TRENDS IN PRESCRIBING ANTIPLATELET DRUGS FOR SECONDARY PREVENTION OF NON-CARDIOEMBOLIC ISCHEMIC STROKE.
Objective: To determine the trends of physicians and neurologists in prescribing anti-platelet agents for secondary prevention of non-cardio embolic stroke after 3 months of stroke.
Study Design: A descriptive study.
Place and Duration of Study: Combined Military Hospital (CMH) Lahore over a period of four months.
Material and Methods: Patients suffering from old ([greater than or equal to]3 months) non-cardio embolic stroke, taking anti-platelet agents for secondary prevention and visiting CMH Lahore neurology clinic. Information about their stroke and treatment was obtained from their previous investigations and medical prescriptions.
Results: A total of 60 patients met the inclusion criteria of the study; 36 (60%) were taking a combination of clopidogrel 75mg plus Aspirin 75 mg and 12 (20%) received Aspirin 75 mg daily while 12 (20%) were getting other regimens.
Conclusion: Combination of clopidogrel 75mg plus Aspirin 75 mg was the most common anti-platelet regimen prescribed for secondary prevention of non-cardio embolic stroke in our study population.
Keywords: Anti-platelet agents, Non-cardio embolic stroke, Secondary prevention of stroke
Stroke is abrupt onset of a neurologic deficit attributedto a focal cerebral vascular cause. It is second leading cause of death in the world1. Theannual incidence of stroke in Pakistan is estimatedto be 250/100,000, which means 350,000 new cases per year2. A community based survey in a slum of Karachi suggested a 21.8% prevalence of stroke3. Ischemic stroke accounts for 80% of strokes and among the ischemic strokes 20-30% result from cardioembolism, 14-40% from atherothrombosis and 15-30% from small penetrating artery disease resulting inlacunar infarcts4. Atheroma is the most common arterial disorder and atheromatous plaques most commonly form at the origin of internal carotid arteries, origin of basilar artery and proximal parts of middle, posterior and anterior cerebral arteries5. Hemodynamic stresses may cause endothelial trauma and ulceration of atheromatous plaques at these sites.
Damaged endothelium activates platelets which release thromboxane A2 and adenosine diphosphate (ADP) which may propagate the process leading to formation of a thrombus. The thrombus may obstruct the arterial lumenor it mayembolize to occlude a distal artery. Such emboli may fragment and vanish or occlude the distal artery leading to infarction in its territory. Primary prevention of stroke is defined as decreasing the risk of stroke by reducing its' modifiable risk factors (table-I)6. It is also suggested that an angiotensin-converting enzyme (ACE) inhibitor may decrease risk of stroke regardless of initial hypertensive status7. Secondary preventionof stroke is defined as measures to prevent a recurrent stroke after first stroke ortransient ischemic attack (TIA). Recurrence risk after TIA or ischemic stroke ranges from 5 to 20% per year with the highest risk in the first few weeks particularly in patients with carotid stenosis8.
Secondary prevention depends on control of vascular risk factors, antithrombotic therapy and vascular surgery. Antiplatelet therapy is the mainstay of secondary stroke prevention. Antiplatelet drugs decrease platelet aggregation and prevent thrombus formation. Aspirin inhibits platelet cyclooxygenase and thromboxane A2 and has been the most widely used antiplatelet agent. Dipyridamole is an inhibitor of phosphodiesterase. It reduces the risk of stroke by the same amount as aspirin. Its' main adverse effects are headache and hypotension induced by peripheral vasodilatation. Ticlopidine and clopidogrel block platelet activation by ADP and are considered to be marginally more effective than aspirin. Clopidogrel is preferred over ticlopidine because the later may produce neutropenia. Newer antiplateletagents such as triflusal and cilostazol are also potentially effective in the secondary prevention of ischemic stroke.
Dual antiplatelet therapy (DAPT) is considered to be superior to aspirin alone in secondary stroke prevention but some studies have suggested an increased risk of cerebral hemorrhage with this regimen9. When carotid doppler studies and angiography reveal a surgically accessible high-grade stenosis (70-99%) on the side of infarction or TIA, carotid endarterectomy or angioplasty and stenting may reduce risk of ipsilateral carotid stroke. Physicians must try to identify TIAs, atrial fibrillation and carotid artery stenosis and encourage their patients to reduce their risk factors of stroke such as hypertension, diabetes mellitus and smoking. The main purpose of this study was to determine trends of physicians and neurologists in our set up in prescribing antiplatelet agents for secondary prevention of non-cardio embolic stroke after 3 months of stroke.
MATERIAL AND METHODS
This descriptive and observational study was conducted at neurology clinic of Combined Military Hospital (CMH) Lahore from 01 Mar 2016 to 30 Jun 2016. Patients suffering from TIAs or ischemic stroke for [greater than or equal to]6 months, taking antiplatelet drugs and presenting consecutively to the Neurology clinic of CMH Lahore were included in this study. Information about their drugs was obtained from their old medical prescriptions. Patients suffering from cardioembolic stroke and those who were taking anticoagulants were not included in the study. Patients who could not produce their old medical record and prescriptions were also excluded from the study. A detailed history was taken from the patients at their presentation and physical examination was done. Their past medical record was reviewed and the patients were inquired regarding their compliance of drugs mentioned in their prescriptions. Table-II shows antiplatelet drugs available in Pakistan10.
