3.3 Cox proportional hazards analyses for the primary endpoint
We carried out univariable and multivariable Cox proportional hazards analyses for the primary endpoints (Table 3). Multivariable Cox proportional hazard analysis was conducted with the forced inclusion model including conventional risk factors and showed that malignancy was an independent predictor of the primary endpoint (HR, 1.49; 95% confidence interval [CI], 1.10–2.04; P = .011) and that BMI (above median = 23.52 kg/m2) and the prevalence of dyslipidemia were independent and significant negative predictors of the primary endpoint (BMI: HR 0.74, 95% CI 0.56–0.96, P = .025; prevalence of dyslipidemia: HR 0.75, 95% CI 0.56–1.00, P = .048)
We next performed univariable and multivariable Cox proportional hazards analyses for the primary endpoint in the malignancy and nonmalignancy groups (Table 4). In patients without histories of malignancy, BMI (above median = 23.52 kg/m2) and the prevalence of dyslipidemia were independent and significant negative predictors of the primary endpoint (BMI: HR 0.73, 95% CI 0.53–0.99, P = .041; prevalence of dyslipidemia: HR 0.72, 95% CI 0.52–0.99, P = .048), while the prevalence of multi-vessel disease (MVD) and the prevalence of PAD were independent and significant positive predictors of the primary endpoint (prevalence of MVD: HR 1.68, 95% CI 1.18–2.40, P = .004; prevalence of PAD: HR 1.51, 95% CI 1.03–2.21, P = .034). In patients with histories of malignancy, no significant independent factors were identified.
3.4 Effect of cancer treatment on cardiovascular events
It has been suggested that chemotherapy and radiotherapy used in cancer treatments sometimes induce cardiotoxicity and cause heart failure, which was the original concept behind onco-cardiology/cardio-oncology. In the present study, 22 and 16 of 177 cancer patients had histories of chemotherapy and radiotherapy, respectively. Of the 177 patients with prognostic data, there was a significant difference in the occurrence of cardiovascular events between the chemotherapy experienced and naïve groups (chemotherapy experienced: 12/22 [54.5%]; chemotherapy naïve: 42/155 [27.1%], P = .009), while there was no significant difference in the occurrence of cardiovascular events between the radiotherapy experienced and naïve groups (radiotherapy experienced: 8/54 [14.8%]; radiotherapy naïve: 8/123 [6.5%], P = .091).
“Onco-cardiology” or “cardio-oncology” has been used in reference to cardiotoxicity during the treatment of malignant diseases.[1,2] While the adverse effects associated with recent progress in chemotherapeutic cancer treatments are concerning,[38,39] the relationship between malignant diseases and cardiovascular diseases has also attracted attention.[6,21,22] However, the comorbidity of malignant diseases and cardiovascular diseases has never been investigated extensively; therefore, we conducted this multicenter collaborative surveillance. As shown in Supplemental Figure 1, http://links.lww.com/MD/D292, the statistically significant coexistence of malignant diseases and atherosclerotic diseases was observed only in clinical departments that deal with atherosclerotic diseases at university hospitals (Group C).
