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Cardiovascular medication after cancer at a young age in Finland: A nationwide registry linkage study

2015; Wiley; Volume: 139; Issue: 3 Linguagem: Inglês

10.1002/ijc.29943

1097-0215

Andreina Kero, Laura Madanat‐Harjuoja, Liisa S. Järvelä, Nea Malila, Jaakko Matomäki, Päivi M. Lähteenmäki,

Acute Lymphoblastic Leukemia research

International Journal of CancerVolume 139, Issue 3 p. 683-690 Cancer Therapy and PreventionFree Access Cardiovascular medication after cancer at a young age in Finland: A nationwide registry linkage study A.E. Kero, Corresponding Author A.E. Kero Department of Pediatric and Adolescent Medicine, Turku University Hospital and Turku University, Turku, FinlandCorrespondence to: Andreina E. Kero, Pediatric Hematology and Oncology, Department of Pediatric and Adolescent Medicine, Turku University Hospital, Kiinamyllynkatu 4-8, FI 20520 Turku, Finland, Tel.: +358-44-0780821, E-mail: aneuke@utu.fiSearch for more papers by this authorL.M. Madanat-Harjuoja, L.M. Madanat-Harjuoja Department of Pediatrics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Finnish Cancer Registry, Helsinki, FinlandSearch for more papers by this authorL.S. Järvelä, L.S. Järvelä Department of Pediatric and Adolescent Medicine, Turku University Hospital and Turku University, Turku, FinlandSearch for more papers by this authorN. Malila, N. Malila Finnish Cancer Registry, Helsinki, Finland School of Health Sciences, University of Tampere, Tampere, FinlandSearch for more papers by this authorJ. Matomäki, J. Matomäki Turku Clinical Research Center, Turku University Hospital, FinlandSearch for more papers by this authorP.M. Lähteenmäki, P.M. Lähteenmäki Department of Pediatric and Adolescent Medicine, Turku University Hospital and Turku University, Turku, FinlandSearch for more papers by this author A.E. Kero, Corresponding Author A.E. Kero Department of Pediatric and Adolescent Medicine, Turku University Hospital and Turku University, Turku, FinlandCorrespondence to: Andreina E. Kero, Pediatric Hematology and Oncology, Department of Pediatric and Adolescent Medicine, Turku University Hospital, Kiinamyllynkatu 4-8, FI 20520 Turku, Finland, Tel.: +358-44-0780821, E-mail: aneuke@utu.fiSearch for more papers by this authorL.M. Madanat-Harjuoja, L.M. Madanat-Harjuoja Department of Pediatrics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland Finnish Cancer Registry, Helsinki, FinlandSearch for more papers by this authorL.S. Järvelä, L.S. Järvelä Department of Pediatric and Adolescent Medicine, Turku University Hospital and Turku University, Turku, FinlandSearch for more papers by this authorN. Malila, N. Malila Finnish Cancer Registry, Helsinki, Finland School of Health Sciences, University of Tampere, Tampere, FinlandSearch for more papers by this authorJ. Matomäki, J. Matomäki Turku Clinical Research Center, Turku University Hospital, FinlandSearch for more papers by this authorP.M. Lähteenmäki, P.M. Lähteenmäki Department of Pediatric and Adolescent Medicine, Turku University Hospital and Turku University, Turku, FinlandSearch for more papers by this author First published: 26 November 2015 https://doi.org/10.1002/ijc.29943Citations: 7 Conflict of interest: Nothing to report AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Abstract Despite improved survival rates, childhood and young adult (YA) cancer survivors face elevated risks for life-threatening morbidities, especially cardiovascular complications. Our nationwide Finnish registry study investigated the purchases of cardiovascular medication from 1993 to 2011 in patients diagnosed with cancer aged below 35 years (N = 8,197) between 1993 and 2004 compared to siblings (N = 29,974) via linkage to the drug purchase registry. The cumulative incidence for purchasing cardiovascular medications was higher in childhood and YA cancer patients compared to siblings with a rising trend over time. After childhood cancer, the highest hazard ratio (HR) was found for purchasing anticoagulants (HR 19.8, 95% CI 8.5–45.9). The HRs for any cardiovascular medication (HR 7.2, 95% CI 5.1–10.1) and cardiac medication (HR 4.8, 95% CI 3.3–6.9) were markedly