Thromboembolic events around the time of cardioversion for atrial fibrillation in patients receiving antiplatelet treatment in the ACTIVE trials

Thromboembolic events around the time of cardioversion for atrial fibrillation in patients... Abstract Aims It is unknown whether cardioversion of atrial fibrillation causes thromboembolic events or is a risk marker. To assess causality, we examined the temporal pattern of thromboembolism in patients having cardioversion. Methods and results We studied patients randomized to aspirin or aspirin plus clopidogrel in the ACTIVE trials, comparing the thromboembolic rate in the peri-cardioversion period (30 days before until 30 days after) to the rate during follow-up, remote from cardioversion. Among 962 patients, the 30-day thromboembolic rate remote from cardioversion was 0.16%; while it was 0.73% in the peri-cardioversion period [hazard ratio (HR) 4.1, 95% confidence interval (CI) 2.1–7.9]. The 30-day thromboembolic rates in the periods immediately before and after cardioversion were 0.47% and 0.96%, respectively (HR 2.2, 95% CI 0.7–7.1). Heart failure (HF) hospitalization increased in the peri-cardioversion period (HR 11.5, 95% CI 6.8–19.4). Compared to baseline, the thromboembolic rate in the 30 days following cardioversion was increased both in patients who received oral anticoagulation or a transoesophageal echocardiogram prior to cardioversion (HR 7.9, 95% CI 2.8–22.4) and in those who did not (HR 4.8, 95% CI 1.6–14.9) (interaction P = 0.2); the risk was also increased with successful (HR 4.5; 95% CI 2.0–10.5) and unsuccessful (HR 10.2; 95% CI 2.3–44.9) cardioversion. Conclusions Thromboembolic risk increased in the 30 days before cardioversion and persisted until 30 days post-cardioversion, in a pattern similar to HF hospitalization. These data suggest that the increased thromboembolic risk around the time of cardioversion may not be entirely causal, but confounded by the overall clinical deterioration of patients requiring cardioversion. Open in new tabDownload slide Open in new tabDownload slide Atrial fibrillation, Cardioversion, Stroke, Rhythm control Introduction Cardioversion is frequently performed in patients with atrial fibrillation (AF), with the goal of restoring sinus rhythm and thus improving quality of life.1 Thromboembolic events, including ischaemic stroke, are recognized as a potential complication of cardioversion,2–4 with a 30-day incidence previously estimated between 0% and 7%.5–10 It is widely believed that cardioversion causes stroke, either by facilitating the expulsion of existing thrombus from the left atrial appendage (LAA) or by transiently impairing the mechanical function of the LA and precipitating the formation of new thrombus.9,11–15 However, patients who require cardioversion may have additional risk factors, including a higher-risk pattern of AF, larger LA size and greater thrombin activation, which among others, contribute to independently increase the risk of thromboembolism.16–18 If cardioversion is causally related to thromboembolic events, there would be an increased risk of events following, but not prior to attempted cardioversion. In order to test this hypothesis, we examined patients having cardioversion in the antiplatelet arms of the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE) programme. The ACTIVE-A and ACTIVE-W clinical trials included 962 patients with AF who underwent cardioversion during the trial and were assigned to antithrombotic therapy with single or dual-antiplatelet therapy, rather than oral anticoagulation (OAC). These trials provide a unique opportunity to assess the temporal risk of thromboembolic events before and after cardioversion for AF, in the absence of background OAC therapy. Methods Study population This analysis used prospectively collected data on cardioversion for patients enrolled in the ACTIVE programme.19 The ACTIVE programme included two different randomized trials comparing antithrombotic strategies. ACTIVE-W was a non-inferiority trial of clopidogrel plus acetylsalicylic acid vs. warfarin in patients with AF and at least one risk factor for stroke.20 ACTIVE-A was a double-blind, placebo-controlled trial of aspirin vs. clopidogrel plus aspirin in patients with AF who also had at least one risk factor for stroke and were unsuitable for chronic treatment with OAC.21 To be eligible for either ACTIVE trial, patients must have had permanent AF or at least two episodes of intermittent AF in the 6 months prior to enrolment.19 They were also required to have at least one of the following risk factors: (i) age >75 years; (ii) systemic hypertension requiring treatment; (iii) prior stroke, transient ischaemic attack (TIA), or systemic embolus; (iv) left ventricular dysfunction with left ventricular ejection fraction <45%; (v) documented peripheral vascular disease; (vi) age 55–74 years and either of diabetes mellitus requiring drug therapy or documented previous myocardial infarction or coronary artery disease. Exclusions were the requirement for clopidogrel or for OAC, documented peptic ulcer disease within the previous 6 months, prior intracerebral haemorrhage, significant thrombocytopenia, and mitral stenosis. Patients randomized to clopidogrel plus aspirin in ACTIVE-W and randomized to either arm in ACTIVE-A were the subjects of this analysis. All patients undergoing cardioversion during the study were included in the analysis. The primary outcome of the analysis was the monthly risk of a thromboembolic event, specifically: ischaemic stroke, systemic embolism, or TIA. The diagnosis of stroke required focal neurological symptoms with rapid onset, lasting at least 24 h.19 A blinded, independent expert confirmed all events. The secondary outcome was the occurrence of hospitalization for heart failure (HF). We considered events occurring in three periods: the 30 days prior to first attempted cardioversion, the 30 days following attempted cardioversion, and all other follow-up time both before and after those periods. Statistical analyses Baseline characteristics are presented with mean and standard deviation for normally distributed variables and median and interquartile range for non-normally distributed variables. We created a Cox regression model with cardioversion status treated as a time-dependent covariate to estimate the 30-day effect of the first attempted cardioversion on the risk of thromboembolic events. This model included three different time periods: the 30 days prior to cardioversion, the 30 days following cardioversion, and the remainder of follow-up time. Follow-up time was censored at the time of any second cardioversion. First, we performed an unadjusted analysis. Subsequently, we adjusted for the participants’ CHA2DS2-VASc score. In ACTIVE, anti-embolic management around the time of cardioversion was open-label and at the discretion of the local clinician. Accordingly, models were stratified according to the use of ‘guideline-based therapy’ as a binary covariate. This was defined as either the use of therapeutic OAC for at least 3 weeks before and after cardioversion or performance of a transoesophageal echocardiogram (TOE) to exclude LAA thrombus, followed by at least 3 weeks of OAC.2–4 All other strategies, including the use of anti-platelets or intravenous heparin, were considered ‘not guideline-based’. In subgroup analyses, we compared cardioversions done electrically and pharmacologically, cardioversions that were successful (defined as discharge in sinus rhythm) and unsuccessful, and cardioversions that were done while patients were or were not hospitalized. In order to explore the possibility that cardioversion is a more general marker of cardiovascular risk, we used a similar approach to evaluate the relationship between cardioversion and hospitalization for HF. Temporal patterns of the risk of thromboembolic events and hospitalization for HF before and after first cardioversion were illustrated with a non-parametric ‘moving-average’ plot. Sequentially overlapping subgroups were created using sliding window approach.22 Each subgroup included patients who contributed person-time to the corresponding sliding 90-day time window. The ‘step size’ between two adjacent subgroups was 10 days. The 90-day event rate was calculated for each subgroup and plotted against corresponding median time. A locally weighted smoothing curve with point-wise 95% confidence intervals (CIs) was fitted to show the overall trend. Statistical significance was claimed if P-value <0.05. All analyses were conducted using SAS version 9.4 (SAS institute Inc., Cary, NC, USA). Results