WHAT IS ALREADY KNOWN ON THIS TOPICWHAT THIS STUDY ADDS

Aetiology and clinical presentation differ in patients with cancer compared with patients who are cancer-free.

However, in-hospital outcomes were comparable in both groups, meaning that cancer status did not appear to affect patient outcomes, once admitted alive in hospital.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

Patients with SCA admitted alive in hospital had similar outcomes regardless of their cancer status.

Cancer should therefore not be a rebuttable factor to the initiation of resuscitation or intensive care therapies in the context of SCA.

Introduction

Cardiovascular diseases and cancer are the two main causes of death in Western countries. Advances in these two areas have led to significant improvements in life expectancy for both conditions over the last decades.1 2

Early detection strategies and advances in treatment have dramatically changed the prognosis for all types of cancer throughout the past 20 years. As a result, the number of patients living with a history of cancer is increasing in North America and Europe. This population is expected to grow beyond 30 million by 2025.3 Advances in cancer survival, however, come at the cost of some risk of cancer therapy-related cardiovascular toxicity (CTR-CVT).4 Among CTR-CVT patterns, there is a growing interest for ventricular arrhythmias and sudden cardiac arrest (SCA) which may be related to cancer therapies.5 However, available data mainly originate from pharmacovigilance sources with a focus on ventricular arrhythmias per drug class without any global data.5

This growing interest in the crossroads between cancer and cardiovascular disease has led to the recent release of guidelines by the European Society of Cardiology regarding cardiovascular management of patients with cancer.4 To the best of our knowledge, no study has assessed specific features of patients with cancer presenting the most severe form of cardiovascular event: SCA. The aim of this study was to describe the characteristics of patients with cancer and SCA, to compare them to cancer-free contemporary patients in the setting of out-of-hospital cardiac arrest (OHCA) and to investigate outcomes according to cancer status.

MethodsStudy setting

The Paris-SDEC registry is an ongoing study and has been described previously.6 Briefly, it is a prospective, population-based registry that includes individuals living in Paris and its suburbs admitted to hospital after OHCA. The registry covers a 762 km2 geographical area, with a residential population of 6.7 million people (10% of the overall French population).

In Paris, management of OHCA involves mobile emergency units (Service d’Aide Médicale Urgente) and the fire Brigade (Brigade de Sapeurs Pompiers de Paris), with at least one physician trained in emergency medicine on board in both systems. The collaboration of 48 different hospitals and forensic units allows to detect every case of OHCA aged ≥18 years occurring in the area has been systematically enrolled in the Paris-SDEC registry since May 2011. This unique collection process allows our registry to exhaustively capture all OHCA, including those without resuscitation attempt by emergency medical services (EMS). Exclusion criteria include age under 18 years and cardiac arrest occurring outside the geographical area of interest. External audits on the Paris-SDEC registry showed that 99% of OHCA admitted alive to hospital were collected.

The study was conducted according to Good Clinical Practice, French Law and the French data protection law. Data file of the Paris-SDEC registry was declared to and authorised by the French data protection committee (Commission Nationale Informatique et Liberté, CNIL, DR-2012-445 authorisation number 912309). No informed consent was required.

Population

All OHCA occurring from May 15, 2011 to December 31, 2019 were prospectively included. Sudden cardiac arrest was defined as an unexpected OHCA with a rapid witnessed collapse within 1 hour of symptom onset, or if unwitnessed, within the 24 hours after last contact. Sudden cardiac arrest with obvious non-cardiac circumstances (trauma, drowning, suicide) were not included. Two investigators (with a third in case of disagreement) thoroughly reviewed and adjudicated each medical report for data completion and validity. The methodology of this study is consistent with the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) checklist for observational studies.7

Utstein templates were followed for reporting resuscitation information.8 Information gathered included demographics, pre-hospital management, delays from call to EMS arrival, in-hospital care and in-hospital survival. In Paris, EMS personnel do not initiate resuscitation attempt in case of obvious clinical signs of irreversible death (eg, rigour mortis).