The different commercial brands of aspirin (Asp), clopidogrel (Clo) and their combinations (CloAsp) were identified. Data was analyzed using SPSS version 18 and descriptive statistics were used to describe the results.
Table-I: Modifiable Risk factors for stroke.
Hypertension(BP>140 mmHg systolic or 90 mmHg diastolic)
Dyslipidemia(High total Cholesterol, Low HDL cholesterol(60%)
Table-II: Oral antiplatelet agents and their combinations available in Pakistan.
Aspirin 75 mg(Asp-75)
Aspirin 150 mg(Asp-150)
Aspirin 300 mg(Dispirin)
Clopidogrel 75 mg(Clo-75)
Combination of Clopidogrel 75 mg plus Aspirin 75 mg(CloAsp-75)
Combination of Clopidogrel 75 mg plus Aspirin 150 mg(CloAsp-150)
Ticlopidin(Ticlid 250 mg)
Dipyridamole(Persantin 25mg, 100 mg)
Prasugrel(Eficlot 5mg, 10 mg)
A total of 60 patients, 36 (60%) males, 24 (40%) females were included in this study. Their ages ranged from 52 to 81 years; mean age 70 years (SD +- 5.98). The duration of their stroke was 6 to 24 months; mean 11 months (SD +- 5.25). Figure shows the frequencies of different antiplatelet drug regimens prescribed to our study population. Combination of clopidogrel 75 mg plus Aspirin 75 mg (CloAsp-75) was the most common antiplatelet regimen taken by the majority of our patients. Dipyradamole and Ticlopidine were not prescribed to any patient in our set up.
Ischemic stroke is the most common formof cerebrovascular disease and the patients surviving it are at increased risk of a recurrent stroke which may be more devastating than the first stroke. According to Jamieson et al 29% of all strokes in the United States are recurrent strokes thus emphasizing the importance of prevention of a recurrent stroke after a TIA or among survivors of a first ischemic stroke11. Early studies indicated that antiplatelet drugs significantly reduce risk of recurrent stroke among patients with a prior TIA or stroke12. Antiplatelet therapy now has become one of the main strategies to prevent recurrent at herothromboticis chemic strokes. Low-dose aspirin (75-162 mgdaily), clopidogrel 75 mg daily and aspirin (50 mg) plus dipyridamole (400 mg) daily can be used for long term prevention of TIAs and recurrent ischemic strokes. Low-dose aspirin (75-162 mg daily) is considered as effective as higher daily doses.
It has the most extensive evidence regarding its benefits in secondary prevention of stroke. The combination of antiplatelet agents for secondary prevention of ischemic stroke has always remained a matter of debate. A combination of dipyridamole and aspirin may further reduce the risk of stroke than aspirin alone. An earlier meta-analysis by Thijs et al showed that a combination of aspirin and dipyridamole was better than either drug alone for secondary prevention of stroke13. This observation was corroborated later on by meta-analysis of Malloy et al which also showed that aspirin plus dipyridamole was more protective than aspirin alone for preventing recurrent stroke14. A combination of clopidogrel and aspirin is considered to be superior to either drug alone for prevention of recurrent stroke but some studies caution about an increased risk of cerebral hemorrhage with this combination.
Wang et al have reported that adding clopidogrel to aspirin in a large population of Chinese patients demonstrated a reduction in stroke recurrence during first 90 days after aTIA or minor stroke with no increase in cerebral bleed15. Nevertheless, American Heart Association/American Stroke Association issued guideline for healthcare professionals in 2014 stressing that combination of aspirin and clopidogrel may be considered within 24 hours of a minor ischemic stroke or TIA and be continued for 21 days.
This combination increases the risk of hemorrhage relative to either agent alone if continued for 2 to 3 years. Hence, this regimen is not recommended for routine long-term secondary prevention of ischemic stroke16. A systematic review and meta-analysis by Gouya et al suggested that combination of clopidogrel 75mg and low dose aspirin (75-100mg) compared with aspirin alone decreases risk of recurrent stroke without increasing risk of intracranial hemorrhage17. Zhang et al analysed eight randomized controlled trials and concluded that compared to monotherapy, short term (a$?3 months) combination of aspirin with clopidogrel is more effective for prevention of recurrent stroke without increasing risk of hemorrhage. Long-term ([greater than or equal to]1 year) combi-nation therapy does not reduce risk of recurrent stroke and is associated with increased risk of major bleed18.
A meta-analysis of 14 trials by Elmariah et al suggested that compared toshort duration (a$?6 months) clopidogrel plus aspirin or aspirin alone, extended duration clopidogrel plus aspirin was not associated with a difference in mortality as compared to aspirin alone19. Pan et al suggest that a combination of Clopidogrel and aspirin may reduce stroke risk out weighing the potential risk of increased bleeding especially within the first 2 weeks compared with aspirin alone in patients with TIA or minor stroke20. The combination of aspirin and clopidogrel may be superior to aspirin alone in prevention of recurrent ischemic stroke. However, it may increase the risk of cerebral bleed in some patients. This regimen should be avoided in patients who are at a high risk of bleeding. Our study was focused on determining the trends of our physicians and neurologists in prescribing antiplatelet agents for secondary prevention of non-cardio embolic stroke after 3 months of stroke.
