Jesper Lindhardsen

Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study.

Objectives To evaluate the individual risk factors composing the CHADS2 (Congestive heart failure, Hypertension, Age≥75 years, Diabetes, previous Stroke) score and the CHA2DS2-VASc (CHA2DS2-Vascular disease, Age 65-74 years, Sex category) score and to calculate the capability of the schemes to predict thromboembolism. Design Registry based cohort study. Setting Nationwide data on patients admitted to hospital with atrial fibrillation. Population All patients with atrial fibrillation not treated with vitamin K antagonists in Denmark in the period 1997-2006. Main outcome measures Stroke and thromboembolism. Results Of 121 280 patients with non-valvular atrial fibrillation, 73 538 (60.6%) fulfilled the study inclusion criteria. In patients at “low risk” (score=0), the rate of thromboembolism per 100 person years was 1.67 (95% confidence interval 1.47 to 1.89) with CHADS2 and 0.78 (0.58 to 1.04) with CHA2DS2-VASc at one year’s follow-up. In patients at “intermediate risk” (score=1), this rate was 4.75 (4.45 to 5.07) with CHADS2 and 2.01 (1.70 to 2.36) with CHA2DS2-VASc. The rate of thromboembolism depended on the individual risk factors composing the scores, and both schemes underestimated the risk associated with previous thromboembolic events. When patients were categorised into low, intermediate, and high risk groups, C statistics at 10 years’ follow-up were 0.812 (0.796 to 0.827) with CHADS2 and 0.888 (0.875 to 0.900) with CHA2DS2-VASc. Conclusions The risk associated with a specific risk stratification score depended on the risk factors composing the score. CHA2DS2-VASc performed better than CHADS2 in predicting patients at high risk, and those categorised as low risk by CHA2DS2-VASc were truly at low risk for thromboembolism.

Stroke and Bleeding in Atrial Fibrillation with Chronic Kidney Disease

BACKGROUND Both atrial fibrillation and chronic kidney disease increase the risk of stroke and systemic thromboembolism. However, these risks, and the effects of antithrombotic treatment, have not been thoroughly investigated in patients with both conditions. METHODS Using Danish national registries, we identified all patients discharged from the hospital with a diagnosis of nonvalvular atrial fibrillation between 1997 and 2008. The risk of stroke or systemic thromboembolism and bleeding associated with non-end-stage chronic kidney disease and with end-stage chronic kidney disease (i.e., disease requiring renal-replacement therapy) was estimated with the use of time-dependent Cox regression analyses. In addition, the effects of treatment with warfarin, aspirin, or both in patients with chronic kidney disease were compared with the effects in patients with no renal disease. RESULTS Of 132,372 patients included in the analysis, 3587 (2.7%) had non-end-stage chronic kidney disease and 901 (0.7%) required renal-replacement therapy at the time of inclusion. As compared with patients who did not have renal disease, patients with non-end-stage chronic kidney disease had an increased risk of stroke or systemic thromboembolism (hazard ratio, 1.49; 95% confidence interval [CI], 1.38 to 1.59; P<0.001), as did those requiring renal-replacement therapy (hazard ratio, 1.83; 95% CI, 1.57 to 2.14; P<0.001); this risk was significantly decreased for both groups of patients with warfarin but not with aspirin. The risk of bleeding was also increased among patients who had non-end-stage chronic kidney disease or required renal-replacement therapy and was further increased with warfarin, aspirin, or both. CONCLUSIONS Chronic kidney disease was associated with an increased risk of stroke or systemic thromboembolism and bleeding among patients with atrial fibrillation. Warfarin treatment was associated with a decreased risk of stroke or systemic thromboembolism among patients with chronic kidney disease, whereas warfarin and aspirin were associated with an increased risk of bleeding. (Funded by the Lundbeck Foundation.).

Association of national initiatives to improve cardiac arrest management with rates of bystander intervention and patient survival after out-of-hospital cardiac arrest

