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BackgroundSurvival from out‐of‐hospital cardiac arrest (OHCA) varies across regions. The aim of this study was to evaluate the association between urbanization (rural, suburban, and urban areas), bystander interventions (cardiopulmonary resuscitation and defibrillation), and 30‐day survival from OHCAs in Denmark.Methods and ResultsWe included OHCAs not witnessed by ambulance staff in Denmark from January 1, 2016, to December 31, 2020. Patients were divided according to the Eurostat Degree of Urbanization Tool in rural, suburban, and urban areas based on the 98 Danish municipalities. Poisson regression was used to estimate incidence rate ratios. Logistic regression (adjusted for ambulance response time) tested differences between the groups with respect to bystander interventions and survival, according to degree of urbanization. A total of 21 385 OHCAs were included, of which 8496 (40%) occurred in rural areas, 7025 (33%) occurred in suburban areas, and 5864 (27%) occurred in urban areas. Baseline characteristics, as age, sex, location of OHCA, and comorbidities, were comparable between groups. The annual incidence rate ratio of OHCA was higher in rural areas (1.54 [95% CI, 1.48–1.58]) compared with urban areas. Odds for bystander cardiopulmonary resuscitation were lower in suburban (0.86 [95% CI, 0.82–0.96]) and urban areas (0.87 [95% CI, 0.80–0.95]) compared with rural areas, whereas bystander defibrillation was higher in urban areas compared with rural areas (1.15 [95% CI, 1.01–1.31]). Finally, 30‐day survival was higher in suburban (1.13 [95% CI, 1.02–1.25]) and urban areas (1.17 [95% CI, 1.05–1.30]) compared with rural areas.ConclusionsDegree of urbanization was associated with lower rates of bystander defibrillation and 30‐day survival in rural areas compared with urban areas. BACKGROUND: Survival from out-of-hospital cardiac arrest (OHCA) varies across regions. The aim of this study was to evaluate the association between urbanization (rural, suburban, and urban areas), bystander interventions (cardiopulmonary resuscitation and defibrillation), and 30-day survival from OHCAs in Denmark. METHODS AND RESULTS: We included OHCAs not witnessed by ambulance staff in Denmark from January 1, 2016, to December 31, 2020. Patients were divided according to the Eurostat Degree of Urbanization Tool in rural, suburban, and urban areas based on the 98 Danish municipalities. Poisson regression was used to estimate incidence rate ratios. Logistic regression (adjusted for ambulance response time) tested differences between the groups with respect to bystander interventions and survival, according to degree of urbanization. A total of 21 385 OHCAs were included, of which 8496 (40%) occurred in rural areas, 7025 (33%) occurred in suburban areas, and 5864 (27%) occurred in urban areas. Baseline characteristics, as age, sex, location of OHCA, and comorbidities, were comparable between groups. The annual incidence rate ratio of OHCA was higher in rural areas (1.54 [95% CI, 1.48–1.58]) compared with urban areas. Odds for bystander cardiopulmonary resuscitation were lower in suburban (0.86 [95% CI, 0.82–0.96]) and urban areas (0.87 [95% CI, 0.80–0.95]) compared with rural areas, whereas bystander defibrillation was higher in urban areas compared with rural areas (1.15 [95% CI, 1.01–1.31]). Finally, 30-day survival was higher in suburban (1.13 [95% CI, 1.02–1.25]) and urban areas (1.17 [95% CI, 1.05–1.30]) compared with rural areas. CONCLUSIONS: Degree of urbanization was associated with lower rates of bystander defibrillation and 30-day survival in rural areas compared with urban areas.

his is the sixth annual summary of the International Liaison Committee on Resuscitation International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. This summary addresses the most recently published resuscitation evidence reviewed by International Liaison Committee on Resuscitation Task Force science experts. Topics covered by systematic reviews include cardiopulmonary resuscitation during transport; approach to resuscitation after drowning; passive ventilation; minimizing pauses during cardiopulmonary resuscitation; temperature management after cardiac arrest; use of diagnostic point-of-care ultrasound during cardiac arrest; use of vasopressin and corticosteroids during cardiac arrest; coronary angiography after cardiac arrest; public-access defibrillation devices for children; pediatric early warning systems; maintaining normal temperature immediately after birth; suctioning of amniotic fluid at birth; tactile stimulation for resuscitation immediately after birth; use of continuous positive airway pressure for respiratory distress at term birth; respiratory and heart rate monitoring in the delivery room; supraglottic airway use in neonates; prearrest prediction of in-hospital cardiac arrest mortality; basic life support training for likely rescuers of high-risk populations; effect of resuscitation team training; blended learning for life support training; training and recertification for resuscitation instructors; and recovery position for maintenance of breathing and prevention of cardiac arrest. Members from 6 task forces have assessed, discussed, and debated the quality of the evidence using Grading of Recommendations Assessment, Development, and Evaluation criteria and generated consensus treatment recommendations. Insights into the deliberations of the task forces are provided in the Justification and Evidence-to-Decision Framework Highlights sections, and priority knowledge gaps for future research are listed. This is the sixth annual summary of the International Liaison Committee on Resuscitation International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. This summary addresses the most recently published resuscitation evidence reviewed by International Liaison Committee on Resuscitation Task Force science experts. Topics covered by systematic reviews include cardiopulmonary resuscitation during transport; approach to resuscitation after drowning; passive ventilation; minimizing pauses during cardiopulmonary resuscitation; temperature management after cardiac arrest; use of diagnostic point-of-care ultrasound during cardiac arrest; use of vasopressin and corticosteroids during cardiac arrest; coronary angiography after cardiac arrest; public-access defibrillation devices for children; pediatric early warning systems; maintaining normal temperature immediately after birth; suctioning of amniotic fluid at birth; tactile stimulation for resuscitation immediately after birth; use of continuous positive airway pressure for respiratory distress at term birth; respiratory and heart rate monitoring in the delivery room; supraglottic airway use in neonates; prearrest prediction of in-hospital cardiac arrest mortality; basic life support training for likely rescuers of high-risk populations; effect of resuscitation team training; blended learning for life support training; training and recertification for resuscitation instructors; and recovery position for maintenance of breathing and prevention of cardiac arrest. Members from 6 task forces have assessed, discussed, and debated the quality of the evidence using Grading of Recommendations Assessment, Development, and Evaluation criteria and generated consensus treatment recommendations. Insights into the deliberations of the task forces are provided in the Justification and Evidence-to-Decision Framework Highlights sections, and priority knowledge gaps for future research are listed.

