The simultaneous occurrence of cancer and coronary heart disease is increasing in the Western world. Nevertheless, the influence of cancer on ST elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI) has not been investigated extensively. This multicenter registry included patients with STEMI treated with primary PCI from 2006 to 2009. Patients were stratified according to history of cancer, and primary focus lay on all-cause and cardiac mortalities during 1-year follow-up. Adjusted effect sizes were calculated using Cox proportional hazard models. In total, 208 patients had a history of cancer (diagnosed ≤6 months ago in 20.7%, 6 months to 3 years ago in 21.7%, and >3 years ago in 57.6%) and 3,215 patients had no history of cancer. Chemotherapy had been administered previously to 23% of patients with cancer. Patients with cancer were older, more frequently women, and more commonly known with previous myocardial infarction or anemia. Reperfusion rates were similar after PCI. Patients with cancer showed greater all-cause (17.4% vs 6.5% in other patients) and cardiac mortalities at 1 year (10.7% vs 5.4% in other patients) because of high early cardiac death (23.8%) in recently diagnosed patients with cancer. After adjustment, a recent cancer diagnosis predicted cardiac mortality at 7 days (hazard ratio 3.34, 95% confidence interval 1.57 to 7.08). The adverse prognosis was partly explained by anemia and occurrence of cardiogenic shock, whereas outcome was independent of cancer treatment. In conclusion, patients with cancer showed greater mortality after STEMI. A cancer diagnosis in the 6 months before primary PCI was strongly associated with early cardiac mortality.
Coronary heart disease (CHD) and cancer are the most common causes of death in the Western world, together responsible for 3.5 million deaths in Europe every year. Simultaneous occurrence of CHD and cancer is increasingly frequent because of high incidences and improving life expectancies for these patients. Moreover, frequently applied treatment methods for cancer have known cardiovascular side effects, which may predispose these patients to cardiac disease. Chemotherapeutic regimens such as anthracyclines and antimetabolites have cardiotoxic properties potentially leading to irreversible cardiomyopathy or cardiac ischemia. External radiation to the thorax is associated with cardiac sequelae including accelerated coronary artery disease, valvular disease, constrictive pericarditis, and/or restrictive cardiomyopathy. In addition, cancer is commonly associated with a hypercoagulable state, increasing the risk for venous and possibly arterial thrombosis. Regardless of the numerous factors influencing development and prognosis of CHD in patients with cancer, there are little to no data covering the influence of cancer on outcome after myocardial infarction. The aim of the present multicenter study was to investigate the influence of cancer and cancer treatment on outcome after ST elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI).
Methods
The current Dutch registry prospectively included patients with STEMI treated in 3 tertiary centers in the Netherlands. The design of this registry has been described previously. In short, all consecutive patients undergoing primary PCI for STEMI from January 2006 to December 2009 were included. Patients without return of spontaneous circulation after out-of-hospital cardiac arrest were excluded, as well as patients permanently living outside the Netherlands to allow follow-up through municipality records. The study complied with the Declaration of Helsinki. Approval from local ethics committees was not required.
Protocols included field triage faxed to the operator on call and in-ambulance treatment with aspirin, heparin, and loading dose of clopidogrel. Glycoprotein IIb/IIIa inhibitors were administered up-front in 1 center and during procedure in the other centers. Patients treated in the Leiden University Medical Center were treated according to the institutional MISSION! protocol, a standardized prehospital, in-hospital, and outpatient clinical framework for STEMI care. These patients were intensively monitored at the outpatient clinic for 1 year, after which they were referred to the general practitioner or regional cardiology clinic. In the other centers, local residents were managed at the outpatient clinics and patients referred from regional hospitals were referred back for further management by regional cardiologists.
