Cardiovascular disease in patients with chronic lymphocytic leukemia: A Swedish nationwide register study with matched comparators
Authors: Karin Larsson, Jonas Söderling, Martin Höglund, Ingrid Glimelius, Mattias Mattsson
Journal: American Journal of Hematology (2022)

Currently, there is an ongoing paradigm shift in the treatment of chronic lymphocytic leukemia (CLL), in which traditional chemoimmunotherapy (CIT) is being replaced by targeted therapies such as Bruton's tyrosine kinase inhibitors (BTKi).1 However, first-generation BTKis have significant cardiovascular side effects, such as an increased risk of atrial fibrillation (AF), hypertension, and increased bleeding tendency.2 The risk for these side effects also appears to be elevated with second-generation BTKi, however at a lower frequency.3 Considering the high median age at diagnosis of CLL, in Sweden 72 years,4 and the increasing use of BTKis, cardiovascular disease (CVD) comorbidity is an important clinical issue to address. Moreover, we hypothesized that CLL patients had a higher prevalence of CVD comorbidity prior to CLL diagnosis than matched general comparators. This is due to long-standing chronic inflammation and antigenic stimulation that potentially could drive the development of both arteriosclerosis, CVD as well as CLL.5 We have previously studied the total disease burden of CVD in CLL alone.6 We now set out to study whether, in relation to a population of matched comparators, (i) CVD is more common in CLL patients at time of diagnosis, (ii) first-line therapy with chemotherapy or CIT for CLL increases the risk for new CVDs, (iii) there is an increased incidence and mortality from CVD in CLL patients during follow-up, and also studied (iv) the usage of prescribed drugs for CVD in CLL patients. All Swedish patients diagnosed with CLL (ICD-10: C91.1) during 2007–2015 were identified in the Swedish Cancer Register. Information on CLL therapy was collected from the Swedish CLL register. The comparators were identified from the Total Population Register (Statistics Sweden) using the Swedish Cancer Register to exclude individuals with CLL. Each CLL patient was assigned up to five comparators matched on year of birth, sex, county, and calendar year. Data on CVD were collected using the International Classification of Diseases (ICD-10 codes for CVD I00-199), from the Patient Register. As diagnoses from general practitioners are not included in the Patient Register, a search for prescribed drugs was performed using Anatomical Therapeutic Chemical (ATC) classification codes in the Prescribed Drug Register. The specific ICD-10 and ATC codes are listed in Table S1. Finally, the Cause of Death Register was used to identify CVD as a main and underlying cause of death. The first CVD occurring within 10 years prior to the diagnosis of CLL was selected for the statistical analysis regarding "Any CVD" (Figure S1A). We performed the analysis both with and without a lag-time period of 3 months immediately prior to the date of CLL diagnosis/matching date. By using this 3-month lag-time period, we aimed to minimize the risk of surveillance bias during diagnostic workup for CLL patients (i.e. CVD diagnoses discovered and registered during the lag-time period of 3 months were excluded) versus comparators. Analyses not using such lag-time period were performed in order to study the total CVD burden among the CLL patients both prior to and after diagnostic workup, respectively. To investigate the risk of a CVD diagnosis among CLL patients versus comparators during follow-up, a re-match with comparators was performed with the addition of history of previous CVD as a matching variable (Figure S1B). To study the risk of a new CVD after CLL therapy, a landmark analysis was performed with a new index date 3 years after CLL diagnosis/matching date, i.e. the landmark time. In this analysis, only patients diagnosed with CLL during 2007–2012 and with a registered follow-up 3 years later in the Swedish CLL register were included. The CLL patients and comparators were divided into two groups depending on "history of CVD" and "no history of CVD" at time of CLL diagnosis/matching date. Following this, the two CLL groups were each divided into "need of CLL therapy" or "watch and wait", with matched corresponding comparators (Figure S1C). A detailed description regarding the national registries and statistical analyses used in the study is presented in the Supplement (National health registries and statistical analysis used). This study was approved by the Regional Board of Ethics in Uppsala (Dnr 2016/178) and conducted in accordance with the Declaration of Helsinki. In total, 4261 patients and 21 304 comparators were included in the analyses regarding CVD at time of CLL diagnosis. Clinical characteristics and specific CVD diagnoses are presented in Table S2. With 3-month lag-time prior to the CLL diagnosis, 39% (n = 1661) of the CLL patients had a history of CVD, compared with 41% (n = 8714) among the comparators (p = .02). Hypertension was seen in 21% (n = 910) of the CLL cases and 23% (n = 4982) of the comparators (p < .001). Prior CVD was less common among CLL patients in need of therapy (i.e., more