elevated after childhood cancer as well. Regarding YA cancer patients, the respective HRs were 2.5 (95% CI 2.0–3.2) for anticoagulants, HR 1.7 (95% CI 1.5–1.9) for any cardiovascular medication and HR 1.5 (95% CI 1.3–1.7) for cardiac medication. Among cancer patients, highest HRs for cardiovascular medication were observed after childhood acute lymphoblastic leukemia (ALL) and bone tumors (HR 10.2, 95% CI 6.8–15.5 and HR 7.4, 95% CI 4.0–13.7) and YA ALL and acute myeloid leukemia (HR 5.1, 95% CI 3.5–7.1 and HR 2.8, 95% CI 1.8–4.0). Our study demonstrated increased HRs for purchasing cardiovascular medication after early-onset cancer compared to siblings reflecting elevated cardiovascular morbidity. Thus, the implementation of long-term cardiovascular disease screening is imperative to prevent, detect and adequately treat cardiovascular late effects after cancer at a young age. Abstract What's new? Children and young adults who survive cancer should remain vigilant against cardiovascular complications according to this report. The authors investigated how often young cancer patients began purchasing cardiovascular medications compared with their cancer-free siblings. They showed that the cancer patients went on cardiovascular medications, especially anticoagulants, far more often than their siblings. Thus, these findings suggest that screening for cardiovascular disease should be emphasized after cancer at a young age. This study may help doctors craft individualized follow-up schedules after early onset cancer. At present, the diagnosis with childhood or young adult (YA) cancer is not an instantaneous death sentence anymore thanks to survival approaching 80%.1, 2 However, virtually any organ system may be susceptible to adverse effects of cancer therapy involving chemotherapy, radiation or surgery.3-5 Nearly two-thirds of childhood cancer survivors have reported to experience health drawbacks after the initial defeat over malignancy: long-term morbidities that may eventually lead to a reduced life expectancy.5 Late cardiovascular morbidity has been demonstrated to be the leading nonmalignant cause of death after childhood and YA cancer in patients aged below 34 years at cancer diagnosis.6-8 Up to date, information on the use of cardiovascular medication after childhood and YA cancer remains limited. Only one study reported that childhood cancer survivors have more likely been treated for hypertension than their siblings.9 As a consequence of the great impact of cardiovascular adverse effects after cancer, a new clinical field has emerged to specifically deal with cardiovascular complications: cardio-oncology.10 Cardio-oncology aims at reducing or preventing cardiovascular damage during cancer therapy, detecting cardiovascular late effects in early, reversible stages and treating cardiovascular complications effectively to avoid lethal outcomes.11 Hence, information on the status of cardiovascular medication is helpful for the evaluation of cardiovascular morbidities after cancer at an early age. Furthermore, this additional knowledge may contribute to individual risk-based strategies to reduce cardiovascular late effects following successful cancer therapy. The aim of our study was to investigate cardiovascular morbidity after early-onset cancer in Finland by analyzing data from the national drug purchase register. Subjects and Methods The Finnish Cancer Registry (FCR) has collected data on incident cancer diagnoses since 1953. The register is population-based, nationwide and has been shown to be almost complete during the time period between 1985 and 198812 (99% for solid tumors and 92% for hematological malignancies) and the coverage is believed to currently be in a similar range. The FCR records information on the personal identity code, date of cancer diagnosis, primary cancer site, morphology, degree of malignancy, spreading (at cancer diagnosis) and possible date and cause of death. The cancer patient cohort was identified from the FCR. A total of 8,197 patients met the following inclusion criteria: aged <35 years at cancer diagnosis; diagnosis with a primary malignant neoplasm [including benign central nervous system (CNS) tumors and