Purpose of review To discuss different approaches to citizen responder activation and possible future solutions for improved citizen engagement in out-of-hospital cardiac arrest (OHCA) resuscitation. Recent findings Activating volunteer citizens to OHCA has the potential to improve OHCA survival by increasing bystander cardiopulmonary resuscitation (CPR) and early defibrillation. Accordingly, citizen responder systems have become widespread in numerous countries despite very limited evidence of their effect on survival or cost-effectiveness. To date, only one randomized trial has investigated the effect of citizen responder activation for which the outcome was bystander CPR. Recent publications are of observational nature with high risk of bias. A scoping review published in 2020 provided an overview of available citizen responder systems and their differences in who, when, and how to activate volunteer citizens. These differences are further discussed in this review. Summary Implementation of citizen responder programs holds the potential to improve bystander intervention in OHCA, with advancing technology offering new improvement possibilities. Information on how to best activate citizen responders as well as the effect on survival following OHCA is warranted to evaluate the cost-effectiveness of citizen responder programs.

Introduction: Pharmacotherapy with proarrhythmic or QT prolonging properties are known to augment the risk of malignant arrhythmias (e.g. TdP). We examined TdP risk drug usage prior to OHCA and how it may be associated with shockable rhythm and survival. Methods: Patients ≥18 years with an OHCA of cardiac origin were identified from the Danish Cardiac Arrest Registry (2001-2014). From nationwide registries TdP risk drug usage before OHCA according to CredibleMeds was assessed. We performed multivariable logistic regression to determine factors associated with TdP risk drug usage among OHCA patients and how usage may affect OHCA related factors (e.g. shockable rhythm or survival). Age and sex controls were identified (matching 1:5). Results: Overall, 10139 OHCA patients were identified, of which 43% were in treatment with a TdP risk drug 0-30 days before OHCA compared with 15% from the control population. Furthermore, this was significantly more than 61-90 days before OHCA (37%). Most common prescribed drugs with known risk of TdP were citalopram (31.1%), methadone (16.4%), and fluconazole (8.2%). OHCA patients in treatment with a TdP risk drug at the time of event had a significantly higher burden of comorbidities compared with OHCA patients not in treatment (e.g. cancer [19.3% and 8.7%], COPD [20.0% and 6.6%], psychiatric disease [21.9% and 13.5%], p Conclusion: Almost half of OHCA patients were in treatment with TdP risk drugs before OHCA. Subsequently, TdP risk drug usage did not modify the likelihood of presenting with a shockable rhythm as first recorded rhythm. However, this could partly be due to the large burden of comorbidities. Figure: Factors associated with TdP risk drug usage (adjusted for below mentioned factors).

Introduction: American studies have pointed out racial disparities regarding Out-of-Hospital Cardiac Arrest (OHCA) occurrence, but to date, no data exists among immigrants in Europe. Hypothesis: The risk of OHCA may vary according to region of origin among immigrants. Methods: This nationwide study included all immigrants identified from the Danish Cardiac Arrest Register with OHCA with presumed cardiac cause between 18 and 80 years from 2001 to 2014. Regions of origin were defined as Asia, Western countries, Eastern Europe, Africa, South America, and Arabic countries. Results: Overall, among 940,207 immigrants present in Denmark, a total of 1,724 (0.2%) OHCA (median 62 (IQR 50,71) years 70% males) were recorded. History of myocardial infarction, heart failure, and diabetes were present in 23%, 18%, and 16% respectively. 217 OHCA occurred in Asians, 673 in Westerners, 347 in Eastern Europeans, 107 in Africans, 19 in South Americans, and 361 in Arabic immigrants.Crude incidence rate (/ 100 000 person-years) was 15.2 (95%CI 9.14-23.7) in South American, 19.4 (95%CI 16.9-22.2) in Asian, 22.8 (95%CI 18.7-27.5) in African, 24.7 (95%CI 22.2-27.3) in Arabic, 26.2 (95%CI 23.5-29.1) in Eastern European and 32.4 (95%CI 30.0-34.9) in Western immigrants.After Cox regression, factors associated with OHCA were Eastern European origin (HR 1.28, 95%CI 1.13-1.47; P Conclusions: This is the first European study assessing the incidence of OHCA among immigrants according to their region of origin. Eastern European and African immigrants had a higher risk of OHCA compared to South American, Asian, Arabic and Western immigrants.

Introduction: In Denmark, survival after out-of-hospital cardiac arrest (OHCA) has increased markedly in the past years, from 3.9% in 2001 to 15.8% in 2019. Still, bystander defibrillation remains low, especially for OHCAs in residential areas. To improve bystander defibrillation, smartphone activated Citizen Responder (CR) Programs have expanded to nationwide coverage in Denmark during September 2017 to May 2020. Hypothesis: Implementation of CR programs in Denmark was associated with increased bystander CPR and defibrillation. Methods: We conducted an observational study of 15,308 OHCAs from the Danish Cardiac Arrest Registry from 2016-2019. App-based CR programs were implemented in four out of five Danish regions during the study period. All OHCAs were divided into two groups according to the date of CR implementation (“before” and “after CR” implementation). The groups were compared focusing on bystander defibrillation, bystander CPR and 30-day survival. Results: “Before CR” included 8,819 OHCAs and the “after CR” 6,489 OHCAs. The proportion of bystander CPR was 77.9% and 78.0% (p-value 0.91) for the before -and after CR implementation groups, respectively. The corresponding numbers for bystander defibrillation were 7.4% and 9.5% (p-value < 0.001), respectively. In residential OHCA, bystander defibrillation went from 4.0% to 6.3% (p-value Conclusion: We found no changes in bystander CPR or 30-day survival following implementation of CR programs in Denmark, but a significant increase in bystander defibrillation for all OHCAs. Importantly bystander defibrillation also increased significantly in residential locations, where the majority of OHCAs occur and where bystander defibrillation has remained low for decades.