The prevalence of obesity has dramatically increased not only in developed countries but also in developing countries, and it has become a social problem worldwide. Although the relationship between obesity and CAD has been deemed to be due to cardiovascular risk factors such as hypertension and DM related to obesity, it has been previously reported that obesity itself was an independent predictor of CAD in longitudinal cohort studies.[26,27] However, in 2002, Gruberg et al reported that BMI was inversely correlated with mortality in CAD patients; this phenomenon was different from general perception, and therefore it led to the proposal of the concept called the “obesity paradox.” After that, similar reports[29–31] were forthcoming. It was thought that the residual confounding factors contribute to this relationship,[41,42] but the mechanism has not been elucidated. As shown in Table 2, it was suggested that the presence of malignant disease might contribute to the discrepancy, which was possibly one of residual confounding factor. Moreover, the occurrence rate of events varies depending on the presence or absence of malignancy as previously reported. Conventional prognostic factors, such as renal function, MI history, and PAD history, have not been applied to the malignant disease group as BMI and abdominal circumference have. The reason conventional prognostic factors do not apply in the malignant disease group is not clear, but the following reasons can be suggested. Because malignant diseases and atherosclerotic diseases share certain risk factors,[43–46] it would be reasonable to expect malignant disease patients to have atherosclerotic diseases. Furthermore, malignant diseases[47–49] and atherosclerosis lesions[50–52] are both characterized by inflammation. We have already reported that the combination of malignancy and high high-sensitivity C-reactive protein levels has been associated with significantly higher incidences of cardiovascular events. Thus, we speculate that local malignancies increase vascular wall inflammation by increasing the levels of various inflammatory cytokines[53–55] and that this circulatory inflammation causes progressive arteriosclerosis. As shown in the present study, conventional prognostic factors such as renal dysfunction and PAD history do not apply to the malignant disease group as BMI and abdominal circumference do (Table 1). Hence, 1 possibility why conventional prognostic factors do not apply to the malignant disease group is that malignancy itself might be a residual risk factor for cardiovascular events. Recently, the concept of clonal hematopoiesis of indeterminate potential was proposed for myeloid malignancies, and Libby and Ebert comprehensively reviewed its contribution to cardiovascular risks. Hence, we believe that the important mechanisms underlying this association are common risk factors, inflammation, and clonal factors.
The results obtained in the present study (Fig. 2) were primarily caused by revascularization (Table 2). In Japan, it is common to perform follow-up coronary angiographies 8 to 12 months after PCI, and the results of these procedures were considered in the present study. We have already reported the details of this mechanism. It is well known that radiotherapy, especially thoracic radiotherapy, promotes atherosclerosis. In this study, the possibility of a synergistic relationship between radiotherapy and revascularization was proposed.
5 Study limitations
The present study has several limitations. First, this study was a retrospective single-center observational study. Despite the relatively small number of patients involved, we included patients from a large catchment area and, thus, included a high number and a wide range of cancers among the patients studied, reflecting the broader incidences observed nationally and/or worldwide. In particular, there is a possibility that predictive factors were not identified in the malignancy group due to the small sample size and low statistical power. Second, the possibility that the clinical endpoints observed in this study were influenced by patient medications, the use of anticancer agents or thoracic irradiation cannot be ignored. Third, it is not clear whether patients with both malignant diseases and atherosclerotic diseases have worse prognoses. Fourth, it is unclear which factors contribute or to what extent specific factors contribute to the development of atherosclerotic diseases and the promotion of malignant diseases. Moreover, accumulating clinical evidence has shown that patients with malignancies, compared with those without malignancies, have a higher likelihood of embolism, such as pulmonary embolism or coronary embolism due to thrombus or tumor tissue/mass, which might partly explain why patients with malignancies have a higher risk of cardiovascular events after PCI. Fifth, we set the endpoint as the time when the first event occurred and many were revascularizations. Revascularization is often resulted from routine follow-up coronary angiography and may not be clinically driven. Therefore, the possibility that many more clinically relevant outcomes are being missed cannot be denied. Finally, we did not set a control group (the history of malignancy only group). Thus, it is difficult to conclude the role of malignancy itself in future cardiovascular events. Therefore, further pathophysiological and molecular physiological studies, including animal experiments, are warranted. Additional detailed, prospective, large-scale, long-term surveillance may be needed to verify our theories.
Despite the limitations mentioned above, the results of this study demonstrate the following: patients with malignancies have significantly higher rates of adverse cardiovascular events but might not have the conventional prognostic factors, possibly due to the mechanism underlying the “obesity paradox.”
The authors thank all of the study collaborators for their devoted retrospective clinical records observations. The authors also thank all the paramedical staff and clinical secretaries for their kind support during this work.