Among 14 261 patients enrolled in the ACTIVE programme (either ACTIVE-A or ACTIVE-W), there were 10 889 randomized to either aspirin alone or to clopidogrel plus aspirin. Of these, 962 (8.8%) had cardioversion during the study, with a median time to first cardioversion of 222 (interquartile range 63–552) days and a median follow-up after cardioversion of 379 (interquartile range 77–980) days. Baseline characteristics of these patients appear in Table 1. Table 1 Baseline characteristics of patients undergoing cardioversion (for the first cardioversion only) All (N = 962) Age (years), mean ± SD 65.5 ± 9.8 Age (≥75), n (%) 176 (18.3) Sex (male), n (%) 557 (57.9) Hypertension, n (%) 865 (89.9) Diabetes, n (%) 156 (16.2) Previous stroke or TIA, n (%) 71 (7.4) Heart failure, n (%) 189 (19.7) CHA2DS2-VASc score, median (IQR) 3.0 (2.0–4.0) Categorized CHA2DS2-VASc score, n (%)  0–1 168 (17.5)  2 247 (25.7)  3–5 502 (52.2)  >5 44 (4.6) AF type, n (%)  Paroxysmal, n (%) 471 (49.1)  Non-paroxysmal, n (%) 488 (50.8) Valvular heart disease, n (%) 265 (27.6) Coronary artery disease, n (%) 252 (26.2) Myocardial infarction, n (%) 117 (12.2) Previous bleeding, n (%) 99 (10.3) Antiarrhythmic drug, n (%) 548 (57.0) Peripheral arterial disease, n (%) 26 (2.7) Cardioversion during cardiovascular hospitalization, n (%) 459 (47.7) ASA, n (%) 384 (39.9) ASA + clopidogrel, n (%) 578 (60.1) All (N = 962) Age (years), mean ± SD 65.5 ± 9.8 Age (≥75), n (%) 176 (18.3) Sex (male), n (%) 557 (57.9) Hypertension, n (%) 865 (89.9) Diabetes, n (%) 156 (16.2) Previous stroke or TIA, n (%) 71 (7.4) Heart failure, n (%) 189 (19.7) CHA2DS2-VASc score, median (IQR) 3.0 (2.0–4.0) Categorized CHA2DS2-VASc score, n (%)  0–1 168 (17.5)  2 247 (25.7)  3–5 502 (52.2)  >5 44 (4.6) AF type, n (%)  Paroxysmal, n (%) 471 (49.1)  Non-paroxysmal, n (%) 488 (50.8) Valvular heart disease, n (%) 265 (27.6) Coronary artery disease, n (%) 252 (26.2) Myocardial infarction, n (%) 117 (12.2) Previous bleeding, n (%) 99 (10.3) Antiarrhythmic drug, n (%) 548 (57.0) Peripheral arterial disease, n (%) 26 (2.7) Cardioversion during cardiovascular hospitalization, n (%) 459 (47.7) ASA, n (%) 384 (39.9) ASA + clopidogrel, n (%) 578 (60.1) AF, atrial fibrillation; ASA, acetylsalicylic acid; IQR, interquartile range; SD, standard deviation; TIA, transient ischaemic attack. Open in new tab Table 1 Baseline characteristics of patients undergoing cardioversion (for the first cardioversion only) All (N = 962) Age (years), mean ± SD 65.5 ± 9.8 Age (≥75), n (%) 176 (18.3) Sex (male), n (%) 557 (57.9) Hypertension, n (%) 865 (89.9) Diabetes, n (%) 156 (16.2) Previous stroke or TIA, n (%) 71 (7.4) Heart failure, n (%) 189 (19.7) CHA2DS2-VASc score, median (IQR) 3.0 (2.0–4.0) Categorized CHA2DS2-VASc score, n (%)  0–1 168 (17.5)  2 247 (25.7)  3–5 502 (52.2)  >5 44 (4.6) AF type, n (%)  Paroxysmal, n (%) 471 (49.1)  Non-paroxysmal, n (%) 488 (50.8) Valvular heart disease, n (%) 265 (27.6) Coronary artery disease, n (%) 252 (26.2) Myocardial infarction, n (%) 117 (12.2) Previous bleeding, n (%) 99 (10.3) Antiarrhythmic drug, n (%) 548 (57.0) Peripheral arterial disease, n (%) 26 (2.7) Cardioversion during cardiovascular hospitalization, n (%) 459 (47.7) ASA, n (%) 384 (39.9) ASA + clopidogrel, n (%) 578 (60.1) All (N = 962) Age (years), mean ± SD 65.5 ± 9.8 Age (≥75), n (%) 176 (18.3) Sex (male), n (%) 557 (57.9) Hypertension, n (%) 865 (89.9) Diabetes, n (%) 156 (16.2) Previous stroke or TIA, n (%) 71 (7.4) Heart failure, n (%) 189 (19.7) CHA2DS2-VASc score, median (IQR) 3.0 (2.0–4.0) Categorized CHA2DS2-VASc score, n (%)  0–1 168 (17.5)  2 247 (25.7)  3–5 502 (52.2)  >5 44 (4.6) AF type, n (%)  Paroxysmal, n (%) 471 (49.1)  Non-paroxysmal, n (%) 488 (50.8) Valvular heart disease, n (%) 265 (27.6) Coronary artery disease, n (%) 252 (26.2) Myocardial infarction, n (%) 117 (12.2) Previous bleeding, n (%) 99 (10.3) Antiarrhythmic drug, n (%) 548 (57.0) Peripheral arterial disease, n (%) 26 (2.7) Cardioversion during cardiovascular hospitalization, n (%) 459 (47.7) ASA, n (%) 384 (39.9) ASA + clopidogrel, n (%) 578 (60.1) AF, atrial fibrillation; ASA, acetylsalicylic acid; IQR, interquartile range; SD, standard deviation; TIA, transient ischaemic attack. Open in new tab Electrical cardioversion was used in 481 (50%) cases and pharmacological cardioversion was used in the other 480 (50%). The overall success rate in restoring sinus rhythm was 88.6%. Table 2 lists the antithromboembolic strategies that were used at the time of cardioversion. Table 2 Antithrombotic strategy used at the time of cardioversion All (N = 962), n (%) Guideline-based therapya 277 (28.8)  OAC ≥3 weeks prior to cardioversion 212 (22.0)  TOE (without OAC ≥3 weeks prior to cardioversion) 65 (6.8) Non-guideline-based therapyb 685 (71.2)  OAC <3 weeks 29 (3.0)  ASA + clopidogrel 254 (26.4)  ASA alone 287 (29.8)  Clopidogrel alone 0 (0.0)  Intravenous heparin 36 (3.7)  LMWH 100 (10.4)  tPA 1 (0.1)  Other 14 (1.5)  None 60 (6.2) All (N = 962), n (%) Guideline-based therapya 277 (28.8)  OAC ≥3 weeks prior to cardioversion 212 (22.0)  TOE (without OAC ≥3 weeks prior to cardioversion) 65 (6.8) Non-guideline-based therapyb 685 (71.2)  OAC <3 weeks 29 (3.0)  ASA + clopidogrel 254 (26.4)  ASA alone 287 (29.8)  Clopidogrel alone 0 (0.0)  Intravenous heparin 36 (3.7)  LMWH 100 (10.4)  tPA 1 (0.1)  Other 14 (1.5)  None 60 (6.2) ASA, acetylsalicylic acid; LMWH, low molecular weight heparin; OAC, oral anticoagulation; TOE, transoesophageal echocardiogram; tPA, tissue plasminogen activator. a Defined as the patients with TOE prior to cardioversion or with OAC ≥3 weeks. b Defined as the patients with no TOE prior to cardioversion and no OAC ≥3 weeks. Components are not mutually exclusive. Eighty-five patients took two therapies; four patients took three therapies; one patient took four therapies. Open in new tab Table 2 Antithrombotic strategy used at the time of cardioversion All (N = 962), n (%) Guideline-based therapya 277 (28.8)  OAC ≥3 weeks prior to cardioversion 212 (22.0)  TOE (without OAC ≥3 weeks prior to cardioversion) 65 (6.8) Non-guideline-based therapyb 685 (71.2)  OAC <3 weeks 29 (3.0)  ASA + clopidogrel 254 (26.4)  ASA alone 287 (29.8)  Clopidogrel alone 0 (0.0)  Intravenous heparin 36 (3.7)  LMWH 100 (10.4)  tPA 1 (0.1)  Other 14 (1.5)  None 60 (6.2) All (N = 962), n (%) Guideline-based therapya 277 (28.8)  OAC ≥3 weeks prior to cardioversion 212 (22.0)  TOE (without OAC ≥3 weeks prior to cardioversion) 65 (6.8) Non-guideline-based therapyb 685 (71.2)  OAC <3 weeks 29 (3.0)  ASA + clopidogrel 254 (26.4)  ASA alone 287 (29.8)  Clopidogrel alone 0 (0.0)  Intravenous heparin 36 (3.7)  LMWH 100 (10.4)  tPA 1 (0.1)  Other 14 (1.5)  None 60 (6.2) ASA, acetylsalicylic acid; LMWH, low molecular weight heparin; OAC, oral anticoagulation; TOE, transoesophageal echocardiogram; tPA, tissue plasminogen activator. a Defined as the patients with TOE prior to cardioversion or with OAC ≥3 weeks. b Defined as the patients with no TOE prior to cardioversion and no OAC ≥3 weeks. Components are not mutually exclusive. Eighty-five patients took two therapies; four patients took three therapies; one patient took four therapies. Open in new tab During the follow-up time excluding the 30 days before and 30 days after cardioversion, 43 thromboembolic events occurred, corresponding to an average rate of 0.16 events per 30 patient days (Table 3, Take home figure). In the 30 days immediately prior to cardioversion, 4 events occurred, corresponding to a rate of 0.47 events per 30 patient days. Nine thromboembolic events occurred within 30 days following cardioversion; the rate was 0.96 events per 30 patient days. As compared with the time period that was not within 60 days of cardioversion, the risk of thromboembolic events was increased in the 60-day period centred on the day of cardioversion [0.73% per 30 days, adjusted hazard ratio (HR) 4.1, 95% CI 2.1–7.9]. The adjusted HR for thromboembolic events in the 30 days before cardioversion was 2.6; 95% CI 0.9–7.4 and in the 30 days following cardioversion, it was 5.6, 95% CI 2.6–12.1. The risk of thromboembolic events was not significantly different in the 30 days following cardioversion as compared to the 30 days before (adjusted HR 2.2, 95% CI 0.7–7.1). Table 3 Association between cardioversion and the incidence of thromboembolic events Not within 30 days of cardioversion Within 30 days before cardioversion Within 30 days after cardioversion Unadjusted Adjusted for CHA2DS2-VASc score Within 30 days before cardioversiona Within 30 days after cardioversiona Within 30 days before cardioversiona