those of uncertain malignancy] and having been diagnosed between January 1, 1993 and December 31, 2004. From the original cancer patient cohort, 20 were excluded owing to insufficient follow-up because of death (19 subjects) or emigration (one subject) immediately after diagnosis (Fig. 1). Early-onset cancer patients were grouped by age at cancer diagnosis into childhood cancer patients (aged 0–19 years at cancer diagnosis) and YA cancer patients (aged 20–34 years at cancer diagnosis). Figure 1Open in figure viewerPowerPoint Overview of the early-onset cancer (a) and sibling (b) cohort examined in our study. The cancer patient cohort was divided into childhood cancer (aged below 20 years at cancer diagnosis) and young adult cancer patients (aged 20–34 years at cancer diagnosis). The cancer patient cohorts shown here were investigated in all analyses of this study. The sibling cohort marked in white was examined in the prevalence analysis, whereas the subcohorts of siblings marked in dark gray were studied in the analysis of cumulative incidence and hazard ratios. Since 1967, each Finnish resident has been assigned a unique personal identification code (PIC), which can be used for record linkages. The Population Register Center hosts a nation-wide population register (CPR) recording the PIC and date of emigration or death of each individual living in Finland. Moreover, links to parents, siblings and children are reliably accessible for family members born after 1955. Siblings of cancer patients were identified by linking the PIC of the patient to his/her parents and by listing all children of the parents. By linkage to the CPR, 29,974 siblings of cancer patients without a cancer diagnosis at early age (below 35 years of age) and born between January 1, 1958, and December 31, 2004 were identified (Fig. 1). From the entire sibling cohort, we separated those born at the start of follow-up on January 1, 1993 or afterward and aged 20 years from the start of follow-up (January 1, 1993) onward (Fig. 1). The follow-up of cancer patients ended at death, diagnosis with a second cancer, date of emigration or on December 31, 2011, whichever came first. Second cancer was chosen as the end of follow-up, since possibly additional cancer therapy may have an impact on cardiovascular conditions. Siblings were followed up until the diagnosis of first cancer, death, date of emigration or December 31, 2011. The drug purchase registry The drug purchase registry (DPR) is managed by the Social Insurance Institution (SII) and has recorded all purchased prescription medication since January 1, 1993. The registry contains information on all purchased drugs that are refundable [except for over-the-counter drugs (OTCs) and medications used in hospital care]. Purchases of medications that have been initially prescribed in hospital care are recorded by the DPR as soon as a patient has been discharged and purchases drugs from the pharmacy, if the use of the medication is prescribed for a longer time period after hospital discharge. Specific medications, including, e.g., cardiovascular, hormonal and diabetes medications, are only available by prescription in Finland. This database registers, e.g., the patients' PIC, the purchase date of the prescription drug, the medication cost and the dispensed package size. All drugs are grouped into specific categories according to Anatomical Therapeutic Chemical (ATC) codes of the World Health Organization (WHO). Drug purchases are registered regardless of the payer, the patient (most commonly) or a private insurance company. Cardiovascular medications For this study, medications were grouped according to the ATC codes as follows: ATC-C01-09 (cardiac), -B01 (anticoagulants) and all these together (cardiovascular). The first purchase of a drug in any of those categories separately or in the overall category (cardiovascular) was considered as outcome in our study. Additionally, we investigated the purchases of specific subgroups of cardiac medications (ATC-C01-09): ATC-C01 (cardiac therapy, including -C01A: cardiac glycosides, -C01B: antiarrhythmic I and III, cardiac stimulants and -C01D: vasodilators), -C02 (antihypertensives), -C03 (diuretics), -C07 (beta-blocking agents), -C08 (calcium channel blockers) and C09 (renin-angiotensin system agents). Statistical analysis The cumulative incidence of purchasing at least one of the drugs according to the particular categories was estimated from cancer diagnosis in cancer patients and from the start of follow-up in siblings with death or secondary (primary in siblings) cancer as competing risks. Follow-up ended at death, secondary/primary cancer, emigration or at the latest on December 31, 2011, whichever came first. The hazard ratios (HRs) for purchasing specific drugs (ATC groups) were analyzed among early-onset cancer patients in comparison to the sibling cohort. Furthermore, we examined HRs for the purchase of any cardiovascular drug among cancer patients by cancer diagnosis and age at cancer diagnosis with siblings as a reference group. HRs were calculated according to the Fine and Gray proportional subdistribution hazards method. For the comparison with siblings, we adjusted for birth year and difference in ages at the start of follow-up. The prevalence of first-time purchases of any cardiovascular medication was analyzed during the time period between 1993 and 2011. Among the midyear population of cancer patients and siblings, the first drug purchase was examined during the determined time intervals: 1995 (1993–1997), 2000 (1998–2002), 2005 (2003–2007) and 2009 (2008–2011). The number and proportion of cancer patients and siblings having purchased their first cardiovascular medication were shown at the specified midyear time point in the group of subjects alive at this time point. Statistical analyses were performed using SAS for Windows version 9.3. Ethics The study protocol was accepted by the ethical committee of the South-West Finland Hospital District Review Board. Permits for registry linkage were obtained from the Finnish Ministry of Social Affairs and Health (THL/1184/5.05.00/2011), the Population Register Center and the Social Insurance Institution. Results From the original early-onset cancer patient cohort of 8,197 subjects, the purchase of cardiovascular medication was investigated among 2,762 childhood, 5,415 YA cancer patients and 29,974 siblings (Fig. 1). The follow-up time of cancer patients extended maximally up to 18 years from cancer diagnosis. To gain an insight into the first purchase of cardiovascular medication over time, we analyzed the cumulative incidence of purchases among childhood and YA cancer patients and siblings (Figs. 2a–2c). In all cardiovascular medication categories, the cumulative incidence of purchases was higher among cancer patients than in controls. After YA cancer, the cumulative incidence for any cardiovascular and cardiac medication reached 40% at the end of follow-up compared to 20% in siblings (Figs. 2a and 2b). Similarly, the cumulative incidence was consistently higher after childhood cancer compared to the younger sibling group in all investigated categories (Figs. 2a–2c). The cumulative incidence for purchasing anticoagulants was rather similar in both the younger and older cancer patient cohort during the first 15 years of follow-up (Fig. 2c). Figure 2Open in figure viewerPowerPoint (a–c) The cumulative incidence of the first purchase of cardiovascular medication in early-onset cancer patients and siblings from cancer diagnosis or the start of follow-up (years). (a) Any cardiovascular medication (ATC-C01-09 or -B01), (b) cardiac medication (ATC-C01-09) and (c) anticoagulants (ATC-B01). Cancer patients (gray) were subdivided by age at cancer diagnosis: 0–19 years (solid) and 20–34 years (dashed). Siblings (black) were subdivided by age at the start of follow-up: 0 years (solid) and 20 years (dashed). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] Furthermore, the cumulative incidence for purchasing cardiovascular drugs differed according to selected cancer diagnoses and also age at cancer diagnosis (Figs. 3a and 3b). At the end of follow-up, the cumulative incidence in YA acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), Hodgkin lymphoma (HL) and non-Hodgkin-lymphoma (NHL) patients exceeded 30%. In childhood cancer patients, the diagnosis with ALL and bone tumors was associated with highest cumulative incidence figures at the end of follow-up around 15% (Figs. 3a and 3b). Interestingly, the cumulative incidence showed different trends during the course of follow-up depending on the cancer diagnosis. Furthermore, the cumulative incidence rose in close temporal proximity to cancer diagnosis among childhood bone tumor, YA ALL and AML patients in contrast to rather gradual increases in the remaining diagnosis groups. Figure 3Open in figure viewerPowerPoint (a and b) Cumulative incidence (%) of purchasing cardiac drugs by cancer diagnosis and age at cancer diagnosis over time from cancer diagnosis (years). Bold lines: cancer diagnosis in young adulthood and thin lines: cancer diagnosis in childhood. (a) Acute lymphoblastic leukemia (ALL): dashed blue, acute myeloid leukemia: solid green and non-Hodgkin-lymphoma (NHL): dotted red. (b) Hodgkin lymphoma (HL): gray, central nervous system (CNS) tumor: turquoise and bone tumor: orange. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] When all cardiovascular drug categories were evaluated together, the HRs for the first purchase of medication were increased in childhood and YA cancer patients [HR 7.2, 95% CI 5.1–10.1 and HR 1.7 (95% CI 1.5–1.9), respectively] compared to siblings (Fig. 4). Additionally, the HRs for purchasing anticoagulants were elevated to 19.8-fold (95% CI 8.5–45.9) and 2.5-fold (95% CI 2.0–3.2) in the younger and older patient cohort (Fig. 4). Moreover, the HR for purchasing cardiac medication was also increased in childhood and YA cancer patients (HR 4.8, 95% CI 3.3–6.9 and HR 1.5, 95% CI 1.3–1.7). Figure 4Open in figure viewerPowerPoint Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for purchasing cardiovascular medication after childhood and young adult cancer compared to siblings. *Major drug category. oSpecific subcategory of drugs. As the category of cardiac medications comprised a large array of drug classes, we further calculated the HRs for purchases in particular cardiac subgroups of drugs (Fig. 4). The majority of HRs were elevated after both childhood and YA cancer compared to siblings except for equal purchases of beta-blockers and renin-angiotensin system agents after YA cancer (Fig. 4). The HRs for purchasing cardiac glycosides were markedly increased after both childhood and YA cancer (HR 9.6, 95% CI 2.6–35.8 and HR 39.3, 95% CI 5.0–308.9) (Fig. 4). To determine the impact of the specific cancer diagnosis and also the age at cancer diagnosis on the likelihood of purchasing cardiovascular drugs, we investigated HRs among selected cancer diagnosis groups with siblings as reference group (Fig. 5). Taken together, we observed elevated HR values in all selected childhood and YA cancer diagnosis groups except for YA CNS tumor patients as compared to siblings. Highest HRs for purchasing cardiovascular drugs were found after childhood ALL and bone tumors (HR 10.2, 95% CI 6.8–15.5 and HR 7.4, 95% CI 4.0–13.7, respectively). After childhood cancer, patients younger than 10 years at cancer diagnosis demonstrated the greatest likelihood of purchasing cardiovascular medication (Table 1, panels A–C). Among this group, the diagnosis with ALL predisposed to highest HR values. Furthermore, ALL and AML patients lead the HR figures among the YA cancer diagnosis groups compared with siblings (HR 5.1, 95% CI 3.5–7.1 and HR 2.8, 95% CI 1.8–4.0). Figure 5Open in figure viewerPowerPoint Hazard ratios (HRs) and 95% confidence intervals (CIs) for purchasing any cardiovascular medication by primary cancer diagnosis and age at diagnosis (childhood and young adult cancer) compared to siblings. Acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), central nervous system (CNS) tumor, Hodgkin lymphoma (HL) and non-HL (NHL). Table 1. Hazard ratios (HRs) and 95% confidence intervals (CIs) among cancer patients aged 0–9 years and 10–19 years at cancer diagnosis for purchasing: (A) any cardiovascular drug, (B) anticoagulants and (C) cardiac medication compared to siblings Age at diagnosis 0–9 years 10–19 years Cancer diagnosis HR 95% CI HR 95% CI (A) ALL 13.3 7.9–22.3 5.4 3.4–8.2 AML 2.7 0.4–9.0 3.4 1.4–7.0 Bone 4.9 0.3–25.1 4.3 2.4–7.3 CNS