STEMI was defined as symptoms of angina lasting >30 minutes along with typical electrocardiographic changes (ST-segment elevation ≥0.2 mV in ≥2 contiguous leads in V 1 through V 3 , ≥0.1 mV in other leads, or presumed new left bundle branch block) and a typical increase and decrease of cardiac biomarkers. Patients with a history of nonmelanoma skin cancer were included in the group without cancer. The cancer population was further subdivided according to time elapsed between diagnosis of cancer and primary PCI (diagnosed >3 years ago, 6 months to 3 years ago, or ≤6 months ago). First moment of diagnosis was used, unless the patient had recently been diagnosed with progression of disease. For example, cancer diagnosed 5 years ago but identified to have metastasized in the 6 months before PCI was considered to be diagnosed in the last 6 months. However, metastasized disease identified 5 years ago was considered to be diagnosed >3 years ago.
Socioeconomic status was based on the average socioeconomic class of the patient’s residential address using income, access to employment, and educational level. These scores are measured yearly by the Netherlands Institute for Social Research, an independent government agency. Vital status was obtained using municipality records. Hospital records and general practitioners provided causes of death. Deaths were considered cardiac unless a clear noncardiac cause could be identified.
Stratification was done according to the history of cancer and subsequently according to the time of diagnosis. Continuous variables are presented as mean with SD or median with interquartile range and were compared using Student t test or nonparametrical tests, as appropriate. Categorical variables are expressed as counts and percentages and were compared using Pearson’s chi-square test. All statistical tests were 2-tailed, and a p value <0.05 was considered statistically significant. Time to end point was analyzed using Kaplan-Meier plots and the log-rank test was applied to compare cumulative incidences of the end point between groups.
To evaluate cancer as a predictor of mortality, multivariate Cox proportional hazard models were used. Univariate predictors of mortality were incorporated in the multivariate models using a forward stepwise approach with a cut-off p value of <0.10. Second, a confounder model was created to investigate the theoretical causal pathway between cancer and mortality. The model included age, gender, socioeconomic status, and smoking status. Confounders were chosen according to their relation with both the occurrence of cancer and mortality. Subsequently, explanatory factors were added to the confounder model. Only those factors that could possibly be a consequence of the presence of cancer were added (previous myocardial infarction, out-of-hospital cardiac arrest, anemia on admission, cardiogenic shock during PCI, Thrombolysis In Myocardial Infarction [TIMI] flow after procedure, stent placement, treatment with abciximab, enzymatic infarct size, and cancer treatment). Analyses were performed using SPSS, version 21 (IBM, Armonk, New York).
Results
During the inclusion period, 208 patients (6.0%) treated for STEMI had a history of cancer (hereafter referred to as patients with cancer) and 3,215 patients (92.3%) had no known history of cancer. Cancer history was uncertain in 60 patients (1.7%). Baseline characteristics are listed in Table 1 . Patients with cancer were on average older, more often women, and more frequently had hypertension compared with patients without a history of cancer. Patients with cancer were less frequently smokers but more commonly had a previous myocardial infarction. Furthermore, previous peripheral vascular disease, cerebrovascular disease, renal insufficiency, and anemia were more common in patients with a history of cancer. Also, the interval between diagnosis and balloon inflation was significantly longer in patients with a history of cancer compared with those without a history of cancer. During PCI, patients with cancer were less likely to receive coronary stents ( Table 2 ). In case of stenting, the percentage of patients receiving bare-metal stents was greater in patients with a history of cancer although most patients received drug-eluting stents. Additionally, patients with cancer were more frequently treated with intra-aortic balloon pumps. Finally, patients with cancer were less likely to receive abciximab treatment compared with patients without a history of cancer and were less frequently discharged on β-blocker therapy. Table 3 lists the characteristics of the cancer history. Exact moment of diagnosis was unknown in 5 patients.