IMPORTANCE Out-of-hospital cardiac arrest is a major health problem associated with poor outcomes. Early recognition and intervention are critical for patient survival. Bystander cardiopulmonary resuscitation (CPR) is one factor among many associated with improved survival. OBJECTIVE To examine temporal changes in bystander resuscitation attempts and survival during a 10-year period in which several national initiatives were taken to increase rates of bystander resuscitation and improve advanced care. DESIGN, SETTING, AND PARTICIPANTS Patients with out-of-hospital cardiac arrest for which resuscitation was attempted were identified between 2001 and 2010 in the nationwide Danish Cardiac Arrest Registry. Of 29,111 patients with cardiac arrest, we excluded those with presumed noncardiac cause of arrest (n = 7390) and those with cardiac arrests witnessed by emergency medical services personnel (n = 2253), leaving a study population of 19,468 patients. MAIN OUTCOMES AND MEASURES Temporal trends in bystander CPR, bystander defibrillation, 30-day survival, and 1-year survival. RESULTS The median age of patients was 72 years; 67.4% were men. Bystander CPR increased significantly during the study period, from 21.1% (95% CI, 18.8%-23.4%) in 2001 to 44.9% (95% CI, 42.6%-47.1%) in 2010 (P < .001), whereas use of defibrillation by bystanders remained low (1.1% [95% CI, 0.6%-1.9%] in 2001 to 2.2% [95% CI, 1.5%-2.9%] in 2010; P = .003). More patients achieved survival on hospital arrival (7.9% [95% CI, 6.4%-9.5%] in 2001 to 21.8% [95% CI, 19.8%-23.8%] in 2010; P < .001). Also, 30-day survival improved (3.5% [95% CI, 2.5%-4.5%] in 2001 to 10.8% [95% CI, 9.4%-12.2%] in 2010; P < .001), as did 1-year survival (2.9% [95% CI, 2.0%-3.9%] in 2001 to 10.2% [95% CI, 8.9%-11.6%] in 2010; P < .001). Despite a decrease in the incidence of out-of-hospital cardiac arrests during the study period (40.4 to 34.4 per 100,000 persons in 2001 and 2010, respectively; P = .002), the number of survivors per 100,000 persons increased significantly (P < .001). For the entire study period, bystander CPR was positively associated with 30-day survival, regardless of witnessed status (30-day survival for nonwitnessed cardiac arrest, 4.3% [95% CI, 3.4%-5.2%] with bystander CPR and 1.0% [95% CI, 0.8%-1.3%] without; odds ratio, 4.38 [95% CI, 3.17-6.06]). For witnessed arrest the corresponding values were 19.4% (95% CI, 18.1%-20.7%) vs 6.1% (95% CI, 5.4%-6.7%); odds ratio, 3.74 (95% CI, 3.26-4.28). CONCLUSIONS AND RELEVANCE In Denmark between 2001 and 2010, an increase in survival following out-of-hospital cardiac arrest was significantly associated with a concomitant increase in bystander CPR. Because of the co-occurrence of other related initiatives, a causal relationship remains uncertain.

Risks of thromboembolism and bleeding with thromboprophylaxis in patients with atrial fibrillation: A net clinical benefit analysis using a ‘real world’ nationwide cohort study

It was the aim of this study to determine the efficacy and safety of vitamin K antagonists (VKAs) and acetylsalicylic acid (ASA) in patients with non-valvular atrial fibrillation (AF), with separate analyses according to predicted thromboembolic and bleeding risk. By individual level-linkage of nationwide registries, we identified all patients discharged with non-valvular AF in Denmark (n=132,372). For every patient, the risk of stroke and bleeding was calculated by CHADS₂, CHA₂DS₂-VASc, and HAS-BLED. During follow-up, treatment with VKA and ASA was determined time-dependently. VKA consistently lowered the risk of thromboembolism compared to ASA and no treatment; the combination of VKA+ASA did not yield any additional benefit. In patients at high thromboembolic risk, hazard ratios (95% confidence interval) for thromboembolism were: 1.81 (1.73-1.90), 1.14 (1.06-1.23), and 1.86 (1.78-1.95) for ASA, VKA+ASA, and no treatment, respectively, compared to VKA. The risk of bleeding was increased with VKA, ASA, and VKA+ASA compared to no treatment, the hazard ratios were: 1.0 (VKA; reference), 0.93 (ASA; 0.89-0.97), 1.64 (VKA+ASA; 1.55-1.74), and 0.84 (no treatment; 0.81-0.88), respectively. There was a neutral or positive net clinical benefit (ischaemic stroke vs. intracranial haemorrhage) with VKA alone in patients with a CHADS₂ score of ≥ 0, and CHA₂DS₂-VASc score of ≥ 1. This large cohort study confirms the efficacy of VKA and no effect of ASA treatment on the risk of stroke/thromboembolism. Also, the risk of bleeding was increased with both VKA and ASA treatment, but the net clinical benefit was clearly positive, in favour of VKA in patients with increased risk of stroke/thromboembolism.