tumor 5.4 2.9–9.8 2.1 1.3–3.3 HL NA 1.7 1.0–2.9 NHL 5.4 2.1–12.2 2.8 1.5–5.0 Overalla 9.4 6.3–14.0 3.2 2.3–4.4 (B) ALL 68.0 26.0–201.4 6.5 3.1–13.0 AML 13.2 0.7–80.8 3.1 0.5–11.2 Bone 58.8 3.0–386.3 8.9 3.8–19.1 CNS tumor 6.7 1.3–27.7 3.2 1.4–6.5 HL NA 3.1 1.3–6.8 NHL 27.5 5.4–113.8 3.5 1.3–8.5 Overalla 38.8 16.2–62.9 3.9 2.2–6.9 (C) ALL 6.0 3.2–11.0 5.0 2.9–8.0 AML 1.1 0.1–5.5 2.8 1.0–6.6 Bone NA 3.1 1.5–5.9 CNS tumor 3.8 1.9–7.7 1.6 0.9–2.7 HL NA 1.3 0.6–2.4 NHL 2.4 0.7–1.1 2.1 1.0–4.0 Overalla 4.6 2.9–7.3 2.9 2.0–4.2 a Overall: all cancer patients aged 0–9 years and 10–19 years at cancer diagnosis taken together in addition to the respective diagnosis groups shown in the table. Abbreviations: ALL: acute lymphoblastic leukemia; AML: acute myeloid leukemia; CNS: central nervous system; HL: Hodgkin lymphoma; NHL: non-Hodgkin lymphoma; NA: not applicable. Lastly, the prevalence on medication purchase was examined at determined time points during the course of follow-up (Supporting Information Table 1). Purchase proportions continuously rose in the investigated midyear populations of YA cancer patients and siblings over time to 25 and 17%, respectively, in the last analyzed midyear population. In contrast, purchase proportions of childhood cancer patients did not grow during our follow-up, but rather remained at stable at 12% in the final observed midyear population compared to the initial value (Supporting Information Table 1). Discussion To the best of our knowledge, this study is the first to present nationwide data on cardiovascular medication after childhood and YA cancer compared to a healthy sibling cohort. Our data on the status of cardiovascular medication after childhood and YA cancer allowed new insights into cardiovascular late adverse effects including long follow-up times. The cumulative incidence of purchasing cardiovascular medication was elevated especially after YA, but also after childhood cancer during follow-up. Additionally, HRs for purchasing these cardiovascular medications were significantly higher after both childhood and YA cancer compared to siblings. Among cancer patients, HRs for cardiovascular drugs were strongly dependent on the primary cancer diagnosis and age at cancer diagnosis. The cumulative incidence of purchasing cardiovascular medication showed an increasing trend in early-onset cancer patients and siblings with no plateau visible by the end of follow-up. This was at least partly due to older age itself being a major risk factor for cardiovascular diseases.13 However, we observed an initial gap in cumulative incidence of cancer patients and siblings, which seemed to increase over time. This early divergence in cumulative incidence may demonstrate an immediate increase in cardiac morbidity after cancer therapy in line with reports on early cardiotoxicity in childhood cancer (AML) patients.14, 15 While acute, yet reversible, cardiotoxicity has rarely been documented, the more common early onset chronic type of cardiotoxicity more than 1 year from cancer therapy has been shown to progress.16 Especially after YA ALL and AML, the cumulative incidence of cardiac medication was increased early on from cancer diagnosis, which may be due to the larger number of bone marrow transplantations among these diagnosis groups.17 The rising trend of cumulative incidence over time in patients underlined the need of long-term cardiac follow-up, as cardiac complications can occur very late after the completion of cancer therapy.18, 19 Furthermore, elevated HRs for the purchase of cardiac medications in childhood bone tumor and ALL patients confirmed previous findings on excess cardiovascular morbidity and mortality in the respective childhood cancer diagnosis groups.20-23 Among YA patients, highest HRs for purchasing cardiac medication were found after ALL and AML, possibly due to more frequent stem cell transplantations.17 Total body irradiation as a treatment before hematopoietic stem cell transplantations and mediastinal radiation have been identified as important cardiovascular risk factors.9, 18 After childhood cancer, elevated HRs for the purchase of several cardiac medication classes, such as cardiac