Introduction: Following the implementation of the Danish AED network and a nationwide citizen responder (CR) program for out-of-hospital cardiac arrest (OHCA), CR and AED coverage for OHCAs according to area types has not been investigated. We aimed to assess AED and CR coverage of historical OHCAs according to area types in daytime (12pm) and nighttime (12am). Methods: We included non-EMS witnessed OHCAs from the Danish Cardiac Arrest Registry (2016-2019) and AEDs registered with the Danish AED network (November 2020) available at 12am (n=22,418) and 12pm (n=14,734). Exact locations of CRs who were registered with the national CR program by December 2020 were identified on a normal working day (Wednesday, December 2, 2020) at 12am and 12pm (representing day- and nighttime location). OHCAs, AEDs, and CRs were identified and geocoded using a geographical information system. Urban Atlas was used to categorize areas into subgroups using satellite images; high density residential areas, low density residential areas, public and industrial sites, nature, sport and leisure facilities, transportation (e.g. airport and railway stations), and fast transit roads. Results: A total of 10,126 OHCAs (63.0% male, median age 73 years). We mapped 14,119 AEDs (12 pm) and 24,372 CR (12 pm) in Urban Atlas. Most OHCAs in all area types were covered by >= 1 AED. A greater variation was observed in CR coverage when compared to AED coverage, according to area type. Little difference in coverage of both AED and CR according to time of day was observed. (Figure 1) Conclusion: The highest CR and AED coverage were observed in high density residential areas, transportation sites, public and industrial areas, and sport and leisure facilities, which is where most OHCAs occurred. These findings indicate a high coverage of citizen responders and AEDs in Denmark.

Introduction: High density of citizen responders (CR) and automated external defibrillators (AEDs) may increase chances for early bystander defibrillation in out-of-hospital cardiac arrest (OHCA). We aimed to assess coverage using current CR and AED positions applied on historical OHCAs in Denmark. Methods: Non-EMS witnessed OHCAs from the Danish cardiac arrest registry with known location (2016-2019) and AEDs registered with the Danish AED network (November 2020) were included. Locations of all CRs registered with the national CR program were identified (Wed, December 2, 2020) at 12pm (noon) and 12am (midnight). Since pilot data showed 25% of alerted CRs accepted the alarm, we investigated OHCA CR coverage defined ≥4 CR within Results: A total of 18,128 OHCAs (median age 73 years, 63.4% male) were included. A total of 22,418 AEDs (386/100,000 inhabitants) were available at 12pm, 65% were accessible 24/7. A total of 34,033 CR (586 CR/100,000 inhabitants) were available at 12am and 33,938 were available at12pm. During daytime, a median of 29 AEDs and 37 CRs were Conclusion: Following the implementation of a nationwide AED network and a citizen responder program, most historical OHCAs (85%) were < 1800m of CRs and AEDs at midnight with a slight decrease during daytime (82%). A decrease in CR and AED coverage were observed for 500m (59%) and 200 m (14%), with little difference according to time of day. During daytime a median of 29 AEDs and 37 CRs were < 1800m of historical OHCAs. Our results indicate successful implementation of a national AED registry and CR program with great potential for improving bystander defibrillation.

Introduction: Since 2007, citizens have been able to register an automated external defibrillator (AED) with the Danish AED Network, which holds >23,000 AEDs (394 AEDs/100,000 inhabitants) linked directly to the Emergency Medical Dispatch Centers. In 2019, 60.8% of sold AEDs were registered in the network. This study aimed to identify motivations and barriers for registration with the nationwide Danish AED Network. Methods: A cross-sectional survey among owners of newly registered AEDs in the Danish AED Network was carried out from September 2017 to December 2020. Each month, 30-50 random AED-owners participated. The survey included items on motivations and barriers to join the AED network and items on AED accessibility. Results: In total, 1,540 AED-owners were included (25.3 % of newly registered in the period (n=6087)). The time from AED-purchase to AED-registration was “1year” in 20.4%, and “Do not know” in 1.9%. Knowledge about the AED network is illustrated in Figure 1. Over half of the AED-owners registered their AED because they felt it was a ‘good cause’ (64.0%), followed by ‘registering upon request’ (20.6%), and ‘after a first aid course’ (5.5%). Of newly registered AEDs, 73.8% (n=1137) were 24/7-accessible. The most frequent reason for choosing limited AED accessibility (AED placed indoors/not available 24/7, n=403) was “greater expenses” (26.8%), whereas “fear of theft/vandalism” only accounted for 12.4%. Conclusion: Among AED-owners registering their AED to the Danish AED Network, most heard about the registry through word of mouth, registered their AED within the first year of purchase, and registered primarily because they felt it was a good cause. Most newly registered AEDs were 24/7-accessible. The biggest expressed barrier to AED accessibility was increased expenses whereas fear of theft or vandalism was a minor issue.

Introduction: Myocardial infarction (MI) patients with atypical symptoms receive poor prehospital management and have high mortality. We studied the importance of emergency ambulance response and prehospital aspirin use for survival of these patients. Methods: In Copenhagen, Denmark, citizens can call a 24-h non-urgent medical helpline or an emergency number 1-1-2 (equivalent to 9-1-1) for medical assistance. The primary symptom/purpose of calls is registered at both services. We included calls regarding patients hospitalized with an MI up to 24 h after the call and categorized calls according to primary symptom of chest pain or atypical symptom. Mediation analysis was used to examine the effect of modifying prehospital management. Results: We identified 5,440 calls regarding MI patients, 4,127 (76%) with chest pain and 1,313 (24%) with atypical symptoms. Compared to MI patients with chest pain, patients with atypical symptoms were older (median 73 vs 67 years), more often female (44% vs 31%), and had more often called the medical helpline (46% vs 32%). Among MI patients, 30-day mortality was 2.8% for chest pain and 10.9% for atypical symptoms. In the mediation analysis, mortality increased slightly to 11.3%, an increase of 0.3% CI95% [-1.2%; 1.8%], when changing the probability of receiving emergency ambulances for MI patients with atypical symptoms to the probability for chest pain patients. Emergency ambulances were dispatched to 4.277 (79%) of the MI patients. Among these, 30-day mortality was 2.9% for patients with chest pain and 13.1% for atypical symptoms. Changing the probability of receiving aspirin for patients with atypical symptoms to the probability for patients with chest pain decreased mortality to 10.5%. A reduction of -2.6% CI95% [-5.1%; -0.1%]. Conclusion: MI patients presenting with atypical symptoms have high mortality. Results from the mediation analysis suggest that increased prehospital use of aspirin could improve survival for these patients.