Cancer characteristics

Cancer status (current or past medical history of cancer) was collected in all participants. In addition to data available in the Paris-SDEC registry, we collected additional information as to cancer type (solid vs haematological), cancer status (active at the time of SCA vs remission), cancer therapies, history of CTR-CVT when available in the hospital charts. A specific long-term follow-up was conducted in patients who presented SCA with a current or past medical history of cancer, with a prospective seek for last medical contact in 2021.

Statistical analysis

Continuous data are reported as mean±SD for normally distributed data or median and 25th and 75th percentiles (Q1-Q3) for non-normally distributed data. Categorical data are reported as numbers and percentages. Comparisons used χ2 or Fisher’s exact test for categorical variables and Student’s t-test or Wilcoxon rank-sum test, when appropriate, for continuous variables. We compared patients with cancer and patients who are cancer-free; and then patients with cancer according to their oncology status (active vs remission). Logistic regression models were used to identify factors associated with in-hospital survival. Variables with p values <0.20 in univariable analyses were considered in multivariable models, with final selection based on most favourable goodness-of-fit measures (Bayesian information criterion). ORs and HRs are presented with their 95% CI (CI). Missing data were handled using a complete case analysis.

P values <0.05 were considered statistically significant. All analyses were two-tailed. Statistical analysis was performed using R software, V.4.2.1.9

ResultsCharacteristics of OHCA

Among the 28 171 OHCA, a total of 4069 patients (14.4%) were admitted alive to the hospital, of which 207 (5.1%) had current or past medical history of cancer (figure 1). When considering patients with resuscitation attempted and information about cancer status during the study period (n=10 515), 16.2% (n=1702) had present or past medical history of cancer. Comparison of patients admitted to hospital according to their history of cancer is shown in table 1. Patients with cancer were older (69.2 vs 59.3 years old, p<0.001) and were more often women (37.2% vs 28.0%, p=0.006). They had more underlying cardiovascular disease including ischaemic or non-ischaemic cardiomyopathy (41.1% vs 32.5%, p=0.01), or history of atrial fibrillation (15.8% vs 10.0%, p=0.01) compared with patients who are cancer-free. Apart from cancer itself, comorbidities did not differ except for chronic kidney disease which was more prevalent in patients with cancer (10.9% vs 5.3%, p=0.001).

Figure 1

Flow chart of the study population. SDEC, Sudden Death Expertise Center.

Table 1

Patients who had SCA according to their cancer status

At the time of OHCA, the cancer group had less initial shockable rhythm (37.4% vs 56.9%, p<0.001) with more asystole (53.3% of patients with cancer vs 35.9% in patients who are cancer-free), less public location (32.4% vs 43.7%, p=0.005), however, with no difference regarding the presence of a witness and whether they performed CPR. Median (Q1–Q3) time to CPR was similar in both groups, but time to return of spontaneous circulation was significantly shorter among patients with cancer (20.0 (13.0–30.0) min vs 23.0 (14.0–39.0) min, respectively, p<0.001). Chest pain was less frequent in patients with cancer (21.7% vs 29.9%, p=0.024) and so was ST segment elevation on first ECG (23.1% vs 40.8%, p<0.001), with also less coronary artery angiography undertaken (33.3% vs 55.5%, p<0.01) among patients with cancer.

The final aetiology of OHCA remained unknown in 28.5% of patients with cancer and 28.7% in patients who are cancer-free, as depicted in figure 2. Among patients with an ascertained aetiology, patients with cancer presented with more respiratory causes (pulmonary embolism and hypoxaemia mainly: 9.4% vs 3.9%, p=0.004, and 24.8% vs 6.9%, p<0.001, respectively) and less cardiac causes (49.7% in patients with cancer vs 76.4% in patients who are cancer-free, p<0.001). Among cardiac causes, ischaemic causes were less frequent and accounted for only 35.1% of cases in patients with cancer vs 61.4% in patients who are cancer-free (p<0.001), followed by non-ischaemic cardiomyopathy (8.1% in patients with cancer vs 10.7% in patients who are cancer-free, p=0.75). Acute coronary syndrome were diagnosed in 25.5% of patients with cancer vs 46.8% of patients who are cancer-free (p<0.001).

