Incidental Statin Use and the Risk of Stroke or Transient Ischemic Attack after Radiotherapy for Head and Neck Cancer

다국어 초록 (Multilingual Abstract)

Background and Purpose Interventions to reduce the risk for cerebrovascular events (CVE; stroke and transient ischemic attack [TIA]) after radiotherapy (RT) for head and neck cancer (HNCA) are needed. Among broad populations, statins reduce CVEs; however, whether statins reduce CVEs after RT for HNCA is unclear. Therefore, we aimed to test whether incidental statin use at the time of RT is associated with a lower rate of CVEs after RT for HNCA.
Methods From an institutional database we identified all consecutive subjects treated with neck RT from 2002 to 2012 for HNCA. Data collection and event adjudication was performed by blinded teams. The primary outcome was a composite of ischemic stroke and TIA. The secondary outcome was ischemic stroke. The association between statin use and events was determined using Cox proportional hazard models after adjustment for traditional and RT-specific risk factors.
Results The final cohort consisted of 1,011 patients (59±13 years, 30% female, 44% hypertension) with 288 (28%) on statins. Over a median follow-up of 3.4 years (interquartile range, 0.1 to 14) there were 102 CVEs (89 ischemic strokes and 13 TIAs) with 17 in statin users versus 85 in nonstatins users. In a multivariable model containing known predictors of CVE, statins were associated with a reduction in the combination of stroke and TIA (hazard ratio [HR], 0.4; 95% confidence interval [CI], 0.2 to 0.8; P=0.01) and ischemic stroke alone (HR, 0.4; 95% CI, 0.2 to 0.8; P=0.01).
Conclusions Incidental statin use at the time of RT for HNCA is associated with a lower risk of stroke or TIA.

참고문헌 (Reference)

1 Weintraub NL, "Understanding radiationinduced vascular disease" 55 : 1237-1239, 2010

2 Taylor F, "Statins for the primary prevention of cardiovascular disease" (1) : CD004816-, 2013

3 Antonopoulos AS, "Statins as anti-inflammatory agents in atherogenesis: molecular mechanisms and lessons from the recent clinical trials" 18 : 1519-1530, 2012

4 Swisher-McClure S, "Risk of fatal cerebrovascular accidents after external beam radiation therapy for early-stage glottic laryngeal cancer" 36 : 611-616, 2014

5 Hong JC, "Risk of cerebrovascular events in elderly patients after radiation therapy versus surgery for early-stage glottic cancer" 87 : 290-296, 2013

6 Moreno PR, "Resolution of inflammation, statins, and plaque regression" 5 : 178-181, 2012

7 Haddad RI, "Recent advances in head and neck cancer" 359 : 1143-1154, 2008

8 Bonner JA, "Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck" 354 : 567-578, 2006

9 Fletcher GH, "Radiotherapeutic management of surgical recurrences and postoperative residuals in tumors of the head and neck" 95 : 185-188, 1970

10 Yusuf SW, "Radiation-induced heart disease: a clinical update" 2011 : 317659-, 2011

11 Xu J, "Radiation-induced carotid artery stenosis: a comprehensive review of the literature" 2 : 183-192, 2014

12 Silverberg GD, "Radiation-induced carotid artery disease" 41 : 130-137, 1978

13 Gujral DM, "Radiation-induced carotid artery atherosclerosis" 110 : 31-38, 2014

14 Snow GB, "Prognostic factors of neck node metastasis" 7 : 185-192, 1982

15 Gold H, "Production of arteriosclerosis in the rat. Effect of xray and a high-fat diet" 71 : 268-273, 1961

16 Sever PS, "Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lowerthan-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial: Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial" 361 : 1149-1158, 2003

17 Gaugler MH, "Pravastatin limits endothelial activation after irradiation and decreases the resulting inflammatory and thrombotic responses" 163 : 479-487, 2005