Introduction: Good quality of cardiopulmonary resuscitation (CPR) provided by bystanders is important for the outcome in out-of-hospital cardiac arrest (OHCA). A live video stream from the bystander’s smartphone to the medical dispatcher might improve the quality of chest compressions performed during CPR. Methods: At the Copenhagen Emergency Medical Services in Denmark, the medical dispatcher can add a live video to the emergency call. In case of OHCA, the medical dispatcher guides bystanders in dispatcher-assisted CPR (DA-CPR). After initiating chest compressions, the medical dispatcher can add live video streaming. A cohort study was conducted with an evaluation of performed chest compressions from the video footage before and after the dispatcher used the video to instruct CPR (video-instructed DA-CPR). Correct chest compressions were defined according to European Resuscitation Council Guidelines. Results: CPR was provided with a live video stream in 52 OHCA calls, in which 90 bystanders performed chest compressions. Thirty OHCA occurred at a public location, and more than four bystanders were present in 32 (62%) cases. In 26 cases, chest compressions were performed by more than one bystander. Eight (9%) bystanders performed correct chest compressions before video-instructed DA-CPR. For the bystanders first initiating insufficient CPR improvements were observed for: hand placement 58% (n=17/29), compressions rate 73% (n=17/21), and compressions depth 62% (n=19/31) following video-instructed DA-CPR. For the second bystander providing CPR (n=26) improvements were still observed for: hand placement 57% (n=4/7), compressions rate 73% (N=8/11), and compressions depth 53% (n=11/21) following video-instructed DA-CPR. For the third and fourth bystander (n=10), providing CPR improvements were seen for: hand placement 100% (n=2/2), compressions rate 50 % (n=2/4), and compressions depth 60% (n=3/5). Eighteen bystanders had a chest compressions performance measurement that could not be observed. Conclusions: A live video from the bystander`s smartphone to the medical dispatcher could improve the quality of chest compressions in CPR, and guidance seems important not just for the first bystander but for all bystanders performing CPR.

Introduction: Multiple citizen responder (CR) programs worldwide which dispatch laypersons to out-of-hospital cardiac arrest (OHCA) to perform cardiopulmonary resuscitation (CPR) and use of automated external defibrillators (AEDs) were affected by the COVID-19 outbreak in 2020, but little is known about how the pandemic affected CR activation and initiation of bystander CPR and defibrillation. In Denmark, the CR program continued to run during lockdown but with the recommendation to perform chest-compression-only CPR in contrast to standard CPR including ventilations. We hypothesized that bystander interventions as CPR and AED usage decreased during the first COVID-19 lockdown in two regions of Denmark in the spring of 2020. Methods: All OHCAs from January 1, 2020 to June 30, 2020 with CR activation from the Danish Cardiac Arrest Registry and the National Citizen Responder database. Bystander CPR, AED usage, and CRs’ alarm acceptance rate during the national lockdown from March 11, 2020 to April 20, 2020 were compared with the non-lockdown period from January 1, 2020 to March 10, 2020 and from April 21 to June 30, 2020. Results: A total of 6,120 CRs were alerted in 443 (23/100.000 inhabitants) cases of presumed OHCA of which 256 (58%) were confirmed cardiac arrests. Bystander CPR remained equally high in the lockdown period compared with non-lockdown period (99% vs. 92%, p=0.07). Likewise, there was no change in bystander defibrillation (9% vs. 14%, p=0.4). There was a slight increase in the number of CRs who accepted an alarm (7 per alarm, IQR 4) during lockdown compared with non-lockdown period (6 per alarm, IQR 4), p=0.0001. The proportion of patients achieving return of spontaneous circulation at hospital arrival was also unchanged (lockdown 23% vs non-lockdown 23%, p=1.0) (Table 1). Conclusion: Bystander initiated resuscitation rates did not change during the first COVID-19 lockdown in Denmark for OHCAs where CRs were activated through a smartphone app.

Introduction: Cardiopulmonary resuscitation (CPR) and early defibrillation are two of the most important factors for survival after out-of-hospital cardiac arrest (OHCA). However, little is known whether bystander interventions and survival are impaired in rural areas compared to more urbanized areas in Denmark. We hypothesized that bystander interventions and survival are lower in rural areas compared to urbanized areas. Methods: We included all non-EMS witnessed OHCAs with known GPS-location in Denmark (January 1, 2016 to December 31, 2019) and geocoded them according to county. All counties in Denmark were classified either as urban, suburban, or rural according to the degree of urbanization tool defined by the European Statistical Agency. Results: A total of 16,670 OHCAs were included, of which 4,555 (27%), 5,457 (33%), and 6,658 (40%) arrests occurred in urban, suburban, and rural areas respectively. The median age (73 vs. 74 vs. 73 years, p=0.003), ambulance response time (6 vs. 7 vs. 8 minutes, p Conclusion: Degree of urbanization was associated with increased rates of bystander CPR in rural areas. Despite this, ROSC and 30-day survival were higher in urban and suburban areas compared to rural areas which could not be explained by cardiac arrest characteristics.