glycosides, diuretics, renin-angiotensin system agents and beta-blockers, indicated an increased risk of a wide range of cardiovascular morbidity. Recent guidelines for the therapy of cardiac failure in adults have included those medication classes in their recommendations.24 The use of beta-blockers and cardiac glycosides has been recommended for pediatric heart failure, though beta-blockers may also be prescribed for treating other cardiac morbidities than cardiac failure.25, 26 The focus of our investigation was the purchase of cardiovascular medication, but it lacked the specific indication, as this was not available from the registry source. Hence, the increased HRs for purchasing cardiovascular medication may reflect a variety of cardiac diseases spanning from hypertension to cardiac insufficiency. Nevertheless, the elevated HRs for buying cardiac glycosides after both childhood and YA cancer confirmed reports of higher HRs for cardiac insufficiency in earlier studies, as their indication is primarily limited to this cardiac outcome.18, 22, 27 In addition to that, HRs were increased for purchasing anticoagulants after early-onset cancer which underlined previous literature on the increased risk of cerebrovascular thrombotic events in childhood and YA cancer survivors.22, 28, 29 A previous questionnaire-based study reported that childhood cancer survivors have a greater likelihood of being treated with antihypertensive drugs than their siblings, supporting our findings on higher HRs for purchasing these medications in childhood and YA cancer patients.9 However, Meacham et al. did not examine the specific subclasses of antihypertensive medications and their time frame of cancer diagnosis ended earlier than in our study. Hypertension has been identified as a predominant etiology of cardiovascular disease in the general population.13, 30 Furthermore, hypertension has been associated with increased risks of various adverse cardiovascular morbidities and excess cardiac mortality in adult survivors of childhood cancer.31 Additionally, younger age at cancer therapy has been considered a key risk factor for developing cardiovascular complications in childhood cancer survivors.32, 33 Strengths and limitations Previous reports have extensively explored cardiac morbidity and mortality after childhood cancer.4, 7, 19, 27, 31, 34 Recently, cardiac late effects and mortality have been studied also in YA cancer patients.6, 18, 22, 35, 36 Our study was unique by analyzing and comparing findings on drug purchases in both childhood and YA cancer patients. Earlier studies have mostly relied on questionnaires concerning cardiovascular medication.9 Fewer investigations have retrieved detailed information on cardiovascular morbidity by abstracting data from medical records or examining cancer patients in follow-up clinics.3 As an alternative, our registry-based analysis of drug purchase information offered an almost complete national coverage of purchased medication. This form of data retrieval was free of recall bias present in self-reported responses or selection bias of particular patient groups or treatment areas.9, 37 Our follow-up extending up to 18 years postdiagnosis enabled to analyze the purchase of cardiovascular medication over a long time period after cancer diagnosis. The first purchase of cardiovascular medication served as a proxy for the use of cardiovascular medication and cardiac morbidity in cancer patients and siblings. As cardiovascular medication is mostly issued on a long-term basis, we regarded the first purchase of cardiovascular medication as sufficient indicator for cardiovascular disease.38 Nevertheless, reversible hypertension especially after stem cell transplantation may confound our results to a minor extent.39 Our data sources could not provide details on the indication of cardiovascular therapy or cancer treatment itself. Nevertheless, international protocols on cancer therapy involving certain chemotherapeutic agents and determined amounts of radiation have been nationally implemented particularly in the treatment of childhood cancer in Finland.40 In previous studies, one in five childhood cancer patients showed late cardiac dysfunction