Within 30 days after cardioversiona Events/ patients Event rate (%/30 days) Events/ patients Event rate (%/30 days) Events/ patients Event rate (%/30 days) HR (95% CI) P-value HR (95% CI) P-value HR (95% CI) P-value HR (95% CI) P-value All patients 43/962 0.16 4/962 0.47 9/962 0.96 2.7 (0.9–7.6) 0.07 5.4 (2.5–11.6) <0.001 2.6 (0.9–7.4) 0.08 5.6 (2.6–12.1) <0.001 Patients who received guideline-based therapy prior to cardioversionb 21/277 0.22 0/277 0 5/277 1.9 — — 7.9 (2.8–22.0) <0.001 — — 7.9 (2.8–22.4) <0.001 Patients who did not receive guideline-based therapy prior to cardioversionb 22/685 0.13 4/685 0.67 4/685 0.6 5.5 (1.8–16.6) 0.003 4.8 (1.6–14.7) 0.006 5.4 (1.8–16.4) 0.003 4.8 (1.6–14.9) 0.006 Not within 30 days of cardioversion Within 30 days before cardioversion Within 30 days after cardioversion Unadjusted Adjusted for CHA2DS2-VASc score Within 30 days before cardioversiona Within 30 days after cardioversiona Within 30 days before cardioversiona Within 30 days after cardioversiona Events/ patients Event rate (%/30 days) Events/ patients Event rate (%/30 days) Events/ patients Event rate (%/30 days) HR (95% CI) P-value HR (95% CI) P-value HR (95% CI) P-value HR (95% CI) P-value All patients 43/962 0.16 4/962 0.47 9/962 0.96 2.7 (0.9–7.6) 0.07 5.4 (2.5–11.6) <0.001 2.6 (0.9–7.4) 0.08 5.6 (2.6–12.1) <0.001 Patients who received guideline-based therapy prior to cardioversionb 21/277 0.22 0/277 0 5/277 1.9 — — 7.9 (2.8–22.0) <0.001 — — 7.9 (2.8–22.4) <0.001 Patients who did not receive guideline-based therapy prior to cardioversionb 22/685 0.13 4/685 0.67 4/685 0.6 5.5 (1.8–16.6) 0.003 4.8 (1.6–14.7) 0.006 5.4 (1.8–16.4) 0.003 4.8 (1.6–14.9) 0.006 HR, hazard ratio. a Reference is not within 30 days of cardioversion. b Guideline-based therapy was defined as either oral anticoagulation for ≥3 weeks prior to cardioversion or a transoesophageal echocardiogram prior to cardioversion. Open in new tab Table 3 Association between cardioversion and the incidence of thromboembolic events Not within 30 days of cardioversion Within 30 days before cardioversion Within 30 days after cardioversion Unadjusted Adjusted for CHA2DS2-VASc score Within 30 days before cardioversiona Within 30 days after cardioversiona Within 30 days before cardioversiona Within 30 days after cardioversiona Events/ patients Event rate (%/30 days) Events/ patients Event rate (%/30 days) Events/ patients Event rate (%/30 days) HR (95% CI) P-value HR (95% CI) P-value HR (95% CI) P-value HR (95% CI) P-value All patients 43/962 0.16 4/962 0.47 9/962 0.96 2.7 (0.9–7.6) 0.07 5.4 (2.5–11.6) <0.001 2.6 (0.9–7.4) 0.08 5.6 (2.6–12.1) <0.001 Patients who received guideline-based therapy prior to cardioversionb 21/277 0.22 0/277 0 5/277 1.9 — — 7.9 (2.8–22.0) <0.001 — — 7.9 (2.8–22.4) <0.001 Patients who did not receive guideline-based therapy prior to cardioversionb 22/685 0.13 4/685 0.67 4/685 0.6 5.5 (1.8–16.6) 0.003 4.8 (1.6–14.7) 0.006 5.4 (1.8–16.4) 0.003 4.8 (1.6–14.9) 0.006 Not within 30 days of cardioversion Within 30 days before cardioversion Within 30 days after cardioversion Unadjusted Adjusted for CHA2DS2-VASc score Within 30 days before cardioversiona Within 30 days after cardioversiona Within 30 days before cardioversiona Within 30 days after cardioversiona Events/ patients Event rate (%/30 days) Events/ patients Event rate (%/30 days) Events/ patients Event rate (%/30 days) HR (95% CI) P-value HR (95% CI) P-value HR (95% CI) P-value HR (95% CI) P-value All patients 43/962 0.16 4/962 0.47 9/962 0.96 2.7 (0.9–7.6) 0.07 5.4 (2.5–11.6) <0.001 2.6 (0.9–7.4) 0.08 5.6 (2.6–12.1) <0.001 Patients who received guideline-based therapy prior to cardioversionb 21/277 0.22 0/277 0 5/277 1.9 — — 7.9 (2.8–22.0) <0.001 — — 7.9 (2.8–22.4) <0.001 Patients who did not receive guideline-based therapy prior to cardioversionb 22/685 0.13 4/685 0.67 4/685 0.6 5.5 (1.8–16.6) 0.003 4.8 (1.6–14.7) 0.006 5.4 (1.8–16.4) 0.003 4.8 (1.6–14.9) 0.006 HR, hazard ratio. a Reference is not within 30 days of cardioversion. b Guideline-based therapy was defined as either oral anticoagulation for ≥3 weeks prior to cardioversion or a transoesophageal echocardiogram prior to cardioversion. Open in new tab Take home figure Open in new tabDownload slide Incidence of thromboembolism according to time from cardioversion—all 962 patients. Each circle represents the 90-day event rate for all the patients who contributed person-time to that 90-day time interval. The ‘step size’ between two adjacent circles is 10 days. The solid line is a locally weighted smoothing curve and the grey area delimits the point-wise 95% confidence interval for this estimate. Take home figure Open in new tabDownload slide Incidence of thromboembolism according to time from cardioversion—all 962 patients. Each circle represents the 90-day event rate for all the patients who contributed person-time to that 90-day time interval. The ‘step size’ between two adjacent circles is 10 days. The solid line is a locally weighted smoothing curve and the grey area delimits the point-wise 95% confidence interval for this estimate. A guideline-based strategy was used in 277 patients (29%); this included 22% who used therapeutic OAC for ≥3 weeks before and 4 weeks after cardioversion and 7% who underwent a TOE and then received OAC for 4 weeks. The risk of thromboembolism in the 30 days following cardioversion was increased both in patients who received guideline-based anti-embolic therapy (adjusted HR 7.9, 95% CI 2.8–22.4) and in those who did not (adjusted HR 4.8; 95% CI 1.6–14.9) (Table 3). This risk was not significantly different between these two groups (P for interaction = 0.2). When electrical and pharmacological cardioversions were considered separately, patients who were cardioverted by either means had a significantly higher risk of thromboembolic events in the 30 days following cardioversion as compared to the rest of the follow-up period (adjusted HR 6.4; 95% CI 2.5–16.7 for electrical and adjusted HR 4.2; 95% CI 1.5–12.0 for pharmacological). There was no significant difference in risk between electrical and chemical cardioversion (P = 0.5). The risk of embolism in the 30 days following cardioversion was increased among individuals for whom cardioversion was successful (adjusted HR 4.5; 95% CI 2.0–10.5) and among patients with failed cardioversion (adjusted HR 10.2; 95% CI 2.3–44.9). There was no significant difference between successful and unsuccessful cardioversion (P = 0.3). When cardioversions performed on hospitalized (n = 459) and non-hospitalized (n = 503) patients were considered separately (Figure 1), patients who were cardioverted while hospitalized for a cardiovascular reason had a significantly higher risk of thromboembolic events in the 30 days following cardioversion as compared to the rest of the follow-up period (adjusted HR 7.4, 95% CI 3.2–17.1) while the risk was not increased among those who were cardioverted while they were not hospitalized (adjusted HR 2.5; 95% CI 0.6–10.5). However, this difference in risks between these two groups was not statistically significant (P = 0.2). Figure 1 Open in new tabDownload slide Incidence of thromboembolism according to time from cardioversion—459 hospitalized (A) and 503 non-hospitalized (B) patients. Each circle represents the 90-day event rate for all the patients who contributed person-time to that 90-day time interval. The ‘step size’ between two adjacent circles is 10 days. The solid line is a locally weighted smoothing curve and the grey area delimits the point-wise 95% confidence interval for this estimate. Figure 1 Open in new tabDownload slide Incidence of thromboembolism according to time from cardioversion—459 hospitalized (A) and 503 non-hospitalized (B) patients. Each circle represents the 90-day event rate for all the patients who contributed person-time to that 90-day time interval. The ‘step size’ between two adjacent circles is 10 days. The solid line is a locally weighted smoothing curve and the grey area delimits the point-wise 95% confidence interval for this estimate. The risk of HF hospitalization was increased in the peri-cardioversion period (adjusted HR 11.5, 95% CI 6.8–19.4). This risk was increased in both in the 30 days before cardioversion (adjusted HR 13.0; 95% CI 7.1–24.0) and in the 30 days following cardioversion (adjusted HR 9.8; 95% CI 4.9–19.6), this difference was not statistically significant (P = 0.5). Figure 2 models the temporal changes in the risk of HF hospitalization before and after cardioversion. Figure 2 Open in new tabDownload slide Incidence of hospitalization for heart failure according to time