Introduction: Though deployment of Automated External Defibrillators (AEDs) is increasing rapidly, AEDs are often deployed in an un-strategic manner. Consequently, little is known about the association between AED density, AED coverage of out-of-hospital cardiac arrest (OHCA), and bystander defibrillation across different countries. This study aimed to investigate the differences in AED densities (AEDS/100,000 inhabitants/1,000 km2), the AED coverage of OHCAs, and bystander defibrillation across Europe. Hypothesis: AED density is directly associated with degree of bystander defibrillation across Europe. Methods: The study is a European Sudden Cardiac Arrest network towards Prevention, Education, New Effective Treatment (ESCAPE-NET) project. We included data from Ticino (Switzerland), Lombardy (Italy), and The Capital Region (Denmark) from 2019, covering over 3.7 million inhabitants. AED accessibility was defined as the AED being accessible 24/7 or not and AED coverage was defined as the OHCA being covered by an AED within 100, 250 and 500 meters. AED coverages were calculated the same way by all participants using a free software program (QGIS). Results: AED densities were: 87.3 for Ticino, 15.2 for Lombardy, and 139.4 for The Capital Region. The percentages of OHCAs covered by any AED and by 24/7 accessible AEDs are shown in Figure 1. The calculated AED density per 1% bystander defibrillation (for the percentage of OHCAs bystander defibrillated within 100, 250 and 500m of an AED) were 34.9, 17.5 and 15.6 for Ticino, 76.0, 50.7 and 38.0 for Lombardy and 19.4, 12.6 and 11.2 for The Capital Region. Conclusion: We found great variation in both AED coverage and 24/7 AED accessibility across regions, as well as marked differences in bystander defibrillation according to local AED density. Other factors like geographical differences in the regions, optimal AED placement and citizen responder programs for AED use might explain the observed differences.

Background Citizen responder programs are implemented worldwide to dispatch volunteer citizens to participate in out‐of‐hospital cardiac arrest resuscitation. However, the risk of injuries in relation to activation is largely unknown. We aimed to assess the risk of physical injury for dispatched citizen responders. Methods and Results Since September 2017, citizen responders have been activated through a smartphone application when located close to a suspected cardiac arrest in the Capital Region of Denmark. A survey was sent to all activated citizen responders, including a specific question about risk of acquiring an injury during activation. We included all surveys from September 1, 2017, to May 15, 2020. From May 15, 2019, to May 15, 2020, we followed up on all survey nonresponders by phone call, e‐mail, or text messages to examine if nonresponders were at higher risk of severe or fatal injuries. In 1665 suspected out‐of‐hospital cardiac arrests, 9574 citizen responders were dispatched and 76.6% (7334) answered the question regarding physical injury. No injury was reported by 99.3% (7281) of the responders. Being at risk of physical injury was reported by 0.3% (24), whereas 0.4% (26) reported an injury (25 minor injuries and 1 severe injury [ankle fracture]). When following up on nonresponders (2472), we reached 99.1% (2449). No one reported acquired injuries, and only 1 reported being at risk of injury. Conclusions We found low risk of physical injury reported by volunteer citizen responders dispatched to out‐of‐hospital cardiac arrest. Risk of injury should be considered and monitored as a safety measure in citizen responder programs.

Background Mathematical optimization of automated external defibrillator (AED) placement may improve AED accessibility and out‐of‐hospital cardiac arrest (OHCA) outcomes compared with American Heart Association (AHA) and European Resuscitation Council (ERC) placement guidelines. We conducted an in silico trial (simulated prospective cohort study) comparing mathematically optimized placements with placements derived from current AHA and ERC guidelines, which recommend placement in locations where OHCAs are usually witnessed. Methods and Results We identified all public OHCAs of presumed cardiac cause from 2008 to 2016 in Copenhagen, Denmark. For the control, we computationally simulated placing 24/7‐accessible AEDs at every unique, public, witnessed OHCA location at monthly intervals over the study period. The intervention consisted of an equal number of simulated AEDs placements, deployed monthly, at mathematically optimized locations, using a model that analyzed historical OHCAs before that month. For each approach, we calculated the number of OHCAs in the study period that occurred within a 100‐m route distance based on Copenhagen’s road network of an available AED after it was placed (“OHCA coverage”). Estimated impact on bystander defibrillation and 30‐day survival was calculated by multivariate logistic regression. The control scenario involved 393 AEDs at historical, public, witnessed OHCA locations, covering 15.8% of the 653 public OHCAs from 2008 to 2016. The optimized locations provided significantly higher coverage (24.2%; P P P Conclusions Mathematical optimization can significantly improve OHCA coverage and estimated clinical outcomes compared with a guidelines‐based approach to AED placement.

Introduction: Survival from out-of-hospital cardiac arrest (OHCA) remains low and with major regional variation. This study explored differences in patients, care, and survival in patients with OHCA in North Carolina (NC), Washington State (WA), and Denmark. Methods: We identified a total of 17,277 adult patients with OHCA from the Cardiac Arrest Registry to Enhance Survival (CARES) registry and the Danish Cardiac Arrest Register of presumed cardiac cause from 2013-2014. Patients were categorized into three regions: two states in the United States (NC, 9.1 million inhabitants, WA, 7.5 million inhabitants) and the country of Denmark (5.8 million inhabitants). Outcomes of cardiopulmonary resuscitation (CPR) and defibrillation performed by either professional first responder or lay bystanders prior to emergency medical service (EMS) arrival, as well as overall survival. Data were analyzed using multivariable logistic regression analyses adjusted for age, sex, calendar year, location of arrest and witnessed status. Results: Patients in NC and WA were younger and had more racial variation compared to Denmark. Survival was 9.3% in NC, 14.5% in WA and 13.3% in Denmark. Using the Danish cohort as reference, the odds for bystander CPR and defibrillation in NC (CPR: OR 0.41, 95%CI 0.38-0.44; defibrillation: OR 0.30, 95%CI 0.23-0.38) and WA (CPR: OR 0.71, 95%CI 0.65-0.77; defibrillation: OR 0.41, 95%CI 0.31-0.53) were lower, respectively. CPR and defibrillation performed by either a bystander or a professional first responder prior to EMS arrival were higher in NC (CPR: OR 2.67, 95%CI 2.43-2.93; defibrillation: OR 2.72 95%CI 2.30-3.21), but not in WA (CPR: OR 1.01, 95%CI 0.92-1.11; defibrillation OR 0.73, 95%CI 0.58-0.90), respectively. Compared with Denmark, survival was lower in NC (OR 0.39, 95%CI 0.34-0.45) and WA (OR 0.83, 95%CI 0.72-0.95). Conclusion: Survival following OHCA was higher in Denmark and WA than in NC, and was associated with higher rates of bystander CPR and defibrillation. However, CPR and defibrillation prior to EMS arrival, mainly from professional first responders, was significantly higher in NC. A combination of both bystander and first responder interventions may be the optimal approach to improve outcomes of cardiac arrest.