Psoriasis is associated with clinically significant cardiovascular risk: a Danish nationwide cohort study

Abstract.  Ahlehoff O, Gislason GH, Charlot M, Jørgensen CH, Lindhardsen J, Olesen JB, Abildstrøm SZ, Skov L, Torp‐Pedersen C, Hansen PR. (Copenhagen University Hospital Gentofte, Hellerup; Copenhagen University Hospital Bispebjerg, Copenhagen; National Institute of Public Health, University of Southern Denmark, Copenhagen; Copenhagen University Hospital Gentofte, Hellerup; University of Copenhagen, Copenhagen, Denmark) Psoriasis is associated with clinically significant cardiovascular risk: a Danish nationwide cohort study. J Intern Med2011; 270: 147–157.

Duration of Treatment With Nonsteroidal Anti-Inflammatory Drugs and Impact on Risk of Death and Recurrent Myocardial Infarction in Patients With Prior Myocardial Infarction A Nationwide Cohort Study

Background— Despite the fact that nonsteroidal anti-inflammatory drugs (NSAIDs) are contraindicated among patients with established cardiovascular disease, many receive NSAID treatment for a short period of time. However, little is known about the association between NSAID treatment duration and risk of cardiovascular disease. We therefore studied the duration of NSAID treatment and cardiovascular risk in a nationwide cohort of patients with prior myocardial infarction (MI). Methods and Results— Patients ≥30 years of age who were admitted with first-time MI during 1997 to 2006 and their subsequent NSAID use were identified by individual-level linkage of nationwide registries of hospitalization and drug dispensing from pharmacies in Denmark. Risk of death and recurrent MI according to duration of NSAID treatment was analyzed by multivariable time-stratified Cox proportional-hazard models and by incidence rates per 1000 person-years. Of the 83 677 patients included, 42.3% received NSAIDs during follow-up. There were 35 257 deaths/recurrent MIs. Overall, NSAID treatment was significantly associated with an increased risk of death/recurrent MI (hazard ratio, 1.45; 95% confidence interval, 1.29 to 1.62) at the beginning of the treatment, and the risk persisted throughout the treatment course (hazard ratio, 1.55; 95% confidence interval, 1.46 to 1.64 after 90 days). Analyses of individual NSAIDs showed that the traditional NSAID diclofenac was associated with the highest risk (hazard ratio, 3.26; 95% confidence interval, 2.57 to 3.86 for death/MI at day 1 to 7 of treatment). Conclusions— Even short-term treatment with most NSAIDs was associated with increased risk of death and recurrent MI in patients with prior MI. Neither short- nor long-term treatment with NSAIDs is advised in this population, and any NSAID use should be limited from a cardiovascular safety point of view.

The risk of myocardial infarction in rheumatoid arthritis and diabetes mellitus: a Danish nationwide cohort study

Objectives To examine in a nationwide cohort whether the risk of myocardial infarction (MI) in patients with rheumatoid arthritis (RA) is comparable to the risk in patients with diabetes mellitus (DM). Methods The study included the entire Danish population followed from 1 January 1997 until 31 December 2006. Through individual level-linkage of nationwide administrative registers, the authors identified subjects who developed RA and DM. The risk of MI was analysed using multivariable Poisson regression models including data on cardioprotective drugs, comorbidity and socioeconomic status. Results From a total of 4 311 022 individuals included in the cohort, 10 477 and 130 215 individuals developed RA and DM respectively. The overall incidence rate ratio (IRR) of MI in RA was 1.7 (95% CI 1.5 to 1.9), which was similar to the risk in DM (1.7 (1.6 to 1.8); p=0.64 for difference). The risk was significantly increased in all groups when stratifying on age and gender, with higher RRs in younger patients. This was especially pronounced in women <50 years with RA or DM, who were subject to a sixfold increase in RR. The RA-related risk of MI was unaffected by the duration of pharmacological RA treatment and corresponded to the overall risk of MI observed in non-RA subjects, who were on the average 10 years older. Conclusions RA is associated with the same risk of MI as DM, and the risk of MI in RA patients generally corresponded to the risk in non-RA subjects 10 years older.