Figure 2

Causes of sudden cardiac arrest in patients with or without cancer.

Outcomes

The proportion of patients admitted alive in hospital was significantly lower among patients with cancer (8.0% vs 21.5%, p<0.001), who were on average 10 years older (p<0.001). Still, in-hospital outcomes did not differ according to the presence of cancer: 26.2% (54/206) of patients with cancer were alive at hospital discharge vs 29.8% (1145/3840) patients who are cancer-free (p=0.27). Analysis on vital status at hospital discharge (data available for 206/207 patients with cancer) showed that 143 out of 206 (69.4%) died in the intesive care unit (ICU), 9 died during their hospital stay, following ICU discharge (4.4%). Factors associated with in-hospital mortality on univariable analysis are depicted in table 2. Multivariable analysis showed that public location (OR 4.44, 95% CI 1.74 to 12.0, p=0.002), CPR by witness (OR 4.69, 95% CI 1.29 to 23.1, p=0.03) and shockable rhythm (OR 4.82, 95% CI 1.93 to 12.7, p<0.001) were independently associated with improved in-hospital outcomes among patients with cancer (table 3). Similar factors correlated with survival at hospital discharge in patients who are cancer-free.

Table 2

Cardiovascular and resuscitation factors according to in-hospital outcomes among patients with sudden cardiac arrest and cancer

Table 3

Multivariable analysis: factors associated with survival at hospital discharge after sudden cardiac arrest

Long-term survival follow-up after hospital discharge was achieved in 53 out of 54 discharged alive patients, during a median duration of 1.2 (Q1–Q3 0.1–3.6) years. Of those 53 patients, 8 died during the follow-up after a median time of 2.3 (Q1–Q3 1.5–2.7) years. Most deaths in patients with cancer occurred during the hospital stay, with no peak incidence of subsequent mortality in hospital survivors (data not shown).

Specific cancer characteristics

Detailed oncology characteristics of patients with OHCA were available for a subset of the study population. In terms of oncology disease, 175 out of 202 (86.6%) had solid cancer (missing data for 5/207 patients with cancer, 2.4%); 53 out of 68 (77.9%) had active cancer (missing data for 139/207 patients with cancer, 67.1%). Previous or current oncology treatments were available for 49 out of 207 patients (23.7%): 17 received antimetabolites, 16 mitotic inhibitors, 15 anthracyclins; 14 alkylating agents; 37 tyrosin kinase inhibitors; 38 poly-ADP ribose polymerase inhibitors; 37 CDK4/CDK6 inhibitors; 10 hormone therapies; 2 intravenous vascular endothelial growth factor inhibitors (VEGFi); 2 had undergone autologous bone marrow transplant; and 2 allogenic bone marrow transplant. History of CTR-CVT was known for 41 out of 207 patients (19.8%), including 5 cases of heart failure (12.2%), 3 of rhythm disorders (7.3%), 2 of atherosclerosis-related events (4.9%) and 31 who presented other CTR-CVT (75.6%). Of note, there was no history of myocarditis due to immune checkpoint inhibitors (ICIs).

The association between cancer characteristics and in-hospital outcomes is shown in table 4. No significant association was found regarding the type or status of cancer with in-hospital outcomes in univariable or multivariable analysis. Also, prior CTR-CVT did not correlate with in-hospital prognosis.