We found that majority of our patients (>60%) were prescribed dual antiplatelet therapy, mainly a combination of Clopidogrel 75 mg plus aspirin 75mg, for long term secondary prevention of stroke. No similar data was found to compare with our study.
The most common anti-platelet regimen employed by majority of our physicians for secondary prevention of ischemic stroke is a combination of clopidogrel plus low dose Aspirin. Although this combination may remain controversial, it mayconfer some benefit over aspirin alone. It appears that majority of our physicians consider the benefits of Clopidogrel plus low dose Aspirin out weigh its' potential risks for prevention of recurrent ischemic stroke in majority of their patients.
CONFLICT OF INTEREST
This study has no conflict of interest to be declared by any author.
1. Smith WS, Johnston SC, Hemphill JC. Cerebrovascular Diseases. In: Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J, et al, editors. Harrison's Principles of Internal Medicine. 19th ed. New York; McGraw-Hill Education 2015; p.2559-86.
2. Khealani BA, Wasay M. Burden of stroke in Pakistan. Int J Stroke 2008; 3: 293-6.
3. Kamal AK, Itrat A, Murtaza M, Khan M, Rasheed A, Ali A, et al. The burden of stroke and transient ischemic attack in Pakistan: a community-based prevalence study. BMC Neurol 2009; 9: 58.
4. Sacco RL. Current epidemiology of troke. In: Fisher M, Bogousslavsky J, ed. Current Review of Cerebrovascular Disease, Philadelphia: Current Medicine 1993; 3-14.
5. Aminoff MJ, Douglas VC. Nervous System Disorders. In: Papadakis MA, McPhee SJ, Rabow MW, editors. CURRENT Medical Diagnosis andamp; Treatment. 56th ed. New York; McGraw-Hill Education 2017; p. 991-3.
6. Greenberg DA, Aminofff MJ, Simon RP. Clinical Neurology. 8thed. New York; McGraw-Hill Inc; 2012; p. 379-418.
7. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000; 342: 145-53.
8. Wilterdink JL, Easton JD.Vascular event rates in patients with atherosclerotic cerebrovascular disease. Arch Neurol 1992: 49: 857-63.
9. Ropper AH, Samuels MA, Klein JP. Adams andamp; Victor's Principles of Neurology. 10th ed. New York; McGraw-Hill Education; 2014; p.778-884.
10. Neeshat MQ, Haque E, Wahab F, Shafiq H, Siddiqui H, Sayya J, et al. Pharmaguide. 24th ed. Karachi; Pharmaguide Publishing Company; 2016: p.280-94.
11. Jamieson DG, Parekh A, Ezekowitz MD. Review of antiplatelet therapy in secondary prevention of cerebrovascular events: a need for direct comparisons between antiplatelet agents. J Cardiovasc Pharmacol Ther 2005; 10: 153-61.
12. American-Canadian Co-operative Study Group. Persantin-aspirin in cerebral ischemia: Endpoint results. Stroke 1985: 16; 406-15.
13. Thijs V, Lemmens R, Fieuws S. Network meta-analysis: simultaneous meta-analysis of common antiplatelet regimens after transient ischaemic attack or stroke Eur Heart J 2008; 29: 1086-92.
14. Malloy RJ, Kanaan AO, Silva MA, Donovan JL. Evaluation of antiplatelet agents for secondary prevention of stroke using mixed treatment comparison meta-analysis. Clin Ther 2013; 35: 1490-500.
15. Wang Y, Wang Y, Zhao X, Liu L, Wang D, Wang C, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med 2013; 369: 11-9.
16. Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI, Ezekowitz MD, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014; 45: 2160-236.
17. Gouya G, Arrich J, Wolzt M, Huber K, Verheugt FW, Gurbal PA, et al. Antiplatelet treatment for prevention of cerebrovascular events in patients with vascular diseases: a systematic review and meta-analysis. Stroke 2014; 45: 492-503.
18. Zhang Q, Wang C, Zheng M, Li Y, Li J, Zhang L, et al. Aspirin plus clopidogrel as secondary prevention after stroke or transient ischemic attack: A systematic review and meta-analysis. Cerebrovasc Dis 2015; 39: 13-22.
19. Elmariah S, Mauri L, Doros G, Galper BZ, O'Neill KE, Steg PG, et al. Extended duration dual antiplatelet therapy and mortality: a systematic review and meta-analysis. Lancet 2015; 385: 792-8.
20. Pan Y, Jing J, Chen W, Meng X, Li H, Zhao X, et al. Risks and benefits of clopidogrel-aspirin in minor stroke or TIA: Time course analysis of CHANCE. Neurology 2017; 88: 1906-11.
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|Publication:||Pakistan Armed Forces Medical Journal|
|Date:||Dec 31, 2018|
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