SI has received honoraria from Daiichi Sankyo Co, Ltd, and has received grants from Astellas Pharma Inc; Bayer Yakuhin Ltd; Nippon Boehlinger Ingelheim Co, Ltd; Boston Scientific Japan K. K.; Daiichi Sankyo Co, Ltd; Eisai Co, Ltd; MSD K.K.; Bristol-Myers Squibb K.K.; Actelion Pharmaceuticals Japan Ltd; Teijin Pharma Ltd; Japan Lifeline Co, Ltd; Takeda Pharmaceutical Co, Ltd; Medtronic Japan Co Ltd; and Mitsubishi Tanabe Pharma. KO has received grants from Astellas Pharma Inc; Boston Scientific Japan K.K.; Mitsubishi Tanabe Pharma; and MSD K.K. SF has received grants from Ono Pharmaceutical Co, Ltd; Merck Sharp & Dohme Co, Ltd; Bristol-Myers Squibb, Chugai Pharmaceutical Co, Ltd; Novartis Pharma K.K. and Ltd; and Maruho Co, Ltd. NY belongs to departments supported by Chugai Pharmaceutical Co, Ltd and Yakuruto Honsya Co, Ltd. TK has received honoraria from Astellas Pharma Inc and Takeda Pharmaceutical Co, Ltd, and has received grants from Kyowa Hakko Kirin Co, Ltd; Eisai Co, Ltd; Astellas Pharma Inc; Taiho Pharmaceutical Co, Ltd; Takeda Pharmaceutical Co, Ltd; Nippon Kayaku Co, Ltd; Ono Pharmaceutical Co, Ltd; Sanofi K.K.; Pfizer Japan, Inc; Asahi Kasei Pharma Corporation. EA received grants from Astellas Pharma; AstraZeneca, Daiichi Sankyo; Kowa Pharmaceutical; Mitsubishi Tanabe Pharma; Ono Pharmaceutical; Pfizer Japan; Nippon Boehringer Ingelheim; Novartis Pharma; Novo Nordisk Pharma; Sanofi; Taisho Toyama Pharmaceutical; and Takeda Pharmaceutical and personal fees from Astellas Pharma; AstraZeneca; Daiichi Sankyo; Eli Lilly; Kowa Pharmaceutical; Mitsubishi Tanabe Pharma; MSD; Nippon Boehringer Ingelheim; Novartis Pharma; Novo Nordisk Pharma; Ono Pharmaceutical; Sanofi; Taisho Toyama Pharmaceutical; and Takeda Pharmaceutical. HIW has received honoraria from AstraZeneca K.K.; Chugai-Roche Co, Ltd; and Takeda Pharmaceutical Co, Ltd, and has received grants from AstraZeneca K.K.; Chugai-Roche Co, Ltd; Daiichi Sankyo Co, Ltd; Eisai Co, Ltd; Kowa Pharmaceutical Co, Ltd, and Pfizer Japan, Inc. YK has received honoraria from Amgen Astellas BioPharma K.K.; AstraZeneca; Bristol-Myers Squibb; Daiichi Sankyo Co, Ltd; Boehringer Ingelheim Japan; and Sanofi K.K. and has received grants from Abbott Vascular Japan; Astellas Pharma Inc; Boehringer Ingelheim Japan; Boston Scientific Japan K.K.; Daiichi Sankyo Co, Ltd; Japan Lifeline; Medtronic; Nipro; Otsuka Pharmaceutical; Pfizer Japan, Inc; Sanofi K.K.; Sumitomo Dainippon Pharma; Takeda Pharmaceutical Co, Ltd; and Terumo. TM discloses lecture fees from Amgen Astellas BioPharma K.K.; Sanofi K.K.; Nippon Boehringer Ingelheim, Co, Ltd; Mitsubishi Tanabe Pharma Corporation; MSD; Bayer Yakuhin Ltd; Daiichi Sankyo Co, Ltd; and Takeda Pharmaceutical Co, Ltd, as well as research funds form Boehringer Ingelheim, Co, Ltd; Mitsubishi Tanabe Pharma Corporation; Astellas