active disease) at time of diagnosis than among comparators (31%, n = 186 vs. 43%, n = 1260, p < .001) (Table S2). In addition, 2203 (52%) of the CLL patients had antihypertensive drugs prescribed compared with 11 157 (52%) among comparators (p = .42). Corresponding numbers for prescribed anticoagulants or platelet aggregation inhibitors were 31% and 33%, respectively (p = .008) (Table S2). Without 3-month lag-time, 46% (n = 1945) of the CLL patients had at least one CVD at time of CLL diagnosis, in relation to 42% (n = 8944) among the comparators (p < .001). Among these, 11% (n = 474) of the CLL patients presented with AF, in relation to 9.8% (n = 2090) among comparators (p = .009). Twenty-six per cent (n = 1126) of the CLL patients were diagnosed with hypertension, in relation to 24% (n = 5164) of the comparators (p = .002) (Table S2). Table S3 shows the clinical characteristics of the studied cohorts after re-match on previous CVD, used in the following analyses. At follow-up after CLL diagnosis, CLL patients overall had an increased risk of being diagnosed with CVD than comparators (HR 1.69, 1.61–1.77). The risk was higher for all subgroups (sex, age, +/−history of CVD, +/−need of CLL therapy) (Table S4). Competing risk regression did not change the significance, hence subdistribution HR was not shown. Clinical characteristics of the study cohorts in the landmark analysis (studying whether CLL therapy with chemotherapy/CIT increases the risk of CVD) are shown in Table S5. The risk of being diagnosed with a CVD during follow-up was increased in all CLL cohorts versus matched comparators (Table S6). Figure 1A,B demonstrates the cumulative incidence of CVD diagnosis for CLL patients and their comparators with a history of CVD on watch and wait and in need of CLL therapy, respectively. Regarding CLL patients without previous CVD, see Figure 1C,D. Mortality from CVD was not increased in CLL patients in relation to comparators (Table S7). In the landmark analysis, no difference in CVD mortality was observed for any of the CLL groups versus comparators (Table S8). All-cause mortality was significantly higher for CLL patients than comparators (HR 2.29; 2.14–2.45) (Table S9). Main and contributory causes of death for CLL patients and comparators are shown in Table S10. A strength of our study is the size and use of nationwide population-based registries with almost complete coverage, and the use of matched comparators. A limitation is that some of our findings on the incidence of CVD at the time of and after CLL diagnosis may be related to surveillance bias. Finally, the choice of a 3-month lag-time before CLL diagnosis might not be optimal in order to exclude all of the surveillance bias during diagnostic workup, leading to inaccurate estimation of CVD comorbidity. To summarize, when analyzing this large population-based CLL cohort with matched comparators, we found no evidence supporting the hypothesis that CVD is more common among CLL patients at the time of diagnosis compared with individuals who do not have CLL (analysis with lag-time). Nonetheless, we found the cardiovascular disease burden to be very high in CLL patients at diagnosis, as well as during treatment. Patients in need of therapy at CLL diagnosis appeared to have less CVD at that time-point than patients not needing treatment, possibly reflecting that clinicians are more prone to choose a watch and wait strategy in patients with preexisting CVD. Irrespective of active treatment or watch and wait, CLL patients had an increased risk of CVD during follow-up, which might be due to surveillance bias. The findings of an increased all-cause mortality but not CVD mortality in CLL patients might be due to these patients succumbing to their hematological disease before obtaining a fatal CVD. Finally, half of the CLL patients (and comparators) were prescribed antihypertensive drugs during the last year prior to CLL diagnosis (with lag-time), and one-third of the patients (and comparators) were on anticoagulants and platelet aggregation inhibitors. We believe our results in this BTKi naïve population-based CLL cohort provides important information for clinical application as the use of BTKi (with known cardiovascular side effects) is currently increasing outside the setting of clinical trials, that is, among real-world CLL patients. Additional data on CVD among these CLL patients treated with BTKis, especially in the era of second-generation BTKis, are of importance to optimize CLL therapy and outcome for these elderly and frail patients. The study was designed by Karin Larsson, Martin Höglund, Ingrid Glimelius, and Mattias Mattsson. Register data were retrieved for each CLL patient and their comparators from central registers. Jonas Söderling performed all of the statistical analyses as well as the figures and tables. All authors wrote and analytically revised the manuscript and gave final approval for submission. The authors declare no conflicts of interest. Data openly available in a public repository that issues datasets with DOIs. Data openly available in a public repository that issues datasets with DOIs. Data S1. Supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.