CMAJ. 2016 Mar 1;188(4):255-260

http://www.cmaj.ca/content/188/4/255.long 

Risk of ischemic stroke during the initiation period of α-blocker therapy among older men

Chao-Lun Lai1,2,3 , Raymond Nien-Chen Kuo4,5, Ho-Min Chen5, Ming-Fong Chen6, K. Arnold Chan7,8, Mei-Shu Lai3,5

 

1Department of Internal Medicine and Center for Critical Care Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan

2Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan

3Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan

4Institute of Health Policy and Management, College of Public Health, National Taiwan University, Taipei, Taiwan

5Center for Comparative Effectiveness Research, National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan

6Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

7Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan

8Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan

 

ABSTRACT

Alpha-blockers are notorious for their first-dose effect referring to the acute hypotensive effect during the early initiation period. As acute cerebral hypoperfusion may precipitate the attack of ischemic stroke, we aimed to provide a quantitative estimate of the risk of ischemic stroke during the early initiation period of alpha-blocker therapy using a self-controlled case series design. All male beneficiaries aged over 50 years as of 2007, who were incident initiators of alpha-blockers and also had a diagnosis of ischemic stroke within the 2007~2009 study period were identified from the National Health Insurance (NHI) claims database, Taiwan. The first day on which the alpha-blocker was prescribed was set as the index date. We partitioned different time periods according to their relationship with the index date as different risk periods and the remainder of the 3-year study period was defined as the background unexposed period. The incidence rate of ischemic stroke within each risk period was compared with that within the background unexposed period using a conditional Poisson regression model and was presented as incidence rate ratio (IRR). A total of 7502 men were included. Compared with the background unexposed period, the IRR of ischemic stroke within the initial 21-day period following the index date was 1.40 (95% confidence interval [CI], 1.22-1.61) for the whole study population and 2.11 (95% CI, 1.73-2.57) among patients without concomitant prescriptions of anti-hypertensive agents. Our results presented evidence that alpha-blockers were associated with an increase in the risk of ischemic stroke during the early initiation period especially in subjects who were not taking other anti-hypertensive agents. We recommend caution in prescribing alpha-blockers in patients without hypertension.

Key Words: Adrenergic Alpha-1 Receptor Antagonists; Stroke; Self-Controlled Case Series Design.

 

Supplements:

All male beneficiaries aged >= 50 years as of 1st Jan. 2007 with continuous coverage of NHI for at least the previous 12 months were extracted from the claims data of the NHI program in Taiwan. Initiators of four alpha-blockers, terazosin, doxazosin, tamsulosin, and alfuzosin, who also had been diagnosed with an ischemic stroke within the 2007~2009 3-year study period were identified. The self-controlled case series design is illustrated as Figure 1.

 

 

Figure 1

Figure 1. Pictorial representation of the study design.

 

As shown in Figure 2, 3, and 4, the association between alpha-blocker therapy and ischemic stroke was driven mostly by the prescription of alpha-blocker following a previous ischemic stroke. For example, higher risks of ischemic stroke were noted within the pre-exposure risk period 1 (IRR 2.87, 95% CI, 2.60-3.17) and the pre-exposure risk period 2 (IRR 1.99, 95% CI, 1.82-2.18) for the whole study population. This phenomenon did not change significantly between patients with and without concomitant use of anti-hypertensive agents. Development of urinary symptoms after an ischemic stroke could be an explanation of this prescription pattern.

Concerning our study aim, the post-exposure risk period 1 possessed a significantly high IRR (1.40, 95% CI, 1.22-1.61) of ischemic stroke compared with the background unexposed period for the whole study population (Figure 2). Besides, the incidence of ischemic stroke within the post-exposure risk period 1 was significantly elevated (IRR 2.11, 95% CI, 1.73-2.57) among subjects without concomitant prescriptions of anti-hypertensive agents at the initiation of alpha-blockers (Figure 3). In contrast, among subjects with concomitant prescriptions of anti-hypertensive agents at the initiation of alpha-blockers, the incidence of ischemic stroke within the post-exposure risk period 1 was similar to that within the background unexposed period (IRR 1.07, 95% CI, 0.88-1.29)(Figure 4).

 

 

Figure 2

Figure 2. Relative risks of ischemic stroke within each risk period compared with that within the background unexposed period in whole study population. Abbreviations: IRR: incidence rate ratio; RP: risk period. I bars denote 95% confidence intervals. The dashed line and arrow indicate initiation of alpha-blockers.

 

 

Figure 3

Figure 3. Relative risks of ischemic stroke within each risk period compared with that within the background unexposed period in patients without anti-hypertensive agents. Abbreviations: HTN: hypertensive; IRR: incidence rate ratio; RP: risk period. I bars denote 95% confidence intervals. The dashed line and arrow indicate initiation of alpha-blockers.

 

One possible explanation of our findings was that patients without underlying hypertension were vulnerable to the first-dose effect of alpha-blockers and contributed to the observed increase in risk of ischemic stroke within the early initiation period of alpha-blockers in the whole study population. On the contrary, patients with underlying hypertension were tolerant of the first-dose effect of alpha-blockers. It has been reported that patients with intracranial carotid artery stenosis are more prone to ischemic stroke provoked by cerebral hypoperfusion than those with extracranial carotid artery stenosis. In addition, Chinese have more intracranial carotid artery stenosis, while Caucasians have more extracranial carotid artery stenosis. Our findings were derived from the ethnic Chinese elderly males in Taiwan. Further research is needed to clarify whether the same condition exists in other ethnic populations.

 

 

Figure 4Figure 4. Relative risks of ischemic stroke within each risk period compared with that within the background unexposed period in patients with anti-hypertensive agents. Abbreviations: HTN: hypertensive; IRR: incidence rate ratio; RP: risk period. I bars denote 95% confidence intervals. The dashed line and arrow indicate initiation of alpha-blockers.

 

References:

  1. Lai CL, Kuo RN, Chen HM, Chen MF, Chan KA, Lai MS. Risk of hip/femur fractures during the initiation period of alpha-adrenoceptor blocker therapy among elderly males: a self-controlled case series study. Br J Clin Pharmacol 2015;80:1208-1218.

 

Acknowledgements:

All data used in this study were released and approved by the Collaboration Center of Health Information Application (CCHIA), Ministry of Health and Welfare, Executive Yuan, Taiwan. This work was supported by the Science and Technology Unit, Ministry of Health and Welfare, Executive Yuan, Taiwan (DOH101-TD-B-111-001, and DOH102-TD-B-111-001).

 

Contact:

Chao-Lun Lai, M.D., Ph.D.

Department of Internal Medicine and Center for Critical Care Medicine

No.25, Lane 442, Sec. 1, Jingguo Rd., Hsinchu City 30059, Taiwan

National Taiwan University Hospital Hsin-Chu Branch

E-mail: chaolunlai@ntu.edu.tw

 

 

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