| Variable | History of Cancer | p | |
|---|---|---|---|
| Yes (n = 208) | No (n = 3,215) | ||
| Age (yrs) | 69.6 ± 11.0 | 62.8 ± 12.4 | <0.001 |
| Men | 141 (67.8) | 2,427 (75.5) | 0.013 |
| Diabetes mellitus, non–insulin dependent | 17 (8.3) | 275 (8.6) | 0.871 |
| Diabetes mellitus, insulin dependent | 6 (2.9) | 86 (2.7) | 0.843 |
| Hypertension ∗ | 88 (42.7) | 1,135 (35.4) | 0.034 |
| Hypercholesterolemia † | 46 (22.4) | 738 (23.1) | 0.839 |
| Current smoker | 61 (31.0) | 1,487 (46.8) | <0.001 |
| Previous myocardial infarction | 35 (17.0) | 335 (10.4) | 0.003 |
| Previous PCI | 21 (10.2) | 267 (8.3) | 0.345 |
| Previous coronary artery bypass grafting | 5 (2.4) | 79 (2.5) | 0.970 |
| Previous peripheral vascular disease | 18 (8.8) | 146 (4.5) | 0.006 |
| Previous cerebrovascular disease | 24 (11.7) | 191 (5.9) | 0.001 |
| Previous renal insufficiency ‡ | 17 (8.3) | 109 (3.4) | <0.001 |
| Anemia on admission § | 53 (11.8) | 152 (5.2) | <0.001 |
| Out-of-hospital cardiac arrest | 18 (8.7) | 203 (6.3) | 0.183 |
| Cardiogenic shock during PCI ¶ | 18 (8.7) | 196 (6.1) | 0.140 |
| Creatine phosphokinase peak (U/L) | 1,360 (686–2,790) | 1,365 (616–2,611) | 0.894 |
| Symptom-to-balloon time (minutes) | 186 (136–259) | 180 (130–284) | 0.708 |
| Diagnosis-to-balloon time (minutes) | 86 (68–107) | 79 (65–99) | 0.024 |
| Door-to-balloon time (minutes) | 52 (37–77) | 46 (33–67) | 0.077 |
∗ Blood pressure ≥140/90 mm Hg or previous pharmacologic treatment.
† Total cholesterol ≥190 mg/dl or previous pharmacologic treatment.
‡ Estimated glomerular filtration rate <60 ml/min/1.73 m 2 .
§ Admission hemoglobin <12 g/dl (<7.4 mmol/L) for women and <13 g/dl (<8.1 mmol/L) for men.
¶ Defined as systolic blood pressure <90 mm Hg with signs of tissue hypoperfusion requiring treatment in the form of inotropic agents or assistant devices.
| Variable | History of Cancer | p | |
|---|---|---|---|
| Yes (n = 208) | No (n = 3,215) | ||
| Coronary culprit vessel | 0.826 | ||
| Left anterior descending | 91 (43.8) | 1,291 (40.2) | |
| Left circumflex | 32 (15.4) | 509 (15.8) | |
| Right | 79 (38.0) | 1,337 (41.6) | |
| Left main | 3 (1.4) | 40 (1.2) | |
| Bypass graft | 3 (1.4) | 36 (1.1) | |
| Number of vessels narrowed >50% | 0.293 | ||
| 1 | 87 (41.8) | 1,522 (47.4) | |
| 2 | 71 (34.1) | 1,005 (31.3) | |
| 3 | 50 (24.0) | 685 (21.3) | |
| Stenting | 192 (92.3) | 3,082 (95.9) | 0.014 |
| Drug-eluting stents | 124 (60.8) | 2,263 (70.8) | 0.002 |
| Bare-metal stents | 67 (32.8) | 812 (25.4) | 0.019 |
| Intra-aortic balloon pump use | 14 (6.7) | 124 (3.9) | 0.041 |
