Statin and the Risk of Ischemic Stroke or Transient Ischemic Attack in Head and Neck Cancer Patients with Radiotherapy.

Dear Sir:

We read with great interest the study entitled “Incidental statin use and the risk of stroke or transient ischemic attack after radiotherapy for head and neck cancer” by Addison et al. [1] The study, which included 1,011 head and neck cancer (HNC) patients with 288 (28%) on statins, found that statin was protective against the development of transient ischemic attack (TIA) and ischemic stroke after radiotherapy during a median followup of 3.4 years.

With the aim to examine the association between statin and stroke risk after radiotherapy in a larger cohort of HNC patients, we conducted a nationwide population-based study using data from the National Health Insurance Research Database. International Classification of Diseases, Ninth Revision, Clinical Modification was used for disease identification and the cancer status was confirmed using the catastrophic illness registry. We identified newly diagnosed HNC patients receiving radiotherapy from January 1, 2000 to December 31, 2010 (n=48,548), and patients with previous cancer or radiotherapy history were excluded for further analysis. Statin user was defined as use of statin during the entire course of radiotherapy. After propensity score matching of the selected comorbidities, there were 1,073 patients receiving statin (user group) and 1,073 matched patient not receiving statin (nonuser group) during radiotherapy and followup. The demographics were not different between the user and nonuser groups except for the use of antithrombotics and antihypertensives, which were of higher incidence in the user group (Table 1). In total, TIA or ischemic stroke developed in 64 patients in the user group and 45 in the nonuser group during the study period, respectively. Cumulative incidences of developing TIA or ischemic stroke in the user and nonuser groups were presented in Figure 1, and no significant difference was observed (log-rank test, P=0.29). The risk of TIA or ischemic stroke was also similar in the competing-risk regression model (adjusted subhazard ratio, 1.35; 95% confidence level, 0.95 to 1.91). Further subgroup analysis showed that statin was associated with reduced risk of TIA or ischemic stroke in patient over 65 years of age, but with elevated risk of TIA or ischemic stroke in female patients (Supplementary Table 1). We also found no significant difference between different statins on the TIA or ischemic stroke incidence.

Table 1.

Comparisons in demographic characteristics and comorbidities in head and neck cancer patient with and without statin during radiotherapy

Characteristic	Statin		P
	No (n=1,073)	Yes (n=1,073)
Gender			0.21
Women	124 (11.6)	143 (13.3)
Men	949 (88.4)	930 (86.7)
Age stratified (yr)			0.69
≤49	149 (13.9)	163 (15.2)
50–64	549 (51.2)	539 (50.2)
≥65	375 (35.0)	371 (34.6)
Age (yr)[*]	60.5±10.2	60.6±10.5	0.90
Comorbidity
Hypertension	840 (78.3)	830 (77.4)	0.60
Hyperlipidemia	882 (82.2)	882 (82.2)	0.99
Diabetes	531 (49.5)	524 (48.8)	0.76
Congestive heart failure	102 (9.5)	123 (11.5)	0.14
Hypercoagulability	4 (0.4)	4 (0.4)	0.99
Atrial fibrillation	19 (1.8)	25 (2.3)	0.36
Coronary artery disease	449 (41.9)	467 (43.5)	0.43
Chronic kidney disease and ESRD	170 (15.8)	181 (16.9)	0.52
Previous stroke	175 (16.3)	180 (16.8)	0.77
Medication
Aspirin	891 (83.0)	937 (87.3)	0.01
Clopidogrel	89 (8.3)	248 (23.1)	<0.01
ACEI	627 (58.4)	706 (65.8)	<0.01
ARB	463 (43.2)	604 (56.3)	<0.01
Warfarin	42 (3.9)	61 (5.7)	0.06
Treatment
Surgery	181 (16.9)	182 (17.0)	0.95
Chemotherapy	776 (72.3)	765 (71.3)	0.60
Cetuximab	18 (1.7)	25 (2.3)	0.28

Values are presented as number (%) or mean±SD. Chi-square test.

ESRD, end-stage renal disease; ACEI, angiotensin-converting-enzyme inhibitor; ARB, angiotensin II receptor blocker.

t-test.

Figure 1.

Cumulative incidence of ischemic stroke or transient ischemic attack (TIA) in the user and nonuser group during follow-up.

The preliminary findings from this study showed that the legacy effect of statin during radiotherapy does not lower the subsequent risk of TIA and ischemic stroke in patient with HNC, which is contradictory to the report by Addison et al. [1] Our study population, which comprised mostly of Asians, was different from that of Addison’s, and the different ethnic background may contribute to divergent statin resistance. Moreover, nasopharyngeal carcinoma consisted of a significant proportion of HNC in Taiwan [2]. The different treatment field in radiotherapy for HNC may result in different carotid artery pathology. The large sample size and wide coverage (>99%) of the National Health Insurance are the strong points of this study, while the study limitation is the potential insufficient adjustments for the various confounding factors from its retrospective design.

In summary, statin use during radiotherapy was not associated with reduced risk of TIA or ischemic stroke in Taiwanese patients with HNC. Possible difference in statin resistance and types of HNC might be the explanation for the inconsistent result with the previous study. Future large-scale prospective studies are necessary to determine effectiveness of statin in preventing radiation-induced vascular disease and stroke.