Table 4

Cancer features associated with in-hospital survival after sudden cardiac arrest among patients with cancer

When comparing baseline characteristics of patients with cancer according to their cancer status, that is, either active or remission (data available in 68/207 patients, 32.9%), no significant difference was found except the dose of epinephrine administered. Epinephrine doses were higher in patients with active compared with in remission cancer (p<0.01), with a signal towards more non-shockable rhythm in patients with active cancer (70.2% vs 50.0% among patients in remission), without reaching statistical significance (p=0.21) (online supplemental table 1). Patients with remission cancer had similar causes of SCA: acute or chronic ischaemic cardiomyopathy was responsible for 26.7% of SCA in patients with cancer remission versus 16.9% in patients with active cancer (p=0.46). Respiratory causes were less frequent in patients with active versus in remission cancer: pulmonary embolism or hypoxaemia was observed in 12 out of 53 (22.6%) vs 5 out of 15 (33.3%), respectively (p=0.50) (online supplemental figure 1).

Discussion

Our study highlights differences in the aetiology and clinical management of OHCA according to cancer status. Patients with cancer are less likely to present with cardiac causes of SCA: mainly less acute coronary syndrome. Yet, despite these differences in aetiology, in-hospital survival remained similar in both groups, with or without a history of cancer. After adjustment, the classic prognostic factors retained their role in the cancer population: notably shockable rhythm and witness-initiated resuscitation as predictors of favourable outcomes. Finally, using data from a subgroup of patients, cancer treatment modalities or history of CT-RCVT did not appear to have an impact on prognosis.

Our data showed that a significantly higher proportion of patients with cancer die before hospital admission in the setting of OHCA when compared with patients who are cancer-free. When admitted alive to hospital, 5% of patients with SCA suffer from either active or past cancer. These data are consistent with prior studies crossing cardiovascular disease and cancer.10 11 The proportion of patients with cancer in large acute coronary syndromes registries is as high as 3%.12–14 This figure may only increase in the coming years due to the improvement of all-cancer at all-stages life expectancy. In addition, different anticancer treatments increase the risk of atherosclerotic cardiovascular events, as chest radiation, vascular endothelial growth factor inhibitors, platinum-based drugs and immune-checkpoint inhibitors.15–17 Other therapies may confer a higher risk of SCA regardless atherosclerosis, as immune-related myocarditis, or Bruton tyrosine kinase inhibitors.5 18

It has been described that 10% to 40% of patients with cancer die of cardiovascular and non-oncological causes.19 20 It is therefore crucial to improve the cardiovascular management of these patients, including that of SCA.

Among these patients with cancer who had suffered from SCA, we showed that cardiac causes were less frequent. This lower proportion of cardiac causes seemed to be offset by an increase in respiratory causes. This lower proportion of cardiac causes has also been demonstrated in other subgroup of patients presenting with SCA notably in women (young or during sports).21 This decrease in the proportion of cardiac causes in certain subgroups of patients with SCA may be explained by several factors. First, it is possible that the presentation of a non-shockable rhythm in patients with cancer led to a more comprehensive search for non-cardiac causes of SCA.22 This is the rhythm that is most often found at the time of initial management in patients with cancer, which could also explain why the dose of epinephrine administered was found to be higher in patients with active (more non-shockable rhythm) versus in remission cancer (more shockable rhythm). Second, cancer is a well-described thromboembolic risk situation, potentially leading to cardiac arrest with non-shockable rhythm.23 24 Third, the proportion of patients with no identified cause of SCA was similar between the two groups of patients with and without cancer. These data are rather reassuring on the carrying out of an equivalent aetiological assessment whatever the oncological status.

Our study found that in-hospital survival was similar among patients with cancer compared with patients who are cancer-free. These results may seem surprising because of the greater proportion of non-shockable rhythms and non-coronary aetiology in patients with cancer. These results might be explained by the lack of information regarding the pre-hospital phase. Indeed, patients with cancer may suffer from increased decision not to initiate resuscitation by the pre-hospital medical team.25 In a registry that studied cardiac arrest complicating myocardial infarction in the USA, patients with cancer had a lower intra-hospital survival.14 They were older and received less coronary angiography than patients without cancer, which is similar to our results. For patients who died outside the hospital, there are very few data from autopsy series. A Dutch series of approximately 10 000 patients with cancer who underwent autopsy showed that more than 10% of them had pulmonary embolism.26 Longer follow-up or neurological outcomes assessment would be informative to better assess the outcomes among patients with cancer who did receive pre-hospital resuscitation.

