1995-1996 to 12.6, 43.8, 4.2, and 1.3% in 2003-2004, respectively. Notably, patients receiving anticoagulants increased from 29.8 to 43.5%. Multivariate logistic regression analysis revealed females to be associated with more use of digoxin, but less use of amiodarone and oral anticoagulants than males. Patients above 80 years received less pharmacotherapy, apart from digoxin treatment that was more commonly used in elderly. CONCLUSION: Pharmacotherapy of atrial fibrillation has changed towards increased beta-blocker use with a coincident decrease in the use of other rate-limiting drugs and sotalol. Treatment with amiodarone or class 1C antiarrhythmics remained very low. Oral anticoagulant therapy increased considerably, but women and elderly were apparently undertreated.

Use of statins and beta-blockers after acute myocardial infarction according to income and education.

OBJECTIVE: To study the initiation of and long-term refill persistency with statins and beta-blockers after acute myocardial infarction (AMI) according to income and education. DESIGN AND SETTING: Linkage of individuals through national registers of hospitalisations, drug dispensation, income and education. PARTICIPANTS: 30 078 patients aged 30-74 years surviving first hospitalisation for AMI in Denmark between 1995 and 2001. MAIN OUTCOME MEASURES: Initiation of statin or beta-blocker treatment (out-patient claim of prescriptions within 6 months of discharge) and refill persistency (first break in treatment lasting at least 90 days, and re-initiation of treatment after a break). RESULTS: When simultaneously estimating the effect of income and education on initiation of treatment, the effect of education attenuated and a clear income gradient remained for both drugs. Among patients aged 30-64 years, high income (adjusted hazard ratio (HR) 1.27; 95% confidence interval (CI) 1.19-1.35) and medium income (HR 1.13; 95% CI 1.06-1.20) was associated with initiation of statin treatment compared with low income. The risk of break in statin treatment was lower for patients with high (HR 0.73; 95% CI 0.66-0.82) and medium (HR 0.82; 95% CI 0.74-0.92) income compared with low income, whereas there was a trend in the opposite direction concerning a break in beta-blocker treatment. There was no gradient in re-initiation of treatment. CONCLUSION: Patients with low compared with high income less frequently initiated preventive treatment post-AMI, had worse long-term persistency with statins, but tended to have better persistency with beta-blockers. Low income by itself seems not to be associated with poor long-term refill persistency post-AMI.

Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation.

BACKGROUND: Patients with atrial fibrillation (AF) often require anticoagulation and platelet inhibition, but data are limited on the bleeding risk of combination therapy. METHODS: We performed a cohort study using nationwide registries to identify all Danish patients surviving first-time hospitalization for AF between January 1, 1997, and December 31, 2006, and their posthospital therapy of warfarin, aspirin, clopidogrel, and combinations of these drugs. Cox proportional hazards models were used to estimate risks of nonfatal and fatal bleeding. RESULTS: A total of 82,854 of 118,606 patients (69.9%) surviving AF hospitalization had at least 1 prescription filled for warfarin, aspirin, or clopidogrel after discharge. During mean (SD) follow-up of 3.3 (2.6) years, 13,573 patients (11.4%) experienced a nonfatal or fatal bleeding. The crude incidence rate for bleeding was highest for dual clopidogrel and warfarin therapy (13.9% per patient-year) and triple therapy (15.7% per patient-year). Using warfarin monotherapy as a reference, the hazard ratio (95% confidence interval) for the combined end point was 0.93 (0.88-0.98) for aspirin, 1.06 (0.87-1.29) for clopidogrel, 1.66 (1.34-2.04) for aspirin-clopidogrel, 1.83 (1.72-1.96) for warfarin-aspirin, 3.08 (2.32-3.91) for warfarin-clopidogrel, and 3.70 (2.89-4.76) for warfarin-aspirin-clopidogrel. CONCLUSIONS: In patients with AF, all combinations of warfarin, aspirin, and clopidogrel are associated with increased risk of nonfatal and fatal bleeding. Dual warfarin and clopidogrel therapy and triple therapy carried a more than 3-fold higher risk than did warfarin monotherapy.

Increased mortality and cardiovascular morbidity associated with use of nonsteroidal anti-inflammatory drugs in chronic heart failure.