Introduction: Bystander defibrillation has increased in public locations but remained stagnated around 2% in private homes, where most out-of-hospital cardiac arrests (OHCAs) occur. Hypothesis: Dispatching citizen responders through a smartphone application can increase bystander defibrillation in residential OHCAs. Methods: From September 2017-2018, a total of 23,117 (1,284/100,000) citizen responders and 5,225 (290/100,000) automated external defibrillators (AEDs) were registered in the Capital Region of Denmark (1.8 mil. inhabitants). In case of suspected OHCA, up to 20 citizen responders Results: Of 433 consecutive OHCAs included, 354 (81.8%) were residential OHCAs. Compared with citizen responders in public locations, those in residential areas were a median of 100m further away from OHCAs but were equally likely to arrive before EMS (~40% of both residential and public OHCAs). A total of 9.3% (33 of 354) of all residential OHCAs were bystander defibrillated. Citizen responders were responsible for 75.8% (25 out of 33) of all bystander defibrillated OHCAs in residential areas compared to 50.0% (13 out of 26) of all bystander defibrillated OHCAs in public areas (Table 1). Conclusions: Dispatched citizen responders arrived before EMS in 40.1% (142 of 354) of all residential OHCAs and performed three out of four of all bystander defibrillated OHCAs in residential areas.

Introduction: Unguided placement of automated external defibrillators (AEDs) often leads to placements in low risk areas and locations with limited temporal availability. Mathematical optimization may improve AED placements and increase AED use in out-of-hospital cardiac arrests (OHCAs). Aim: To conduct the first in silico public AED location trial to determine whether optimization models (interventions) trained on historical OHCA data will recommend AED locations that significantly improve OHCA coverage on prospective OHCAs, compared to locations of actually deployed AEDs (control). Methods: We identified all public OHCAs of presumed cardiac cause (1994-2016) and already deployed AEDs (2007-2016) in Copenhagen, Denmark. We computed the number of OHCAs that occurred within 100m of a temporally available AED after it was deployed (“OHCA coverage”). We then divided 2007-2016 into 30-day intervals and determined the number of AEDs deployed in each interval. Using previously validated optimization models, we determined an equal number of optimal AED locations in each time interval, either indoor locations with actual availability (intervention #1) or outdoor locations with 24/7 availability (intervention #2). OHCA coverage was calculated for the interventions similarly to the already deployed AEDs. Finally, we repeated the analysis 25 times to evaluate sensitivity and generate confidence intervals, by randomizing the location and time of the OHCAs. Results: A total of 2,149 public OHCAs (744 between 2007-2016) and 1,573 registered AEDs were identified. OHCA coverage of actually deployed AEDs was 22.3% (166 of 744 OHCAs). For optimally located indoor AEDs, mean OHCA coverage was 32.6% (mean: 242.5 OHCAs; 95% CI: 239.7 - 245.3). For optimally located outdoor AEDs, mean OHCA coverage was 43.9% (mean: 326.6 OHCAs; 95% CI: 324.0 - 329.2). Conclusions: Optimizing AED locations in a real-time deployment approach mimicking the time horizon of actual AED deployment in Copenhagen, Denmark results in significantly higher OHCA coverage compared to the actual AEDs deployed. Between the two interventions, optimal locations that are 24/7 available significantly outperform optimal indoor locations with more limited temporal availability.

Introduction: Survival after out-of-hospital cardiac arrest (OHCA) is dependent on early defibrillation. To increase bystander defibrillation in OHCAs, a first-responder program dispatching lay rescuers (Heart Runners) through a smartphone application (Heart Runner-app) was implemented in the Capital Region of Denmark. We investigated the proportion of Heart Runners arriving prior to the Emergency Medical Services (EMS) and rates of bystander defibrillation. Methods: The Capital Region of Denmark comprises 1.8 mil. inhabitants and 19,048 Heart Runners were registered. In cases of suspected OHCA, the Heart Runner-app was activated by the Emergency Medical Dispatch Center. Up to 20 Heart Runners < 1.8 km from the OHCA were dispatched to either start cardiopulmonary resuscitation (CPR) or to retrieve and use a publicly accessible automated external defibrillator (AED). Through an electronic survey, Heart Runners reported if they arrived before EMS and if they applied an AED. OHCAs where at least one Heart Runner arrived before EMS were compared with OHCAs where EMS arrived first. All OHCAs from September 2017 to May 2018, where Heart Runners had been dispatched, were included. Results: Of 399 EMS treated OHCAs, 78% (n=313/399) had a matching survey. A Heart Runner arrived before EMS in 47% (n=147/313) of the cases, and applied an AED in 41% (n=61/147) of these cases. Rate of bystander defibrillation was 2.5-fold higher compared to cases where the EMS arrived first (Table 1). Conclusions: By activation of the Heart Runner-app, Heart Runners arrived prior to EMS in nearly half of all the OHCA cases. Bystander defibrillation rate was significantly higher when Heart Runners arrived prior to EMS.

Introduction: Use of automated external defibrillators (AEDs) for early defibrillation in out-of-hospital cardiac arrest (OHCA) substantially increases chance of survival. Aim: To examine the relationship between number of nearby accessible AEDs and chance of bystander defibrillation. Methods: All OHCAs (2008-2016), and all publicly available AEDs (2007-2016) in Copenhagen were identified. The route distances between OHCAs and AEDs were calculated to determine the number of accessible AEDs ≤100m of an OHCA (OHCA coverage). Multiple logistic regression was performed to identify the adjusted Odds Ratios (ORs) of OHCA characteristics, including the number of AEDs covering an OHCA, on bystander defibrillation. The regression model was evaluated using receiver operator characteristics (ROC). Multiple logistic regression was also used to determine the predicted probability (through a 2000 iteration bootstrap approach) of bystander defibrillation for public vs. residential OHCAs, according to the number of accessible AEDs covering the OHCA, defined as covered by 0, 1 or >1 AED. Results: There were 1830 AEDs registered in Copenhagen. Of 2500 OHCAs, 75.2% (n=1879) occurred in residential locations of which 98.1% were not covered by an AED, 1.7% were covered by 1 AED only, and 0.2% were covered by >1 AED. The corresponding figures for public OHCAs (n=621, 24.8%) were 87.5%, 9.0%, and 3.5%, respectively. Overall, the number of accessible AEDs covering the OHCA, public location, bystander witnessed arrest and bystander CPR were significantly associated with bystander defibrillation (OR (95%CI): 1.75 (1.24-2.46); 4.25 (2.75-6.57); 3.12 (1.84-5.27); 2.33 (1.44-3.75), respectively. (ROC=82%)). The predicted probability of bystander defibrillation for public OHCAs was 12.2% (95%CI: 9.5-14.9) with no AED covering the OHCA, 24.7% (95%CI: 18.2-31.3) with 1 AED, and 39.8% (95%CI: 23.4-56.7) with >1 AED. The corresponding figures for residential OHCAs were 2.1% (95%CI: 1.5-2.8), 4.3% (95%CI: 2.5-6.8), and 4.0% (95%CI: 0.9-10.8), respectively. Conclusions: Rates of bystander defibrillation significantly improved with increasing number of accessible AEDs covering the OHCA, especially for public OHCAs.