from cardioversion—all 962 patients. Each circle represents the 90-day event rate for all the patients who contributed person-time to that 90-day time interval. The ‘step size’ between two adjacent circles is 10 days. The solid line is a locally weighted smoothing curve and the grey area delimits the point-wise 95% confidence interval for this estimate. Figure 2 Open in new tabDownload slide Incidence of hospitalization for heart failure according to time from cardioversion—all 962 patients. Each circle represents the 90-day event rate for all the patients who contributed person-time to that 90-day time interval. The ‘step size’ between two adjacent circles is 10 days. The solid line is a locally weighted smoothing curve and the grey area delimits the point-wise 95% confidence interval for this estimate. Discussion The main finding of this study is that among patients undergoing cardioversion, the risk of thromboembolism increases over the 30 days prior to cardioversion and returns to baseline over the 30 days following the procedure. The increased risk during the peri-cardioversion period is present whether or not sinus rhythm is successfully restored by cardioversion, and whether or not patients receive guideline-based OAC in the peri-cardioversion period. Cardioversions that are performed on hospitalized patients appear to confer the highest risk of thromboembolism. The risk of hospitalization for HF follows a similar temporal pattern as the risk of thromboembolism. Together, these data suggest that cardioversion may not directly cause all thromboembolic events in the peri-cardioversion period, but some events may represent an epiphenomenon of clinical deterioration in patients selected for cardioversion. In the 1960s, shortly after the advent of cardioversion, clinicians recognized an increased rate of embolic events occurring around the time of this procedure.7,23 Investigators also noted that patients who were taking chronic OAC had lower rates than those who were not.8,24 In 1969, Bjerkelund and Orning8 published a prospective observational cohort study of 437 patients who underwent cardioversion, reporting that the crude rate of embolic events was significantly lower in patients who were taking OAC (0.8% vs. 5.3%, P = 0.02). This study played a key role in the formulation of early clinical practice guidelines.9,25 These guidelines remain largely unchanged today, as there have been no randomized data testing to determine if anticoagulation at the time of cardioversion improves outcomes in patients who would otherwise not require anticoagulation for management of their AF.2,3,26 It is not known if cardioversion directly causes embolic stroke, but two potential mechanisms have been proposed: (i) restoration of mechanical function leading to ejection of existing thrombus from the LAA9,11 and (ii) cardioversion-induced electromechanical stunning and the formation of de novo thrombus in the LAA.12–15 There is, however, little direct evidence that either of these mechanisms actually cause stroke in humans. In the present study, we observed that the risk of thromboembolic events began to increase prior to cardioversion, peaked around the time of cardioversion and returned to baseline thereafter. This temporal pattern suggests that, at least in some patients, cardioversion is a marker for increased risk of thromboembolic events rather than a direct cause. This is supported by three other observations. First, the increased risk of stroke following cardioversion was not different between patients in whom cardioversion was successful or unsuccessful. Second, the increased risk of stroke at time of cardioversion was similar in patients managed with guideline-based OAC prior to cardioversion as compared with those in whom OAC was not used. Third, we observed a similar increase in risk of HF hospitalization in the peri-cardioversion period as we observed for thromboembolic events. The observed increase in the risk of thromboembolism prior to cardioversion is likely underestimated, as it is plausible that many clinicians might have avoided cardioversion in a patient with a recent stroke for fear of precipitating a second event. This further suggests that part of the increase in thromboembolic risk is the result of the overall clinical status of the patient who dictated the need for cardioversion, rather than the direct result of cardioversion itself. In this study, patients who had their cardioversion while hospitalized appeared to be at higher risk of thromboembolism. Thus, the indication for hospitalization and cardioversion appear to be a marker of thromboembolic risk; rather than cardioversion solely being the direct cause of stroke. This observation is not unique to this cohort; in the ACUTE trial, 57% of all deaths in the peri-cardioversion period were due to HF or were sudden, and most of these patients had New York Heart Association III or IV symptoms at the time of cardioversion.10 Furthermore, prior publications have demonstrated that HF is the most common cause of death in patients with AF, an independent risk factor for stroke in patients with AF, and an independent risk factor for cardioversion-associated thromboembolism.27,28 Finally, investigators have also demonstrated that a significant proportion of AF-related strokes are not cardioembolic, which again supports the idea that the need for cardioversion is acting as a risk marker for thromboembolism in the peri-cardioversion period.29,30 The findings of this observational study are hypothesis-generating. However, they provide rationale for future randomized trials of peri-cardioversion anticoagulation, particularly in low-risk patients (i.e. CHA2DS2-VASc score of 0). Limitations The key weakness of this post-hoc study is the observational design, which limits the inference of causality. Even after adjustment for known prognostic factors, the findings remain subject to residual confounding. Additionally, the number of participants and events was small, but this study still is one of the largest cardioversion studies among patients not receiving OAC. Finally, we did not collect specific information on the indication for cardioversion—this could confound the relationship between any acute underlying conditions and the occurrence of thromboembolic events. Conclusions Atrial fibrillation patients undergoing cardioversion have an increased thromboembolic risk. This risk increases before cardioversion is performed, and is present regardless of whether cardioversion was successful and whether or not OAC or TOE were used prior to cardioversion. This temporal pattern suggests that at least part of the thromboembolic risk associated with cardioversion is not causal. Ethical Committee Approval Local ethics committees at enrolling centres approved the original ACTIVE trials. Acknowledgement The authors would like to acknowledge Dr Emilie Belley-Côté for her assistance with a systematic review to guide this study. Conflict of interest: W.F.M. reports personal fees from Servier, from Bayer, from BMS-Pfizer, outside the submitted work. S.J.C. reports grants and personal fees from PORTOLA PHARMACEUTICALS, grants and personal fees from BRISTOL MYERS SQUIBB, grants and personal fees from BAYER, grants and personal fees from DAIICHI SANKYO, outside the submitted work. A.P.B. reports other from St. Jude Medical/Abbott, outside the submitted work. D.C. reports personal fees from Servier, outside the submitted work. J.S.H. reports grants and personal fees from BMS/Pfizer, grants from Medtronic, grants from Boston Scientific, personal fees from Servier, outside the submitted work. All other authors declared no conflict of interest. See page 3033 for the editorial comment on this article (doi: 10.1093/eurheartj/ehz563) References 1 Sandhu RK , Smigorowsky M , Lockwood E , Savu A , Kaul P , McAlister FA. Impact of electrical cardioversion on quality of life for the treatment of atrial fibrillation . Can J Cardiol 2017 ; 33 : 450 – 455 . 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Google Scholar Crossref Search ADS PubMed WorldCat 30 Kamel H , Okin PM , Elkind MSV , Iadecola C. Atrial fibrillation and mechanisms of stroke: time for a new model . Stroke 2016 ; 47 : 895 – 900 . Google Scholar Crossref Search ADS PubMed WorldCat Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Heart Journal Oxford University Press

Thromboembolic events around the time of cardioversion for atrial fibrillation in patients receiving antiplatelet treatment in the ACTIVE trials

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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.
