br No cancer Preexisting cancer New onset
No cancer Preexisting cancer New-onset cancer p value
* Antiplatelet or NSAID.
784 The American Journal of Cardiology (www.ajconline.org)
In all patients with bleeding events and new-onset can-cer, the bleeding events always preceded the diagnosis of cancer (Table 2, mean duration from bleeding events to cancer diagnosis: 128 § 206 days). Bleeding events were independently correlated with new-onset cancers (new-onset cancer vs without cancer; odds ratio 7.89, 95% confi-dence interval 2.53 to 24.61, p = 0.001) after multivariate binary logistic regression including age, history of stroke, diabetes mellitus, hypertension, HA 1077 failure, coronary artery disease, history of GI bleeding, hyperlipidemia,
alcohol consumption, medication usage predisposing patient to bleeding, HAS-BLED score, and CHA2DS2-VASc score. Eight patients underwent active surveillance of the relevant bleeding source after bleeding events, and cancers were diagnosed within 2 months at the relevant bleeding sites (1 lung cancer, 3 GI cancers, 4 urinary tract cancers). One patient developed recurrent extremity ecchy-mosis, which was not relevant to the cancer origin (lung cancer). There were 2 patients with low gastrointestinal tract bleeding without active surveillance, and GI cancer was diagnosed one year later. Similarly, 1 patient ignored recurrent hemoptysis for more than 3 months. Lung cancer with bone metastasis was identified accidentally during the follow-up of an aortic aneurysm by computed tomography scan.
There were 14 (77.8%) patients with new-onset cancers diagnosed in the early stage (less than stage III). Seven (38.9%) patients with new-onset cancer had a significant period of drug interruption after the diagnosis of cancer with a duration longer than 2 to 3 months, which was attrib-uted to cancer surveillance and surgery. In these patients, 1 patient developed a stroke after the resumption of NOACs. Four (22.2%) patients refused to receive NOACs after the
Arrhythmias & Conduction Disturbances/New-Onset Cancers and Nonvitamin K Anticoagulants 785 Table 2
The clinical information about cancer and bleeding in the patients with new-onset cancers
Duration of between first
NOAC use to bleeding event
cancer diagnosis and cancer Bleeding NOAC use after
(y/o) Gender type Stage (days) diagnosis (days) events cancer diagnosis
1 80 Female Colorectal CA IIb 787 649 Major/minor Interrupted, 2 months 2 82 Male Gastric CA IV 220 9 Minor Continued 3 86 Male Esophageal CA Ia 319 − No Continued 4 84 Male Colorectal CA IIa 421 16 Major Discontinued 5 82 Male Colorectal CA I 462 464 Minor Interrupted, 3 months 6 77 Female Colorectal CA I 442 9 Minor Interrupted, 2 months 7 66 Male Colorectal CA I 592 36 Minor Interrupted, 4 months 8 70 Female Bladder CA II 1110 60 Minor Interrupted, 2 months 9 87 Male Prostate CA IIb 573 29 Minor Continued 10 71 Male Prostate CA IIa 54 − No Interrupted, 2 months 11 92 Male Bladder CA I 456 62 Minor Discontinued 12 92 Male Prostate CA I 17 17 Minor Discontinued 13 84 Male Prostate CA IV 714 − No Continued 14 69 Male Lung CA IV 1057 97 Minor Continued 15 70 Female Lung CA IIIa 946 90 Minor Discontinued 16 75 Male Lung CA IIa 1314 − No Continued 17 69 Male Lung CA I 155 − No Continued 18 91 Male Polycythemia vera − 863
No Interrupted, 2 months
diagnosis of new-onset cancer due to recurrent minor bleed-ing (n = 3) and major bleeding (n = 1).
The patients with new-onset cancers had higher HAS-BLED scores and experienced bleeding events preceding cancer diagnosis. The bleeding events in AF patients receiving NOACs indicated a 7.89-fold higher probability of having new-onset cancers. More than half of the patients (61%) with new-onset cancer either had a significant period of drug interruption for at least 2 months after the diagnosis of cancer or discontinued NOACs.
The present study suggested that bleeding could a potential alerting sign for new-onset cancer. Although the results remain exploratory due to the limited number of patients, the findings implied that thorough cancer surveil-lance might be needed for the early diagnosis of new-onset cancer in AF patients. Few studies have addressed the potential clinical link between bleeding after anticoagu-lants and new-onset cancer.7,16 Clemens A. et al observed a similar incidence of GI cancer and bleeding from phase III trials of AF patients with NOACs, leading to the
hypothesis that anticoagulant-related GI bleeding might reveal and increase the detection of GI cancers.7 Yu HT et al demonstrated that 40 of 3,570 AF patients with hematu-ria (1.1%) were diagnosed with urinary tract cancer.16 The patients receiving oral anticoagulants had a higher inci-dence of urinary tract cancers than did those who did not receive oral anticoagulants.16 These studies first observed the potential link between bleeding and cancer in patients with AF receiving anticoagulants but did not inspect the direct link between bleeding and new-onset cancers. Lim-ited by retrospective or cross-section designs, both studies also derived their data from an electronic recorded data-base in which crucial clinical information and details might be lacking. The present study prospectively fol-lowed up patients with bleeding events and their cancer surveillance in order to identify the important link between new-onset cancer and bleeding. We also observed that bleeding as a risk factor for new-onset cancer is prob-ably not confined to GI or urinary tract cancers. Two patients with hemoptysis in the present study were diag-nosed with lung cancers. Bleeding is not uncommon in the patients receiving NOACs.10 The HAS-BLED score in AF patients with new-onset cancer was significantly higher than in those without. The clinicians may attribute the cause of bleeding to the concomitant use of NOACs-related coagulopathy and ignore the underlying pathology, such as occult cancer. Clinical predictors, such as CHA2DS2-VASc score, could not adequately detect the presence of new-onset cancers. Addressing the important link between new-onset cancers and bleeding will help in the diagnosis and treatment of cancer at an early stage for AF patients, as there were 78% patients identified with cancer in early stages in the present study.