Background— Although increased dissemination of automated external defibrillators (AEDs) has been associated with more frequent AED use, the trade-off between the number of deployed AEDs and coverage of cardiac arrests remains unclear. We investigated how volunteer-based AED dissemination affected public cardiac arrest coverage in high- and low-risk areas. Methods and Results— All public cardiac arrests (1994–2011) and all registered AEDs (2007–2011) in Copenhagen, Denmark, were identified and geocoded. AED coverage of cardiac arrests was defined as historical arrests ≤100 m from an AED. High-risk areas were defined as those with ≥1 arrest every 2 years and accounted for 1.0% of the total city area. Of 1864 cardiac arrests, 18.0% (n=335) occurred in high-risk areas throughout the study period. From 2007 to 2011, the number of AEDs and the corresponding coverage of cardiac arrests increased from 36 to 552 and from 2.7% to 32.6%, respectively. The corresponding increase for high-risk areas was from 1 to 30 AEDs and coverage from 5.7% to 51.3%, respectively. Since the establishment of the AED network (2007–2011), few arrests (n=55) have occurred ≤100 m from an AED with only 14.5% (n=8) being defibrillated before the arrival of emergency medical services. Conclusions— Despite the lack of a coordinated public access defibrillation program, the number of AEDs increased 15-fold with a corresponding increase in cardiac arrest coverage from 2.7% to 32.6% over a 5-year period. The highest increase in coverage was observed in high-risk areas (from 5.7% to 51.3%). AED networks can be used as useful tools to optimize AED placement in community settings.

We thank Chertoff et al, Karam et al, and El-Battrawy et al for their interest in our recently published systematic review.1 Chertoff et al suggest analyzing whether the choice of initial intervention, bystander CPR compared with direct defibrillation, has an effect on survival. Although we agree this would be of great interest, the heterogeneity of our included studies does not allow such a comparison. However, a recent large study by Kragholm et al2 showed that 1-year survival and neurological outcomes among 30-day survivors of out-of-hospital cardiac arrest (OHCA) significantly improved if the patient had …

Background— The cardiovascular risk after the first myocardial infarction (MI) declines rapidly during the first year. We analyzed whether the cardiovascular risk associated with using nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with the time elapsed following first-time MI. Methods and Results— We identified patients aged 30 years or older admitted with first-time MI in 1997 to 2009 and subsequent NSAID use by individual-level linkage of nationwide registries of hospitalization and drug dispensing from pharmacies in Denmark. We calculated the incidence rates of death and a composite end point of coronary death or nonfatal recurrent MIs associated with NSAID use in 1-year time intervals up to 5 years after inclusion and analyzed risk by using multivariable adjusted time-dependent Cox proportional hazards models. Of the 99 187 patients included, 43 608 (44%) were prescribed NSAIDs after the index MI. There were 36 747 deaths and 28 693 coronary deaths or nonfatal recurrent MIs during the 5 years of follow-up. Relative to noncurrent treatment with NSAIDs, the use of any NSAID in the years following MI was persistently associated with an increased risk of death (hazard ratio 1.59 [95% confidence interval, 1.49–1.69]) after 1 year and hazard ratio 1.63 [95% confidence interval, 1.52–1.74] after 5 years) and coronary death or nonfatal recurrent MI (hazard ratio, 1.30 [95% confidence interval,l 1.22–1.39] and hazard ratio, 1.41 [95% confidence interval, 1.28–1.55]). Conclusions— The use of NSAIDs is associated with persistently increased coronary risk regardless of time elapsed after first-time MI. We advise long-term caution in the use of NSAIDs for patients after MI.

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.

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 100×100-m (109.4×109.4-yd) residential area according to its underlying demographic characteristics. By combining ≥2 demographic characteristics, it was possible to identify 100×100-m (109.4×109.4-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 P P P P 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.

Background— Studies have raised concern on the cardiovascular safety of nonsteroidal antiinflammatory drugs (NSAIDs). We studied safety of NSAID therapy in a nationwide cohort of healthy individuals. Methods and Results— With the use of individual-level linkage of nationwide administrative registers, we identified a cohort of individuals without hospitalizations 5 years before first prescription claim of NSAIDs and without claimed drug prescriptions for selected concomitant medication 2 years previously. The risk of cardiovascular death, a composite of coronary death or nonfatal myocardial infarction, and fatal or nonfatal stroke associated with the use of NSAIDs was estimated by case-crossover and Cox proportional hazard analyses. The entire Danish population age 10 years or more consisted of 4 614 807 individuals on January 1, 1997, of which 2 663 706 (57.8%) claimed at least 1 prescription for NSAIDs during 1997 to 2005. Of these; 1 028 437 individuals were included in the study after applying selection criteria regarding comorbidity and concomitant pharmacotherapy. Use of the nonselective NSAID diclofenac and the selective cyclooxygenase-2 inhibitor rofecoxib was associated with an increased risk of cardiovascular death (odds ratio, 1.91; 95% confidence interval, 1.62 to 2.42; and odds ratio, 1.66; 95% confidence interval, 1.06 to 2.59, respectively), with a dose-dependent increase in risk. There was a trend for increased risk of fatal or nonfatal stroke associated with ibuprofen treatment (odds ratio, 1.29; 95% confidence interval, 1.02 to 1.63), but naproxen was not associated with increased cardiovascular risk (odds ratio for cardiovascular death, 0.84; 95% confidence interval, 0.50 to 1.42). Conclusions— Individual NSAIDs have different degrees of cardiovascular safety, which must be considered when choosing appropriate treatment. In particular, rofecoxib and diclofenac were associated with increased cardiovascular mortality and morbidity and should be used with caution in most individuals, whereas our results suggest that naproxen has a safer cardiovascular risk-profile.