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Abstract

Abstract Aims It is unknown whether cardioversion of atrial fibrillation causes thromboembolic events or is a risk marker. To assess causality, we examined the temporal pattern of thromboembolism in patients having cardioversion. Methods and results We studied patients randomized to aspirin or aspirin plus clopidogrel in the ACTIVE trials, comparing the thromboembolic rate in the peri-cardioversion period (30 days before until 30 days after) to the rate during follow-up, remote from cardioversion. Among 962 patients, the 30-day thromboembolic rate remote from cardioversion was 0.16%; while it was 0.73% in the peri-cardioversion period [hazard ratio (HR) 4.1, 95% confidence interval (CI) 2.1–7.9]. The 30-day thromboembolic rates in the periods immediately before and after cardioversion were 0.47% and 0.96%, respectively (HR 2.2, 95% CI 0.7–7.1). Heart failure (HF) hospitalization increased in the peri-cardioversion period (HR 11.5, 95% CI 6.8–19.4). Compared to baseline, the thromboembolic rate in the 30 days following cardioversion was increased both in patients who received oral anticoagulation or a transoesophageal echocardiogram prior to cardioversion (HR 7.9, 95% CI 2.8–22.4) and in those who did not (HR 4.8, 95% CI 1.6–14.9) (interaction P = 0.2); the risk was also increased with successful (HR 4.5; 95% CI 2.0–10.5) and unsuccessful (HR 10.2; 95% CI 2.3–44.9) cardioversion. Conclusions Thromboembolic risk increased in the 30 days before cardioversion and persisted until 30 days post-cardioversion, in a pattern similar to HF hospitalization. These data suggest that the increased thromboembolic risk around the time of cardioversion may not be entirely causal, but confounded by the overall clinical deterioration of patients requiring cardioversion. Open in new tabDownload slide Open in new tabDownload slide Atrial fibrillation, Cardioversion, Stroke, Rhythm control Introduction Cardioversion is frequently performed in patients with atrial fibrillation (AF), with the goal of restoring sinus rhythm and thus improving quality of life.1 Thromboembolic events, including ischaemic stroke, are recognized as a potential complication of cardioversion,2–4 with a 30-day incidence previously estimated between 0% and 7%.5–10 It is widely believed that cardioversion causes stroke, either by facilitating the expulsion of existing thrombus from the left atrial appendage (LAA) or by transiently impairing the mechanical function of the LA and precipitating the formation of new thrombus.9,11–15 However, patients who require cardioversion may have additional risk factors, including a higher-risk pattern of AF, larger LA size and greater thrombin activation, which among others, contribute to independently increase the risk of thromboembolism.16–18 If cardioversion is causally related to thromboembolic events, there would be an increased risk of events following, but not prior to attempted cardioversion. In order to test this hypothesis, we examined patients having cardioversion in the antiplatelet arms of the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE) programme. The ACTIVE-A and ACTIVE-W clinical trials included 962 patients with AF who underwent cardioversion during the trial and were assigned to antithrombotic therapy with single or dual-antiplatelet therapy, rather than oral anticoagulation (OAC). These trials provide a unique opportunity to assess the temporal risk of thromboembolic events before and after cardioversion for AF, in the absence of background OAC therapy. Methods Study population This analysis used prospectively collected data on cardioversion for patients enrolled in the ACTIVE programme.19 The ACTIVE programme included two different randomized trials comparing antithrombotic strategies. ACTIVE-W was a non-inferiority trial of clopidogrel plus acetylsalicylic acid vs. warfarin in patients with AF and at least one risk factor for stroke.20 ACTIVE-A was a double-blind, placebo-controlled trial of aspirin vs. clopidogrel plus aspirin in patients with AF who also had at least one risk factor for stroke and were unsuitable for chronic treatment with OAC.21 To be eligible for either ACTIVE trial, patients must have had permanent AF or at least two episodes of intermittent AF in the 6 months prior to enrolment.19 They were also required to have at least one of the following risk factors: (i) age >75 years; (ii) systemic hypertension requiring treatment; (iii) prior stroke, transient ischaemic attack (TIA), or systemic embolus; (iv) left ventricular dysfunction with left ventricular ejection fraction <45%; (v) documented peripheral vascular disease; (vi) age 55–74 years and either of diabetes mellitus requiring drug therapy or documented previous myocardial infarction or coronary artery disease. Exclusions were the requirement for clopidogrel or for OAC, documented peptic ulcer disease within the previous 6 months, prior intracerebral haemorrhage, significant thrombocytopenia, and mitral stenosis. Patients randomized to clopidogrel plus aspirin in ACTIVE-W and randomized to either arm in ACTIVE-A were the subjects of this analysis. All patients undergoing cardioversion during the study were included in the analysis. The primary outcome of the analysis was the monthly risk of a thromboembolic event, specifically: ischaemic stroke, systemic embolism, or TIA. The diagnosis of stroke required focal neurological symptoms with rapid onset, lasting at least 24 h.19 A blinded, independent expert confirmed all events. The secondary outcome was the occurrence of hospitalization for heart failure (HF). We considered events occurring in three periods: the 30 days prior to first attempted cardioversion, the 30 days following attempted cardioversion, and all other follow-up time both before and after those periods. Statistical analyses Baseline characteristics are presented with mean and standard deviation for normally distributed variables and median and interquartile range for non-normally distributed variables. We created a Cox regression model with cardioversion status treated as a time-dependent covariate to estimate the 30-day effect of the first attempted cardioversion on the risk of thromboembolic events. This model included three different time periods: the 30 days prior to cardioversion, the 30 days following cardioversion, and the remainder of follow-up time. Follow-up time was censored at the time of any second cardioversion. First, we performed an unadjusted analysis. Subsequently, we adjusted for the participants’ CHA2DS2-VASc score. In ACTIVE, anti-embolic management around the time of cardioversion was open-label and at the discretion of the local clinician. Accordingly, models were stratified according to the use of ‘guideline-based therapy’ as a binary covariate. This was defined as either the use of therapeutic OAC for at least 3 weeks before and after cardioversion or performance of a transoesophageal echocardiogram (TOE) to exclude LAA thrombus, followed by at least 3 weeks of OAC.2–4 All other strategies, including the use of anti-platelets or intravenous heparin, were considered ‘not guideline-based’. In subgroup analyses, we compared cardioversions done electrically and pharmacologically, cardioversions that were successful (defined as discharge in sinus rhythm) and unsuccessful, and cardioversions that were done while patients were or were not hospitalized. In order to explore the possibility that cardioversion is a more general marker of cardiovascular risk, we used a similar approach to evaluate the relationship between cardioversion and hospitalization for HF. Temporal patterns of the risk of thromboembolic events and hospitalization for HF before and after first cardioversion were illustrated with a non-parametric ‘moving-average’ plot. Sequentially overlapping subgroups were created using sliding window approach.22 Each subgroup included patients who contributed person-time to the corresponding sliding 90-day time window. The ‘step size’ between two adjacent subgroups was 10 days. The 90-day event rate was calculated for each subgroup and plotted against corresponding median time. A locally weighted smoothing curve with point-wise 95% confidence intervals (CIs) was fitted to show the overall trend. Statistical significance was claimed if P-value <0.05. All analyses were conducted using SAS version 9.4 (SAS institute Inc., Cary, NC, USA). Results Among 14 261 patients