BACKGROUND: Accumulating evidence indicates increased cardiovascular risk associated with nonsteroidal anti-inflammatory drug (NSAID) use, in particular in patients with established cardiovascular disease. We studied the risk of death and hospitalization because of acute myocardial infarction and heart failure (HF) associated with use of NSAIDs in an unselected cohort of patients with HF. METHODS: We identified 107,092 patients surviving their first hospitalization because of HF between January 1, 1995, and December 31, 2004, and their subsequent use of NSAIDs from individual-level linkage of nationwide registries of hospitalization and drug dispensing by pharmacies in Denmark. Data analysis was performed using Cox proportional hazard models adjusted for age, sex, calendar year, comorbidity, medical treatment, and severity of disease, and propensity-based risk-stratified models and case-crossover models. RESULTS: A total of 36,354 patients (33.9%) claimed at least 1 prescription of an NSAID after discharge; 60,974 (56.9%) died, and 8970 (8.4%) and 39,984 (37.5%) were hospitalized with myocardial infarction or HF, respectively. The hazard ratio (95% confidence interval) for death was 1.70 (1.58-1.82), 1.75 (1.63-1.88), 1.31 (1.25-1.37), 2.08 (1.95-2.21), 1.22 (1.07-1.39), and 1.28 (1.21-1.35) for rofecoxib, celecoxib, ibuprofen, diclofenac, naproxen, and other NSAIDs, respectively. Furthermore, there was a dose-dependent increase in risk of death and increased risk of hospitalization because of myocardial infarction and HF. Propensity-based risk-stratified analysis and case-crossover models yielded similar results. CONCLUSIONS: NSAIDs are frequently used in patients with HF and are associated with increased risk of death and cardiovascular morbidity. Inasmuch as even commonly used NSAIDs exerted increased risk, the balance between risk and benefit requires careful consideration when any NSAID is given to patients with HF.

Hospital variation in use of secondary preventive medicine after discharge for first acute myocardial infarction during 1995-2004.

OBJECTIVE: To examine temporal trends in hospital use of secondary preventive medicine after discharge for first acute myocardial infarction (AMI) in Denmark. DESIGN: Observational study from national administrative databases of 60,339 patients who survived a first AMI at 73 acute-care hospitals during 1995-2004. OUTCOME MEASURES: At least 1 prescription claim for angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, or statins within 90 days of discharge for AMI. FINDINGS: The odds ratios between hospitals in the highest and lowest deciles, adjusted for age, gender, period, income, comorbidity, concomitant, and prior pharmaceutical therapy, in 1995 were 8.5 [95% confidence interval (CI), 5.5-12.2] for beta-blockers, 3.0 (2.3-3.7) for ACE inhibitors, and 6.2 (4.1-8.8) for statins. By 2004, the hospital variation had decreased for beta-blockers (3.2; 2.3-4.0) and statins (4.2; 3.0-5.5) but had increased for ACE inhibitors (3.8; 2.7-4.9). All the changes over time were significant (P < 0.001). Geographical characteristics of the hospital explained 32% of the variation in use of beta-blockers in 2004 and 27% in 1995, 39% of the variation in use of ACE inhibitors in 2004 and 3% in 1995, and 29% of the variation in use of statins and 19% in 1995. CONCLUSIONS: Hospital use of secondary preventive medicine after discharge for AMI varied substantially. Hospital variation in use of beta-blockers and statins decreased with time whereas variation in use of ACE inhibitors increased. This may be attributed to gradually better agreement for the use of beta-blockers and statins and lesser agreement for the use of ACE inhibitors.

Persistent socio-economic differences in revascularization after acute myocardial infarction despite a universal health care system-a Danish study.

BACKGROUND: Use of invasive revascularization [percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG)] after acute myocardial infarction (AMI) in Denmark increased between 1996 and 2004. We investigated how this affected socioeconomic differences in their use. MATERIALS AND METHODS: All patients aged 30-74 years in hospital for a first AMI in Denmark between 1996 and 2004 were included. Cox proportional hazard models were used to estimate the association between individual income (tertiles) and education (>12, 10-12 and <10 years) and time to revascularization within 6 months. Revascularization was stratified into CABG, acute PCI (within 2 days of admission) and non-acute PCI (after the third day). RESULTS: A total of 38,803 patients were included. In 1996-1998, 6.8% received CABG, 9.3% non-acute PCI and 2.4% acute PCI; in 2002-2004, these numbers were 11.8, 36.1 and 29.1%. CABG was more likely to be performed for patients with a high income [hazard ratio (HR), 1.18; 95% confidence interval (CI), 1.08-1.28] or a medium income (HR, 1.16; 95% CI, 1.07-1.25) than for those with a low income throughout the period. A similar income gradient was seen for non-acute PCI, but not for acute PCI, for which no gradient was seen. No educational gradient was found for CABG, and that for non-acute and acute PCI decreased during the period; by the end of the period, more patients with low than high education received acute PCI. CONCLUSION: In the universal health care system of Denmark, income differences in CABG and non-acute PCI persisted, whereas no such differences were seen for acute PCI.