Introduction: Cardiopulmonary resuscitation (CPR) training has been implemented widely across communities but little is known about what empowers trained bystanders to initiate and perform CPR. We sought to identify which factors that empower bystanders to initiate and perform CPR. Methods: From January 2012-April 2015, we conducted 128 semi-structured qualitative telephone interviews with bystanders to consecutive out-of-hospital cardiac arrests (OHCA) in Denmark. Purposive maximum variation sampling was used to select interviews and capture a wide range of perspectives using the following characteristics: (1) diverse demographics, (2) location of OHCA, (3) type of initial contact with OHCA, (4) resuscitation attempt alone or with others. Interviews were included until data saturation was reached. We used NVIVO software (QSR International Pty Ltd, Doncaster, VIC) to conduct in-depth qualitative thematic analysis. According to these methods, a small size is common because study validity is based upon the information richness of the selected participants rather than reaching a representative sample. Results: Bystander characteristics are shown in Table 1. Among bystanders previously trained in CPR, the following were described as empowering to initiate and perform CPR: (1) knowledge that intervention cannot cause harm and is decisive to improve survival, (2) the ability to work with other bystanders, (3) bystander leadership skills, (5) use of a ventilation mask and (6) use of an AED. Conclusions: Trained bystanders were empowered by: knowing the intervention could not cause harm and was decisive to improve survival; their leadership skills and ability to work with others; using a ventilation mask and an AED. Promoting these conditions through CPR courses, emergency dispatcher instructions as well as access to ventilation masks and AEDs is likely to increase bystander CPR rates. Implementing compression-only CPR may increase bystander CPR rates.

Background: Non steroidal anti-inflammatory drugs(NSAIDs) utilization has been associated with worsened outcomes among patients with established cardiovascular disease.We analyzed the cause-specific cardiovascular risk associated with use of NSAIDs in a nationwide cohort of patients with prior myocardial infarction (MI). Methods: By individual-level linkage of nationwide registries of hospitalizations and drug dispenses from pharmacies in Denmark, patients aged >30 years admitted with first-time MI during 1997-2009 and their subsequent NSAID use were identified. The risk of cardiovascular death, a composite of coronary death or nonfatal MI, and fatal or nonfatal stroke with NSAID use was analyzed by adjusted Cox proportional hazard models. Results: Of 97,698 patients included (mean age 69 years (SD 13.0), 63.0% men),44.0% received NSAIDs during follow-up. Relative to no NSAID use, overall NSAID was associated with an increased risk of cardiovascular death (hazard ratio [HR] 1.52 95% confidence interval [CI] 1.34-1.73). In particular, use of the nonselective NSAID diclofenac and the selective cyclooxygenase-2 (COX-2) inhibitor rofecoxib was associated with increased risk of cardiovascular death (HR 2.05 95% confidence interval CI 1.88-2.23) and HR 1.74(CI.1.53-1.98), respectively) with a dose dependent increase in risk. Use of ibuprofen was associated with increased risk of fatal/nonfatal stroke (HR 1.27(CI. 1.14-1.41)).Naproxen was associated with the lowest risk of all outcomes, although higher than no NSAID use. Conclusion: The cause specific cardiovascular risks associated with the use of individual NSAIDs found to differ and in particular rofecoxib and diclofenac were associated with increased cardiovascular morbidity and mortality. These results further support caution in use of NSAIDs in patients with prior MI.

Background: Use of NSAID has shown to be associated with a substantially increased risk of athero-thrombotic adverse events in patients with a history of myocardial infarction. Whether a similar increase in risk is found for VTE is unknown. Methods: Patients aged >30 years admitted with first-time MI during 1997-2009 and their subsequent NSAID use were identified by individual-level linkage of nationwide registries of hospitalization and drug dispensing from pharmacies in Denmark. The risk of VTE associated with NSAID use was analyzed by time-dependent Cox proportional hazard models adjusted for age, gender, calendar year, concomitant drug use, and comorbidity. Results A total of 98,901 patients were included (mean age 68 years (SD 13.0), 64.0% men), 44.0% received NSAIDs during follow-up. There were 1847 VTEs. Relative to no NSAID use, the Cox-analyses showed increased risk of VTE with use of any NSAIDs. Overall NSAID use was associated with increased risk of VTE (Hazard ratio [HR] 1.75 95% confidence interval [CI] 1.52-2.02). In particular use of the selective cyclooxygenase-2 (COX-2) inhibitors rofecoxib and the nonselective NSAID diclofenac was associated with significantly increased risk of VTE (HR 2.56 (CI 1.60-4.08) and HR 2.03(CI.1.50-2.74), respectively). Conclusion: Use of most NSAIDs was associated with an increased risk of VTE. The use of rofecoxib and diclofenac was associated with highest risk. Further studies, preferably randomized clinical studies, are warranted to establish the cardiovascular safety of NSAIDs, however this study suggests that risk of VTE should be considered when prescribing NSAIDs patients with MI.

We appreciate the interest in our article in Circulation 1 and welcome further discussion on this important topic. Dr Naimer, Dr Alla, and colleagues comment on the influence that stress and rheumatic diseases have on risk in patients. We agree that confounding by indication may influence observational studies such as ours, and that lack of information on nonsteroidal anti-inflammatory drug (NSAID) treatment indication is a limitation of the study. However, our findings were consistent, and we found different degree of risk between the individual NSAIDs, which were probably all used for the same indications, a clear correlation between the degree of cyclooxygenase-2 inhibition (as reported in the literature) and risk, and a clear dose-dependent increase in …