enrolled in the ACTIVE programme (either ACTIVE-A or ACTIVE-W), there were 10 889 randomized to either aspirin alone or to clopidogrel plus aspirin. Of these, 962 (8.8%) had cardioversion during the study, with a median time to first cardioversion of 222 (interquartile range 63–552) days and a median follow-up after cardioversion of 379 (interquartile range 77–980) days. Baseline characteristics of these patients appear in Table 1. Table 1 Baseline characteristics of patients undergoing cardioversion (for the first cardioversion only) All (N = 962) Age (years), mean ± SD 65.5 ± 9.8 Age (≥75), n (%) 176 (18.3) Sex (male), n (%) 557 (57.9) Hypertension, n (%) 865 (89.9) Diabetes, n (%) 156 (16.2) Previous stroke or TIA, n (%) 71 (7.4) Heart failure, n (%) 189 (19.7) CHA2DS2-VASc score, median (IQR) 3.0 (2.0–4.0) Categorized CHA2DS2-VASc score, n (%)  0–1 168 (17.5)  2 247 (25.7)  3–5 502 (52.2)  >5 44 (4.6) AF type, n (%)  Paroxysmal, n (%) 471 (49.1)  Non-paroxysmal, n (%) 488 (50.8) Valvular heart disease, n (%) 265 (27.6) Coronary artery disease, n (%) 252 (26.2) Myocardial infarction, n (%) 117 (12.2) Previous bleeding, n (%) 99 (10.3) Antiarrhythmic drug, n (%) 548 (57.0) Peripheral arterial disease, n (%) 26 (2.7) Cardioversion during cardiovascular hospitalization, n (%) 459 (47.7) ASA, n (%) 384 (39.9) ASA + clopidogrel, n (%) 578 (60.1) All (N = 962) Age (years), mean ± SD 65.5 ± 9.8 Age (≥75), n (%) 176 (18.3) Sex (male), n (%) 557 (57.9) Hypertension, n (%) 865 (89.9) Diabetes, n (%) 156 (16.2) Previous stroke or TIA, n (%) 71 (7.4) Heart failure, n (%) 189 (19.7) CHA2DS2-VASc score, median (IQR) 3.0 (2.0–4.0) Categorized CHA2DS2-VASc score, n (%)  0–1 168 (17.5)  2 247 (25.7)  3–5 502 (52.2)  >5 44 (4.6) AF type, n (%)  Paroxysmal, n (%) 471 (49.1)  Non-paroxysmal, n (%) 488 (50.8) Valvular heart disease, n (%) 265 (27.6) Coronary artery disease, n (%) 252 (26.2) Myocardial infarction, n (%) 117 (12.2) Previous bleeding, n (%) 99 (10.3) Antiarrhythmic drug, n (%) 548 (57.0) Peripheral arterial disease, n (%) 26 (2.7) Cardioversion during cardiovascular hospitalization, n (%) 459 (47.7) ASA, n (%) 384 (39.9) ASA + clopidogrel, n (%) 578 (60.1) AF, atrial fibrillation; ASA, acetylsalicylic acid; IQR, interquartile range; SD, standard deviation; TIA, transient ischaemic attack. Open in new tab Table 1 Baseline characteristics of patients undergoing cardioversion (for the first cardioversion only) All (N = 962) Age (years), mean ± SD 65.5 ± 9.8 Age (≥75), n (%) 176 (18.3) Sex (male), n (%) 557 (57.9) Hypertension, n (%) 865 (89.9) Diabetes, n (%) 156 (16.2) Previous stroke or TIA, n (%) 71 (7.4) Heart failure, n (%) 189 (19.7) CHA2DS2-VASc score, median (IQR) 3.0 (2.0–4.0) Categorized CHA2DS2-VASc score, n (%)  0–1 168 (17.5)  2 247 (25.7)  3–5 502 (52.2)  >5 44 (4.6) AF type, n (%)  Paroxysmal, n (%) 471 (49.1)  Non-paroxysmal, n (%) 488 (50.8) Valvular heart disease, n (%) 265 (27.6) Coronary artery disease, n (%) 252 (26.2) Myocardial infarction, n (%) 117 (12.2) Previous bleeding, n (%) 99 (10.3) Antiarrhythmic drug, n (%) 548 (57.0) Peripheral arterial disease, n (%) 26 (2.7) Cardioversion during cardiovascular hospitalization, n (%) 459 (47.7) ASA, n (%) 384 (39.9) ASA + clopidogrel, n (%) 578 (60.1) All (N = 962) Age (years), mean ± SD 65.5 ± 9.8 Age (≥75), n (%) 176 (18.3) Sex (male), n (%) 557 (57.9) Hypertension, n (%) 865 (89.9) Diabetes, n (%) 156 (16.2) Previous stroke or TIA, n (%) 71 (7.4) Heart failure, n (%) 189 (19.7) CHA2DS2-VASc score, median (IQR) 3.0 (2.0–4.0) Categorized CHA2DS2-VASc score, n (%)  0–1 168 (17.5)  2 247 (25.7)  3–5 502 (52.2)  >5 44 (4.6) AF type, n (%)  Paroxysmal, n (%) 471 (49.1)  Non-paroxysmal, n (%) 488 (50.8) Valvular heart disease, n (%) 265 (27.6) Coronary artery disease, n (%) 252 (26.2) Myocardial infarction, n (%) 117 (12.2) Previous bleeding, n (%) 99 (10.3) Antiarrhythmic drug, n (%) 548 (57.0) Peripheral arterial disease, n (%) 26 (2.7) Cardioversion during cardiovascular hospitalization, n (%) 459 (47.7) ASA, n (%) 384 (39.9) ASA + clopidogrel, n (%) 578 (60.1) AF, atrial fibrillation; ASA, acetylsalicylic acid; IQR, interquartile range; SD, standard deviation; TIA, transient ischaemic attack. Open in new tab Electrical cardioversion was used in 481 (50%) cases and pharmacological cardioversion was used in the other 480 (50%). The overall success rate in restoring sinus rhythm was 88.6%. Table 2 lists the antithromboembolic strategies that were used at the time of cardioversion. Table 2 Antithrombotic strategy used at the time of cardioversion All (N = 962), n (%) Guideline-based therapya 277 (28.8)  OAC ≥3 weeks prior to cardioversion 212 (22.0)  TOE (without OAC ≥3 weeks prior to cardioversion) 65 (6.8) Non-guideline-based therapyb 685 (71.2)  OAC <3 weeks 29 (3.0)  ASA + clopidogrel 254 (26.4)  ASA alone 287 (29.8)  Clopidogrel alone 0 (0.0)  Intravenous heparin 36 (3.7)  LMWH 100 (10.4)  tPA 1 (0.1)  Other 14 (1.5)  None 60 (6.2) All (N = 962), n (%) Guideline-based therapya 277 (28.8)  OAC ≥3 weeks prior to cardioversion 212 (22.0)  TOE (without OAC ≥3 weeks prior to cardioversion) 65 (6.8) Non-guideline-based therapyb 685 (71.2)  OAC <3 weeks 29 (3.0)  ASA + clopidogrel 254 (26.4)  ASA alone 287 (29.8)  Clopidogrel alone 0 (0.0)  Intravenous heparin 36 (3.7)  LMWH 100 (10.4)  tPA 1 (0.1)  Other 14 (1.5)  None 60 (6.2) ASA, acetylsalicylic acid; LMWH, low molecular weight heparin; OAC, oral anticoagulation; TOE, transoesophageal echocardiogram; tPA, tissue plasminogen activator. a Defined as the patients with TOE prior to cardioversion or with OAC ≥3 weeks. b Defined as the patients with no TOE prior to cardioversion and no OAC ≥3 weeks. Components are not mutually exclusive. Eighty-five patients took two therapies; four patients took three therapies; one patient took four therapies. Open in new tab Table 2 Antithrombotic strategy used at the time of cardioversion All (N = 962), n (%) Guideline-based therapya 277 (28.8)  OAC ≥3 weeks prior to cardioversion 212 (22.0)  TOE (without OAC ≥3 weeks prior to cardioversion) 65 (6.8) Non-guideline-based therapyb 685 (71.2)  OAC <3 weeks 29 (3.0)  ASA + clopidogrel 254 (26.4)  ASA alone 287 (29.8)  Clopidogrel alone 0 (0.0)  Intravenous heparin 36 (3.7)  LMWH 100 (10.4)  tPA 1 (0.1)  Other 14 (1.5)  None 60 (6.2) All (N = 962), n (%) Guideline-based therapya 277 (28.8)  OAC ≥3 weeks prior to cardioversion 212 (22.0)  TOE (without OAC ≥3 weeks prior to cardioversion) 65 (6.8) Non-guideline-based therapyb 685 (71.2)  OAC <3 weeks 29 (3.0)  ASA + clopidogrel 254 (26.4)  ASA alone 287 (29.8)  Clopidogrel alone 0 (0.0)  Intravenous heparin 36 (3.7)  LMWH 100 (10.4)  tPA 1 (0.1)  Other 14 (1.5)  None 60 (6.2) ASA, acetylsalicylic acid; LMWH, low molecular weight heparin; OAC, oral anticoagulation; TOE, transoesophageal echocardiogram; tPA, tissue plasminogen activator. a Defined as the patients with TOE prior to cardioversion or with OAC ≥3 weeks. b Defined as the patients with no TOE prior to cardioversion and no OAC ≥3 weeks. Components are not mutually exclusive. Eighty-five patients took two therapies; four patients took three therapies; one patient took four therapies. Open in new tab During the follow-up time excluding the 30 days before and 30 days after cardioversion, 43 thromboembolic events occurred, corresponding to an average rate of 0.16 events per 30 patient days (Table 3, Take home figure). In the 30 days immediately prior to cardioversion, 4 events occurred, corresponding to a rate of 0.47 events per 30 patient days. Nine thromboembolic events occurred within 30 days following cardioversion; the rate was 0.96 events per 30 patient days. As compared with the time period that was not within 60 days of cardioversion, the risk of thromboembolic events was increased in the 60-day period centred on the day of cardioversion [0.73% per 30 days, adjusted hazard ratio (HR) 4.1, 95% CI 2.1–7.9]. The adjusted HR for thromboembolic events in the 30 days before cardioversion was 2.6; 95% CI 0.9–7.4 and in the 30 days following cardioversion, it was 5.6, 95% CI 2.6–12.1. The risk of thromboembolic events was not significantly different in the 30 days following cardioversion as compared to the 30 days before (adjusted HR 2.2, 95% CI 0.7–7.1). Table 3 Association between cardioversion and the incidence of thromboembolic events Not within 30 days of cardioversion Within 30 days before cardioversion Within 30 days after cardioversion Unadjusted Adjusted