Finally, we had some information about cancer therapies in patients admitted alive after SCA, as well as possible induced CTR-CVT. It is now well documented that an increasing number of cancer therapies can cause cardiac toxicity leading to heart failure with an associated risk of cardiac arrest or sudden death.27 28 The risk of ventricular arrhythmias has been assessed mainly via indirect criteria such as the measurement of the corrected QT under treatment.27 However, there are many situations at risk of cardiac arrest, which are not exclusively related to the torsadal risk of long QT.29 Our sample size is small with few patients treated with anthracyclines, but it appeared that there was no over-representation of this treatment among patients with SCA. There has been a significant number of studies describing the fatality of myocarditis due to ICIs.18 ICIs may lead to a wide range of cardiovascular side effects, from atherosclerosis-related events, heart failure, to fulminant myocarditis.18 30 Our study did not identify a subgroup of patients with cancer that died suddenly on ICIs, but very few patients were given this therapy during the study period since ICI therapy (ie, Nivolumab) was approved in France in June 2018. Our results highlight the fact that patients with cancer mainly present with respiratory causes of SCA and therefore off put the cancer therapies’ toxicity mechanism.

Limitations

Although we have provided the first global picture of OHCA in patients with cancer, we acknowledge a series of limitations. Our data are based on medical records, as always in the field of SCA. Even if a central committee adjudicates data and diagnosis, this process relied on previously documented medical information from the hospitals, with scope for missing information. The small sample of patients with cancer admitted alive after OHCA could not permit extensive multivariable variate analysis and the conclusions remains to be confirmed. Also, our data are based on a large population with several centres involved, and we cannot exclude disparities in hospital care depending on the centre. Missing data regarding cancer status and oncology treatments may influence our results. However, these data are often missing at the scene of cardiac arrest, and medical teams take decisions with regard to resuscitation without this information. We therefore feel that the results presented are useful for everyday clinical practice. Nevertheless, subgroup analyses (notably on active/remitting cancer status) should be considered exploratory and preparatory for further work. We cannot exclude a selection bias of patients with cancer included in the analysis since only patients admitted alive in hospital were analysed. Most severe patients with terminal cancer may not have been included in the analysis since resuscitation was not initiated at all. Finally, we were unable to calculate the incidence of SCA among patients with cancer .

Conclusions

Cancer is frequent among patients presenting with OHCA. Patients with cancer are more rarely admitted alive to hospital in the setting of OHCA. Patients with cancer are more likely to present non-cardiovascular causes of SCA. Despite these disparities, in-hospital mortality remains similar regardless of cancer status. Prognostic factors are identical to those in patients who are cancer-free: public location, CPR by witness and shockable rhythm. These results should be incorporated into our daily practice to avoid underestimating the chances of survival of a patient presenting with SCA and a history of cancer.

Data availability statement

No data are available. The registry is an ongoing regional registry. Therefore updated data cannot be shared as such.

Ethics statementsPatient consent for publication

Not applicable.

Ethics approval

This study involves human participants and was approved by French data protection committee (Commission Nationale Informatique et Liberté, CNIL, DR-2012-445 authorization number 912309). Ethics committee waved patient’s consent for this registry on out of hospital sudden cardiac arrest with high in-hospital mortality rates. Patients admitted for SCA are seldom able to provide consent.

Acknowledgments

The authors thank the Paris-SDEC for providing the logistical support and the Paris-SDEC collaborators for their multidisciplinary expertise that has allowed an optimal approach in the fight against sudden cardiac death through this collaborative network since 2011. SDEC Executive Committee is part of the ESCAPE-NET project (Horizon2020 programme).