| TIMI flow before procedure | 0.058 | ||
| Grade 0 | 132 (63.5) | 2,198 (68.5) | |
| Grade 1 | 26 (12.5) | 356 (11.1) | |
| Grade 2 | 35 (16.8) | 358 (11.1) | |
| Grade 3 | 15 (7.2) | 299 (9.3) | |
| TIMI flow after procedure ≤2 | 21 (10.1) | 270 (8.4) | 0.384 |
| Abciximab treatment | 137 (67.2) | 2,397 (75.1) | 0.012 |
| Discharge medication | |||
| Aspirin/Warfarin | 187 (98.4) | 3,097 (99.3) | 0.202 |
| Clopidogrel | 186 (97.9) | 3,058 (98.0) | 0.885 |
| β Blocker | 160 (84.2) | 2,812 (90.5) | 0.005 |
| ACE-inhibitor/angiotensin II antagonist | 139 (73.2) | 2,220 (71.5) | 0.622 |
| Statin | 171 (90.0) | 2,897 (93.2) | 0.095 |
| Cancer Location | Diagnosis >3 yrs Ago | Diagnosis 6 Months <3 yrs Ago | Diagnosis ≤6 Months Ago | Total | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| n (%) | Chemotherapy | Radiation | n (%) | Chemotherapy | Radiation | n (%) | Chemotherapy | Radiation | ||
| Oral cavity | 3 (1.5) | 0/3 | 0/3 | 3 (1.5) | 0/3 | 1/3 | — | — | — | 6 (3.0) |
| Larynx | 7 (3.4) | 0/7 | 5/7 | 2 (1.0) | 0/2 | 2/2 | 1 (0.5) | 0/1 | 0/1 | 10 (4.9) |
| Lung | 3 (1.5) | 1/3 | 1/3 ∗ | 3 (1.5) | 2/3 | 1/3 ∗ | 4 (2.0) | 1/4 | 2/4 ∗ | 10 (4.9) |
| Breast | 25 (12.3) | 4/25 | 12/25 ∗ | 5 (2.5) | 2/5 | 4/5 ∗ | 3 (1.5) | 1/3 | 1/3 ∗ | 33 (16.3) |
| Esophagus | 1 (0.5) | 1/1 | 1/1 | 2 (1.0) | 0/2 | 0/2 | 2 (1.0) | 2/2 | 0/2 | 5 (2.5) |
| Stomach | 1 (0.5) | 0/1 | 0/1 | — | — | — | 1 (0.5) | 0/1 | 0/1 | 2 (1.0) |
| Pancreas | — | — | — | — | — | — | 2 (1.0) | 0/2 | 0/2 | 2 (1.0) |
| Colorectal | 17 (8.4) | 2/17 | 0/17 | 4 (2.0) | 0/4 | 1/4 | 8 (3.9) | 1/8 | 1/8 | 29 (14.3) |
| Kidney | 7 (3.4) | 0/7 | 0/7 | 1 (0.5) | 0/1 | 0/1 | 1 (0.5) | 0/1 | 0/1 | 9 (4.4) |
| Bladder | 12 (5.9) | 3/12 | 0/12 | 6 (3.0) | 0/6 | 0/6 | 7 (3.4) | 3/7 | 0/7 | 25 (12.3) |
| Prostate | 6 (3.0) | 0/6 | 1/6 | 14 (6.9) | 8/14 | 7/14 | 10 (4.9) | 5/10 | 1/10 | 30 (14.8) |
| Testis | 5 (2.5) | 1/5 | 2/5 | — | — | — | — | — | — | 5 (2.5) |
| Ovary | 1 (0.5) | 0/1 | 0/1 | 1 (0.5) | 0/1 | 0/1 | — | — | — | 2 (1.0) |
| Uterus/cervical | 5 (2.5) | 0/5 | 1/5 | — | — | — | — | — | — | 5 (2.5) |
| Skin (melanoma) | 8 (3.9) | 0/8 | 0/8 | 1 (0.5) | 0/1 | 0/1 | — | — | — | 9 (4.4) |
| Lymphoma | 11 (5.4) | 7/11 | 7/11 | 2 (1.0) | 1/2 | 2/2 | 1 (0.5) | 1/1 | 1/1 | 14 (6.9) |
| Other † | 5 (2.5) | 1/5 | 0/5 | — | — | — | — | — | — | 5 (2.5) |
| Primary tumor unknown | — | — | — | — | — | — | 2 (1.0) | 0/2 | 0/2 | 2 (1.0) |
| Total | 117 (57.6) | 20/117 | 30/117 | 44 (21.7) | 13/44 | 18/44 | 42 (20.7) | 14/42 | 6/42 | 203 (100) |
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