for CHA2DS2-VASc score Within 30 days before cardioversiona Within 30 days after cardioversiona Within 30 days before cardioversiona Within 30 days after cardioversiona Events/ patients Event rate (%/30 days) Events/ patients Event rate (%/30 days) Events/ patients Event rate (%/30 days) HR (95% CI) P-value HR (95% CI) P-value HR (95% CI) P-value HR (95% CI) P-value All patients 43/962 0.16 4/962 0.47 9/962 0.96 2.7 (0.9–7.6) 0.07 5.4 (2.5–11.6) <0.001 2.6 (0.9–7.4) 0.08 5.6 (2.6–12.1) <0.001 Patients who received guideline-based therapy prior to cardioversionb 21/277 0.22 0/277 0 5/277 1.9 — — 7.9 (2.8–22.0) <0.001 — — 7.9 (2.8–22.4) <0.001 Patients who did not receive guideline-based therapy prior to cardioversionb 22/685 0.13 4/685 0.67 4/685 0.6 5.5 (1.8–16.6) 0.003 4.8 (1.6–14.7) 0.006 5.4 (1.8–16.4) 0.003 4.8 (1.6–14.9) 0.006 Not within 30 days of cardioversion Within 30 days before cardioversion Within 30 days after cardioversion Unadjusted Adjusted for CHA2DS2-VASc score Within 30 days before cardioversiona Within 30 days after cardioversiona Within 30 days before cardioversiona Within 30 days after cardioversiona Events/ patients Event rate (%/30 days) Events/ patients Event rate (%/30 days) Events/ patients Event rate (%/30 days) HR (95% CI) P-value HR (95% CI) P-value HR (95% CI) P-value HR (95% CI) P-value All patients 43/962 0.16 4/962 0.47 9/962 0.96 2.7 (0.9–7.6) 0.07 5.4 (2.5–11.6) <0.001 2.6 (0.9–7.4) 0.08 5.6 (2.6–12.1) <0.001 Patients who received guideline-based therapy prior to cardioversionb 21/277 0.22 0/277 0 5/277 1.9 — — 7.9 (2.8–22.0) <0.001 — — 7.9 (2.8–22.4) <0.001 Patients who did not receive guideline-based therapy prior to cardioversionb 22/685 0.13 4/685 0.67 4/685 0.6 5.5 (1.8–16.6) 0.003 4.8 (1.6–14.7) 0.006 5.4 (1.8–16.4) 0.003 4.8 (1.6–14.9) 0.006 HR, hazard ratio. a Reference is not within 30 days of cardioversion. b Guideline-based therapy was defined as either oral anticoagulation for ≥3 weeks prior to cardioversion or a transoesophageal echocardiogram prior to cardioversion. Open in new tab Table 3 Association between cardioversion and the incidence of thromboembolic events Not within 30 days of cardioversion Within 30 days before cardioversion Within 30 days after cardioversion Unadjusted Adjusted for CHA2DS2-VASc score Within 30 days before cardioversiona Within 30 days after cardioversiona Within 30 days before cardioversiona Within 30 days after cardioversiona Events/ patients Event rate (%/30 days) Events/ patients Event rate (%/30 days) Events/ patients Event rate (%/30 days) HR (95% CI) P-value HR (95% CI) P-value HR (95% CI) P-value HR (95% CI) P-value All patients 43/962 0.16 4/962 0.47 9/962 0.96 2.7 (0.9–7.6) 0.07 5.4 (2.5–11.6) <0.001 2.6 (0.9–7.4) 0.08 5.6 (2.6–12.1) <0.001 Patients who received guideline-based therapy prior to cardioversionb 21/277 0.22 0/277 0 5/277 1.9 — — 7.9 (2.8–22.0) <0.001 — — 7.9 (2.8–22.4) <0.001 Patients who did not receive guideline-based therapy prior to cardioversionb 22/685 0.13 4/685 0.67 4/685 0.6 5.5 (1.8–16.6) 0.003 4.8 (1.6–14.7) 0.006 5.4 (1.8–16.4) 0.003 4.8 (1.6–14.9) 0.006 Not within 30 days of cardioversion Within 30 days before cardioversion Within 30 days after cardioversion Unadjusted Adjusted for CHA2DS2-VASc score Within 30 days before cardioversiona Within 30 days after cardioversiona Within 30 days before cardioversiona Within 30 days after cardioversiona Events/ patients Event rate (%/30 days) Events/ patients Event rate (%/30 days) Events/ patients Event rate (%/30 days) HR (95% CI) P-value HR (95% CI) P-value HR (95% CI) P-value HR (95% CI) P-value All patients 43/962 0.16 4/962 0.47 9/962 0.96 2.7 (0.9–7.6) 0.07 5.4 (2.5–11.6) <0.001 2.6 (0.9–7.4) 0.08 5.6 (2.6–12.1) <0.001 Patients who received guideline-based therapy prior to cardioversionb 21/277 0.22 0/277 0 5/277 1.9 — — 7.9 (2.8–22.0) <0.001 — — 7.9 (2.8–22.4) <0.001 Patients who did not receive guideline-based therapy prior to cardioversionb 22/685 0.13 4/685 0.67 4/685 0.6 5.5 (1.8–16.6) 0.003 4.8 (1.6–14.7) 0.006 5.4 (1.8–16.4) 0.003 4.8 (1.6–14.9) 0.006 HR, hazard ratio. a Reference is not within 30 days of cardioversion. b Guideline-based therapy was defined as either oral anticoagulation for ≥3 weeks prior to cardioversion or a transoesophageal echocardiogram prior to cardioversion. Open in new tab Take home figure Open in new tabDownload slide Incidence of thromboembolism according to time from cardioversion—all 962 patients. Each circle represents the 90-day event rate for all the patients who contributed person-time to that 90-day time interval. The ‘step size’ between two adjacent circles is 10 days. The solid line is a locally weighted smoothing curve and the grey area delimits the point-wise 95% confidence interval for this estimate. Take home figure Open in new tabDownload slide Incidence of thromboembolism according to time from cardioversion—all 962 patients. Each circle represents the 90-day event rate for all the patients who contributed person-time to that 90-day time interval. The ‘step size’ between two adjacent circles is 10 days. The solid line is a locally weighted smoothing curve and the grey area delimits the point-wise 95% confidence interval for this estimate. A guideline-based strategy was used in 277 patients (29%); this included 22% who used therapeutic OAC for ≥3 weeks before and 4 weeks after cardioversion and 7% who underwent a TOE and then received OAC for 4 weeks. The risk of thromboembolism in the 30 days following cardioversion was increased both in patients who received guideline-based anti-embolic therapy (adjusted HR 7.9, 95% CI 2.8–22.4) and in those who did not (adjusted HR 4.8; 95% CI 1.6–14.9) (Table 3). This risk was not significantly different between these two groups (P for interaction = 0.2). When electrical and pharmacological cardioversions were considered separately, patients who were cardioverted by either means had a significantly higher risk of thromboembolic events in the 30 days following cardioversion as compared to the rest of the follow-up period (adjusted HR 6.4; 95% CI 2.5–16.7 for electrical and adjusted HR 4.2; 95% CI 1.5–12.0 for pharmacological). There was no significant difference in risk between electrical and chemical cardioversion (P = 0.5). The risk of embolism in the 30 days following cardioversion was increased among individuals for whom cardioversion was successful (adjusted HR 4.5; 95% CI 2.0–10.5) and among patients with failed cardioversion (adjusted HR 10.2; 95% CI 2.3–44.9). There was no significant difference between successful and unsuccessful cardioversion (P = 0.3). When cardioversions performed on hospitalized (n = 459) and non-hospitalized (n = 503) patients were considered separately (Figure 1), patients who were cardioverted while hospitalized for a cardiovascular reason had a significantly higher risk of thromboembolic events in the 30 days following cardioversion as compared to the rest of the follow-up period (adjusted HR 7.4, 95% CI 3.2–17.1) while the risk was not increased among those who were cardioverted while they were not hospitalized (adjusted HR 2.5; 95% CI 0.6–10.5). However, this difference in risks between these two groups was not statistically significant (P = 0.2). Figure 1 Open in new tabDownload slide Incidence of thromboembolism according to time from cardioversion—459 hospitalized (A) and 503 non-hospitalized (B) patients. Each circle represents the 90-day event rate for all the patients who contributed person-time to that 90-day time interval. The ‘step size’ between two adjacent circles is 10 days. The solid line is a locally weighted smoothing curve and the grey area delimits the point-wise 95% confidence interval for this estimate. Figure 1 Open in new tabDownload slide Incidence of thromboembolism according to time from cardioversion—459 hospitalized (A) and 503 non-hospitalized (B) patients. Each circle represents the 90-day event rate for all the patients who contributed person-time to that 90-day time interval. The ‘step size’ between two adjacent circles is 10 days. The solid line is a locally weighted smoothing curve and the grey area delimits the point-wise 95% confidence interval for this estimate. The risk of HF hospitalization was increased in the peri-cardioversion period (adjusted HR 11.5, 95% CI 6.8–19.4). This risk was increased in both in the 30 days before cardioversion (adjusted HR 13.0; 95% CI 7.1–24.0) and in the 30 days following cardioversion (adjusted HR 