Pharma Inc; Daiichi Sankyo Co, Ltd; Pfizer Japan Inc; Bayer Yakuhin Ltd; Takeda Pharmaceutical Co, Ltd; Bristol-Myers Squibb; Novartis Pharma K.K.; and AstraZeneca K.K. MY has received honoraria from Daiichi Sankyo Co, Ltd and Sanofi K.K. KM has received honoraria from Daiichi Sankyo Co, Ltd; MSD K.K.; Nippon Boehlinger Ingelheim Co, Ltd; and Actelion Pharmaceuticals Japan Ltd and has grants from Astellas Pharma Inc; Bayer Yakuhin Ltd; Nippon Boehlinger Ingelheim Co, Ltd; Boston Scientific Japan K.K.; Daiichi Sankyo Co, Ltd; Eisai Co, Ltd; MSD K.K.; Bristol-Myers Squibb K.K.; Actelion Pharmaceuticals Japan Ltd; Teijin Pharma Ltd; Japan Lifeline Co, Ltd; Takeda Pharmaceutical Co, Ltd; Medtronic Japan Co, Ltd; and Mitsubishi Tanabe Pharma. HB has received honoraria from Eli Lilly Japan K.K. and Ono Pharmaceutical Co, Ltd and has received grants from Chugai Pharmaceutical Co, Ltd; Covidien Japan Inc; Eli Lilly Japan K.K.; Shionogi & Co, Ltd; Toyama Chemical Co, Ltd; Taiho Pharmaceutical Co, Ltd; Yakult Honsha Co, Ltd; Takeda Pharmaceutical Co, Ltd; Shin Nippon Biomedical Laboratories, Ltd; Merck Serono Co, Ltd; Novartis-Pharma K.K.; and Johnson & Johnson K.K. KT has received honoraria from Amgen Astellas BioPharma K.K.; Bayer Yakuhin, Ltd; Daiichi Sankyo Co, Ltd; MSD K.K.; and Sanofi K.K. and has received grants from AstraZeneca K.K.; Astellas Pharma Inc; Bayer Yakuhin, Ltd; Boehringer Ingelheim Japan; Boston Scientific Japan K.K.; Chugai Pharmaceutical Co, Ltd; Daiichi Sankyo Co, Ltd; Eisai Co, Ltd; Kowa Pharmaceutical Co, Ltd; Mitsubishi Tanabe Pharma; MSD K.K.; Pfizer Japan Inc; Sanofi K.K.; Shionogi & Co, Ltd; and Takeda Pharmaceutical Co, Ltd. The remaining authors have nothing to disclose.
Conceptualization: Daisuke Sueta, Noriaki Tabata.
Data curation: Daisuke Sueta, Noriaki Tabata, Satoshi Ikeda, Yuichi Saito, Kazuyuki Ozaki, Kenji Sakata, Takeshi Matsumura, Mutsuko Yamamoto-Ibusuki, Yoji Murakami, Takayuki Jodai, Satoshi Fukushima, Naoya Yoshida.
Formal analysis: Daisuke Sueta, Noriaki Tabata.
Investigation: Daisuke Sueta, Noriaki Tabata, Tomomi Kamba, Eiichi Araki, Hirotaka Iwase, Kazuhiko Fujii, Hironobu Ihn, Yoshio Kobayashi, Tohru Minamino, Masakazu Yamagishi, Koji Maemura, Hideo Baba.
Methodology: Daisuke Sueta.
Project administration: Daisuke Sueta, Kenichi Tsujita.
Resources: Daisuke Sueta.
Software: Daisuke Sueta, Noriaki Tabata.
Supervision: Hideo Baba, Kenichi Tsujita.
Validation: Noriaki Tabata, Kunihiko Matsui, Kenichi Tsujita.
Visualization: Daisuke Sueta, Noriaki Tabata, Kunihiko Matsui.
Writing – original draft: Daisuke Sueta.
Writing – review and editing: Kenichi Tsujita.
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atherosclerotic disease; cardiovascular events; malignant disease; obesity paradox; prognostic factors
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