Introduction

Cancer patients are at increased risk for venous thromboembolism (VTE) and arterial thromboembolism (ATE) [1, 2]. The risk of cancer-related thrombosis is multifactorial, and many risk factors have been reported [3]. Among them, anticancer agents such as platinum and angiogenesis inhibitors have been found to increase the risk of VTE and ATE [3,4,5].

There have been an increasing number of reports regarding the risk of thromboembolism with immune checkpoint inhibitors (ICIs) [6,7,8,9,10] because ICIs have revolutionized the treatment of malignancies (e.g., malignant melanoma, lung cancer, and renal cell carcinoma). ICIs could increase the levels of inflammatory cytokines [11] and enhance prothrombotic conditions by activating coagulation and impairing fibrinolysis [12,13,14]. A cohort study (n = 2,299) using data from a U.S. database demonstrated the cumulative 6-month VTE incidence following first-line treatment for non-small cell lung cancer in patients treated with ICIs alone, chemotherapy alone, and ICI plus chemotherapy was 8.1%, 10.9%, and 12.8%, respectively [15]. Regarding the risk of develo** ATE, a previous matched-pair cohort study (n = 5,684) reported a threefold higher risk of atherosclerotic cardiovascular events after initiation of ICI therapy [16]. However, none of these studies have examined the risk of thromboembolism with ICIs compared with conventional chemotherapy [17] despite the fact that additional administration of ICIs with platinum-based therapy for lung cancer is becoming common.

This study aimed to determine the risk of thromboembolism associated with adding ICIs to platinum combination chemotherapy compared with platinum combination chemotherapy alone in patients with advanced non-small cell lung cancer.

Materials and methods

Data source

This nationwide retrospective cohort study used the Japanese Diagnosis Procedure Combination database. The database includes discharge abstracts and administrative claims data for approximately 8,000,000 inpatient admissions from more than 1,200 hospitals throughout Japan. It covers about half of all patients admitted to acute care hospitals in Japan [18, 19]. All 82 academic hospitals are required to participate in the database, whereas the participation of community hospitals is voluntary.

The database contains the following information: unique hospital identifiers; patient age and sex; smoking history (including both current and former smoking status) at admission; body mass index (BMI) at admission; activities of daily living (ADL) at admission; dates of admission and discharge; length of hospital stay; in-hospital mortality; cancer stage; blood transfusions and medications; and interventional/surgical procedures indexed by original Japanese codes. Diagnoses, comorbidities, and complications are recorded using the International Classification of Diseases, Tenth Revision (ICD-10) codes, and Japanese text data. The database includes no laboratory data. A previous validation study showed good sensitivity and specificity for the diagnoses and procedures recorded in this database [18].

The need for informed consent for this study was waived because the patient database was anonymized. The study was approved by the Institutional Review Board of the University of Tokyo (Approval number: 3501– (5), May 19, 2021).

Patient selection

Patients hospitalized for the first administration of platinum combination therapy for advanced non-small cell lung cancer between July 1, 2010, and March 31, 2021, were identified. Non-small cell lung cancer was identified using the ICD-10 code of C34 and Japanese text data. Platinum combination therapy was defined as the following regimens, including cisplatin (CDDP) or carboplatin (CBDCA): (a) CDDP plus pemetrexed (PEM), (b) CBDCA plus PEM, (c) CBDCA plus nab-paclitaxel (nabPTX), (d) CBDCA plus paclitaxel (PTX), (e) CBDCA plus PTX plus bevacizumab (BEV), and (f) above-stated regimens plus ICI (pembrolizumab or atezolizumab). The ICIs used in each regimen were described.

Eligible patients were divided into the ICI and non-ICI groups. The ICI group included patients administered platinum combination regimens plus an ICI (pembrolizumab or atezolizumab), and the non-ICI group included those without ICI therapy. The following patients were excluded: (i) those with pulmonary sarcoma, pediatric pleuropulmonary blastoma, or pulmonary malignant melanoma; (ii) those aged less than 18 years; (iii) those who started chemotherapy after October 1, 2020 (because of the observation period being less than 6 months); (iv) those treated with multiple regimens in the same hospitalization; (v) those who received anticancer agents of the regimen on separate days; (vi) those who received multiple cycles of platinum combination regimens in the same hospitalization; (vii) those who were administered anticoagulants (direct oral anticoagulants [dabigatran, rivaroxaban, apixaban, and edoxaban] and warfarin) within the past 1 year; and (viii) those who had experienced VTE or ATE within the past 1 year.

Outcomes

The primary outcomes were VTE and ATE, requiring hospitalization within 6 months after the start of platinum combination chemotherapy. VTE included deep vein thrombosis (ICD-10 codes: I80.1, I80.2, I80.3, I80.8, I80.9, and I82.8) and pulmonary embolism (I26.0 and I26.9) [20]. According to previous studies, ATE was defined as ischemic heart disease (I20.0, I20.1, I20.8, I20.9, I21.0, I21.1, I21.2, I21.3, I21.4, and I21.9), ischemic brain disease (I63 and G45.9), and peripheral arterial occlusion (I74.0, I74.1, I74.2, I74.3, I74.4, I74.5, I74.8, and I74.9) [1, 8]. VTE or ATE onset was defined as the date when the patient received direct oral anticoagulants or warfarin for a VTE or ATE diagnosis. The secondary outcome was all-cause in-hospital death within 6 months after the start of platinum combination chemotherapy.