9.8; 95% CI 4.9–19.6), this difference was not statistically significant (P = 0.5). Figure 2 models the temporal changes in the risk of HF hospitalization before and after cardioversion. Figure 2 Open in new tabDownload slide Incidence of hospitalization for heart failure according to time from cardioversion—all 962 patients. Each circle represents the 90-day event rate for all the patients who contributed person-time to that 90-day time interval. The ‘step size’ between two adjacent circles is 10 days. The solid line is a locally weighted smoothing curve and the grey area delimits the point-wise 95% confidence interval for this estimate. Figure 2 Open in new tabDownload slide Incidence of hospitalization for heart failure according to time from cardioversion—all 962 patients. Each circle represents the 90-day event rate for all the patients who contributed person-time to that 90-day time interval. The ‘step size’ between two adjacent circles is 10 days. The solid line is a locally weighted smoothing curve and the grey area delimits the point-wise 95% confidence interval for this estimate. Discussion The main finding of this study is that among patients undergoing cardioversion, the risk of thromboembolism increases over the 30 days prior to cardioversion and returns to baseline over the 30 days following the procedure. The increased risk during the peri-cardioversion period is present whether or not sinus rhythm is successfully restored by cardioversion, and whether or not patients receive guideline-based OAC in the peri-cardioversion period. Cardioversions that are performed on hospitalized patients appear to confer the highest risk of thromboembolism. The risk of hospitalization for HF follows a similar temporal pattern as the risk of thromboembolism. Together, these data suggest that cardioversion may not directly cause all thromboembolic events in the peri-cardioversion period, but some events may represent an epiphenomenon of clinical deterioration in patients selected for cardioversion. In the 1960s, shortly after the advent of cardioversion, clinicians recognized an increased rate of embolic events occurring around the time of this procedure.7,23 Investigators also noted that patients who were taking chronic OAC had lower rates than those who were not.8,24 In 1969, Bjerkelund and Orning8 published a prospective observational cohort study of 437 patients who underwent cardioversion, reporting that the crude rate of embolic events was significantly lower in patients who were taking OAC (0.8% vs. 5.3%, P = 0.02). This study played a key role in the formulation of early clinical practice guidelines.9,25 These guidelines remain largely unchanged today, as there have been no randomized data testing to determine if anticoagulation at the time of cardioversion improves outcomes in patients who would otherwise not require anticoagulation for management of their AF.2,3,26 It is not known if cardioversion directly causes embolic stroke, but two potential mechanisms have been proposed: (i) restoration of mechanical function leading to ejection of existing thrombus from the LAA9,11 and (ii) cardioversion-induced electromechanical stunning and the formation of de novo thrombus in the LAA.12–15 There is, however, little direct evidence that either of these mechanisms actually cause stroke in humans. In the present study, we observed that the risk of thromboembolic events began to increase prior to cardioversion, peaked around the time of cardioversion and returned to baseline thereafter. This temporal pattern suggests that, at least in some patients, cardioversion is a marker for increased risk of thromboembolic events rather than a direct cause. This is supported by three other observations. First, the increased risk of stroke following cardioversion was not different between patients in whom cardioversion was successful or unsuccessful. Second, the increased risk of stroke at time of cardioversion was similar in patients managed with guideline-based OAC prior to cardioversion as compared with those in whom OAC was not used. Third, we observed a similar increase in risk of HF hospitalization in the peri-cardioversion period as we observed for thromboembolic events. The observed increase in the risk of thromboembolism prior to cardioversion is likely underestimated, as it is plausible that many clinicians might have avoided cardioversion in a patient with a recent stroke for fear of precipitating a second event. This further suggests that part of the increase in thromboembolic risk is the result of the overall clinical status of the patient who dictated the need for cardioversion, rather than the direct result of cardioversion itself. In this study, patients who had their cardioversion while hospitalized appeared to be at higher risk of thromboembolism. Thus, the indication for hospitalization and cardioversion appear to be a marker of thromboembolic risk; rather than cardioversion solely being the direct cause of stroke. This observation is not unique to this cohort; in the ACUTE trial, 57% of all deaths in the peri-cardioversion period were due to HF or were sudden, and most of these patients had New York Heart Association III or IV symptoms at the time of cardioversion.10 Furthermore, prior publications have demonstrated that HF is the most common cause of death in patients with AF, an independent risk factor for stroke in patients with AF, and an independent risk factor for cardioversion-associated thromboembolism.27,28 Finally, investigators have also demonstrated that a significant proportion of AF-related strokes are not cardioembolic, which again supports the idea that the need for cardioversion is acting as a risk marker for thromboembolism in the peri-cardioversion period.29,30 The findings of this observational study are hypothesis-generating. However, they provide rationale for future randomized trials of peri-cardioversion anticoagulation, particularly in low-risk patients (i.e. CHA2DS2-VASc score of 0). Limitations The key weakness of this post-hoc study is the observational design, which limits the inference of causality. Even after adjustment for known prognostic factors, the findings remain subject to residual confounding. Additionally, the number of participants and events was small, but this study still is one of the largest cardioversion studies among patients not receiving OAC. Finally, we did not collect specific information on the indication for cardioversion—this could confound the relationship between any acute underlying conditions and the occurrence of thromboembolic events. Conclusions Atrial fibrillation patients undergoing cardioversion have an increased thromboembolic risk. This risk increases before cardioversion is performed, and is present regardless of whether cardioversion was successful and whether or not OAC or TOE were used prior to cardioversion. This temporal pattern suggests that at least part of the thromboembolic risk associated with cardioversion is not causal. Ethical Committee Approval Local ethics committees at enrolling centres approved the original ACTIVE trials. Acknowledgement The authors would like to acknowledge Dr Emilie Belley-Côté for her assistance with a systematic review to guide this study. Conflict of interest: W.F.M. reports personal fees from Servier, from Bayer, from BMS-Pfizer, outside the submitted work. S.J.C. reports grants and personal fees from PORTOLA PHARMACEUTICALS, grants and personal fees from BRISTOL MYERS SQUIBB, grants and personal fees from BAYER, grants and personal fees from DAIICHI SANKYO, outside the submitted work. A.P.B. reports other from St. Jude Medical/Abbott, outside the submitted work. D.C. reports personal fees from Servier, outside the submitted work. J.S.H. reports grants and personal fees from BMS/Pfizer, grants from Medtronic, grants from Boston Scientific, personal fees from Servier, outside the submitted work. All other authors declared no conflict of interest. See page 3033 for the editorial comment on this article (doi: 10.1093/eurheartj/ehz563) References 1 Sandhu RK , Smigorowsky M , Lockwood E , Savu A , Kaul P , McAlister FA. Impact of electrical cardioversion on quality of life for the treatment of atrial fibrillation . Can J Cardiol 2017 ; 33 : 450 – 455 . 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Journal

European Heart JournalOxford University Press

Published: Sep 21, 2019

References

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