18 Bernier J, "Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer" 350 : 1945-1952, 2004

19 Chang CF, "Neck dissection and stroke in patients with oral cavity cancer: a population-based cohort study" 39 : 63-70, 2017

20 Neilan TG, "Myocardial extracellular volume expansion and the risk of recurrent atrial fibrillation after pulmonary vein isolation" 7 : 1-11, 2014

21 Ridker PM, "Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events" 344 : 1959-1965, 2001

22 Wilbers J, "Long term cerebral and vascular complications after irradiation of the neck in head and neck cancer patients: a prospective cohort study: study rationale and protocol" 14 : 132-, 2014

23 Plummer C, "Ischemic stroke and transient ischemic attack after head and neck radiotherapy: a review" 42 : 2410-2418, 2011

24 Paraskevas KI, "Irradiation-induced carotid artery stenosis: a preventable complication of neck radiotherapy?" 60 : 273-275, 2009

25 De Bruin ML, "Increased risk of stroke and transient ischemic attack in 5-year survivors of Hodgkin lymphoma" 101 : 928-937, 2009

26 Dorresteijn LD, "Increased risk of ischemic stroke after radiotherapy on the neck in patients younger than 60 years" 20 : 282-288, 2002

27 Amarenco P, "High-dose atorvastatin after stroke or transient ischemic attack" 355 : 549-559, 2006

28 Meschia JF, "Guidelines for the primary prevention of stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association" 45 : 3754-3832, 2014

29 Jemal A, "Global cancer statistics" 61 : 69-90, 2011

30 Vesselinovitch D, "Experimental production of atherosclerosis in mice. 2. Effects of atherogenic and highfat diets on vascular changes in chronically and acutely irradiated mice" 8 : 497-523, 1968

31 Favre JP, "Endovascular treatment for carotid artery stenosis after neck irradiation" 48 : 852-858, 2008

32 Morawietz H, "Endothelial protection, AT1 blockade and cholesterol-dependent oxidative stress: the EPAS trial" 114 (114): I296-I301, 2006

33 Cholesterol Treatment Trialists' (CTT) Collaborators, "Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis" 371 : 117-125, 2008

34 Albert MA, "Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study" 286 : 64-70, 2001

35 Neilan TG, "Effect of sleep apnea and continuous positive airway pressure on cardiac structure and recurrence of atrial fibrillation" 2 : e000421-, 2013

36 Nissen SE, "Effect of intensive compared with moderate lipidlowering therapy on progression of coronary atherosclerosis: a randomized controlled trial" 291 : 1071-1080, 2004

37 Easton JD, "Definition and evaluation of transient ischemic attack: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association Stroke Council; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; and the Interdisciplinary Council on Peripheral Vascular Disease. The American Academy of Neurology affirms the value of this statement as an educational tool for neurologists" 40 : 2276-2293, 2009

38 Lamberts HB, "Contributions to the study of immediate and early x-ray reactions with regard to chemo-protection. VII. X-ray-induced atheromatous lesions in the arterial wall of hypercholesterolaemic rabbits" 6 : 343-350, 1963

39 Zidar N, "Contribution to the pathogenesis of radiation-induced injury to large arteries" 111 : 988-990, 1997

40 Kramer S, "Combined radiation therapy and surgery in the management of advanced head and neck cancer: final report of study 73-03 of the Radiation Therapy Oncology Group" 10 : 19-30, 1987

41 Smith GL, "Cerebrovascular disease risk in older head and neck cancer patients after radiotherapy" 26 : 5119-5125, 2008

42 National Cancer Institute, "Cancer trends progress report: 2011/2012 update"

43 Sigurdsson AF, "Benefits of statins in healthy elderly subjects: what is the number needed to treat?" 63 : 2302-, 2014

44 Sacco RL, "An updated definition of stroke for the 21st century: a statement for healthcare professionals from the American Heart Association/American Stroke Association" 44 : 2064-2089, 2013

45 Stone NJ, "American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines" 129 (129): S1-S45, 2014