Covariates

Covariates were age, sex, BMI, weight, smoking status (nonsmoker, current/past smoker, missing), ADL at admission, combined small cell lung carcinoma, comorbidities, clinical cancer stage (III or IV), treatments before admission (molecular-targeted medications, dialysis, radiotherapy, and surgery within 6 months prior to the index hospitalization), pretreatment medications and procedures during the index hospitalization, baseline chemotherapy, days from admission to initiation of chemotherapy, type of hospital (academic hospital or non-academic hospital), and hospital volume.

Age was categorized into six groups: 18–39, 40–49, 50–59, 60–69, 70–79, and 80 or more years. BMI was categorized using the World Health Organization classifications: less than 18.5 kg/m2 (underweight), 18.5–24.9 kg/m2 (normal weight), 25.0–29.9 kg/m2 (overweight), and more than or equal to 30.0 kg/m2 (obese and severely obese). ADL at admission was assessed using the Barthel index and categorized into three groups: less than or equal to 40, 45–80, and 85–100 [21, 22]. Comorbidities were investigated using the ICD-10 codes (Supplemental Table 1) and assessed using the Charlson comorbidity index [23]. The index was categorized into three groups: less than or equal to 2, 3–4, and more than or equal to 5. Pretreatment medications included antihypertensives, antiplatelet drugs, antipsychotics, corticosteroids, estrogen preparations, non-steroidal anti-inflammatory drugs, proton pump inhibitors/potassium-competitive acid, and statins. Pretreatment procedures included central venous catheterization, radiotherapy, surgery, and transfusion of red cell concentrate. A previous study reported that CDDP-based regimens were associated with a higher risk of VTE than CBDCA-based regimens in patients with lung cancer [24]; therefore, to account for differences in the risk of thrombosis, we adjusted for the baseline chemotherapy regimens in the current analysis. Hospital volume was defined as the annual number of eligible patients at each hospital and categorized into tertiles with approximately equal numbers of patients in each group.

Table 1 Patient background before and after overlap weighting
Full size table

Statistical analysis

We conducted propensity-score overlap weighting to control for potential confounding factors. The overlap weighting analysis balanced the two groups by minimizing the asymptotic variance of the nonparametric estimates of the weighted average treatment effect within a class of weights [25,26,27,16], but the current study had a different population with BMIs less than 25 kg/m2in more than 80% of participants; this difference might have resulted in the low ATE incidence regardless of ICI administration in the current cohort. Additionally, the difference in chemotherapy combined with ICI in the present study may have affected ATE incidence. Platinum chemotherapy requires high-volume infusion and special attention to cardiac function [43]. Thus, clinicians would have selected patients with good cardiac function in the current population treated with platinum chemotherapy.

All-cause mortality within 6 months was significantly lower in the ICI group than in the non-ICI group (Fig. 2). The reduced mortality in the present study is similar to previous randomized controlled trials (e.g., the HR for mortality was 0.71 in KEYNOTE-407) [44,45,46,47]. These trials demonstrated long-term survival (approximately 17–22 months) in patients treated with ICI, whereas the current study revealed that ICI use was associated with a better prognosis even in a shorter period.

The strength of this study lies in the fact that it was conducted in a real-world clinical setting and compared several advanced lung cancer patients to determine whether the addition of ICI increases the risk of thromboembolism, using a platinum-based chemotherapy arm as a control: we showed that the risk of venous thrombosis is approximately 1.3-fold higher with the addition of ICIs. Furthermore, instrumental variable methods were used to adjust for unmeasured confounding, and the results showed a similar trend, indicating that the results are robust. We believe that the current study may provide important information in the decision-making process for lung cancer treatment. However, this study had some limitations. First, outpatient treatment data were unavailable. In Japan, most platinum combination chemotherapies are initiated in an inpatient setting [24]. Therefore, the first administration of the target regimen could be identified using inpatient data only. Second, the unavailability of echocardiographic and electrocardiographic results and information on programmed cell death-ligand 1 antibodies could have led to a bias in the treatment choice to administer ICI. Furthermore, information on histological types (squamous cell carcinoma, adenocarcinoma) and oncogenic gene mutations could not be obtained from the database [48]. In lung and esophageal cancer, the risk of VTE has been reported to be higher for adenocarcinoma than for squamous cell carcinoma [49, 50]. Oncogenic gene mutations, especially ALK fusion gene mutations, are known risk factors for thrombosis [51]. However, the instrumental variable method can adjust for such unmeasured confounders and would support the results of the main analyses. Third, information on outcomes outside the hospital (e.g., thromboembolisms treated in other hospitals and death at home) could not be obtained. Mild venous thrombosis without inpatient treatment may also have been missed. Hence, there may be an underestimation of the outcomes. Moreover, angina pectoris treated only with antiplatelet agents was not included as an outcome. However, because the lack of information is expected to occur equally in the two groups, they are not likely to skew the results. Fourth, with the approval of direct oral anticoagulants, the detection of thrombosis in the ICI and non-ICI groups may be different. For example, in Trousseau syndrome, heparin and direct oral anticoagulants are more likely to be used and warfarin is less frequently selected. Patients with ischemic brain disease in the non-ICI group before direct oral anticoagulants approval may not have been treated with warfarin and thus may have been undetected. Finally, since patients with a history of thromboembolism and patients already taking anticoagulants were excluded, further investigation on this population is needed.

Conclusion

Adding ICIs to platinum combination chemotherapy was associated with an increased risk of in-hospital VTE within 6 months after the start of platinum combination chemotherapy compared with platinum combination chemotherapy alone, while the risk of in-hospital ATE was similar. Therefore, clinicians should closely monitor patients for the risk of thromboembolism when using regimens with ICI added to platinum combination chemotherapy.