Bleeding risk in ‘real world’ patients with atrial fibrillation: comparison of two established bleeding prediction schemes in a nationwide cohort

Summary.  Background: Oral anticoagulation (OAC) in patients with atrial fibrillation (AF) is a double‐edged sword, because it decreases the risk of stroke at the cost of an increased risk of bleeding. We compared the performance of a new bleeding prediction scheme, HAS‐BLED, with an older bleeding prediction scheme, HEMORR2HAGES, in a cohort of ‘real‐world’ AF patients. Methods: By individual‐level‐linkage of nationwide registers, we identified all patients (n = 118 584) discharged with non‐valvular AF in Denmark during the period 1997–2006, with and without OAC. Major bleeding rates during 1 year of follow‐up were determined, and the predictive capabilities of the two schemes were compared by c‐statistics. The risk of bleeding associated with individual risk factors composing HAS‐BLED was estimated using Cox proportional‐hazard analyses. Results: Of AF patients receiving OAC (n = 44 771), 34.8% and 47.3% were categorized as ‘low bleeding risk’ by HAS‐BLED and HEMORR2HAGES, respectively, and the bleeding rates per 100 person‐years were 2.66 (95% confidence interval [CI], 2.40–2.94) and 3.06 (2.83–3.32), respectively. C‐statistics for the two schemes were 0.795 (0.759–0.829) and 0.771 (0.733–0.806), respectively. The risk factors composing HAS‐BLED were associated with varying risks, with a history of bleeding (hazard ratio [HR] 2.98; 95% CI 2.68–3.31) and being elderly (HR 1.93; 95% CI 1.71–2.18) being associated with the highest risks. Comparable results were found in AF patients not receiving OAC (n = 77 813). Conclusions: In an unselected nationwide cohort of hospitalized patients with atrial fibrillation, the HAS‐BLED score performs similarly to HEMORR2HAGES in predicting bleeding risk but HAS‐BLED is much simpler and easier to use in everyday clinical practise.

Psoriasis and risk of atrial fibrillation and ischaemic stroke: a Danish Nationwide Cohort Study

AIMS Psoriasis is a chronic inflammatory disease and inflammation contributes to the pathogenesis of atrial fibrillation (AF) and ischaemic stroke. We therefore investigated the risk of these endpoints in patients with psoriasis. METHODS AND RESULTS Cohort study of the entire Danish population followed from 1997 to 2006 by individual-level-linkage of nationwide prospectively recorded registers. Multivariable Poissons regression and sensitivity analyses were used to assess the psoriasis-related risk of AF and ischaemic stroke. A total of 36 765 patients with mild psoriasis and 2793 with severe psoriasis were compared with 4 478 926 individuals, i.e., the reference population. In patients with mild psoriasis, the adjusted rate ratios (RRs) for AF were 1.50 (1.21-1.86) and 1.16 (1.08-1.24) in patients aged <50 and ≥50 years, respectively. Patients with severe psoriasis had a higher risk of AF with RRs 2.98 (1.80-4.92) in patients aged <50 years and 1.29 (1.01-1.65) in patients aged ≥50 years. Patients with psoriasis also demonstrated a disease severity-dependent increased risk of ischaemic stroke, i.e. RRs 1.97 (1.66-2.34) and 2.80 (1.81-4.34) in patients aged <50 years with mild and severe psoriasis, and RRs 1.13 (1.04-1.21) and 1.34 (1.04-1.71) in patients aged ≥50 years with mild and severe psoriasis, respectively. A range of sensitivity analyses yielded comparable results. CONCLUSION Psoriasis is associated with increased risk of AF and ischaemic stroke. These novel results add to a growing body of evidence, suggesting that patients with psoriasis could be considered at increased cardiovascular risk.

Proton pump inhibitor use and risk of adverse cardiovascular events in aspirin treated patients with first time myocardial infarction: nationwide propensity score matched study

Objective To examine the effect of proton pump inhibitors on adverse cardiovascular events in aspirin treated patients with first time myocardial infarction. Design Retrospective nationwide propensity score matched study based on administrative data. Setting All hospitals in Denmark. Participants All aspirin treated patients surviving 30 days after a first myocardial infarction from 1997 to 2006, with follow-up for one year. Patients treated with clopidogrel were excluded. Main outcome measures The risk of the combined end point of cardiovascular death, myocardial infarction, or stroke associated with use of proton pump inhibitors was analysed using Kaplan-Meier analysis, Cox proportional hazard models, and propensity score matched Cox proportional hazard models. Results 3366 of 19 925 (16.9%) aspirin treated patients experienced recurrent myocardial infarction, stroke, or cardiovascular death. The hazard ratio for the combined end point in patients receiving proton pump inhibitors based on the time dependent Cox proportional hazard model was 1.46 (1.33 to 1.61; P<0.001) and for the propensity score matched model based on 8318 patients it was 1.61 (1.45 to 1.79; P<0.001). A sensitivity analysis showed no increase in risk related to use of H2 receptor blockers (1.04, 0.79 to 1.38; P=0.78). Conclusion In aspirin treated patients with first time myocardial infarction, treatment with proton pump inhibitors was associated with an increased risk of adverse cardiovascular events.