secondary prevention of stroke , AHA guidelines, various research evidences and protocols, antiplatelet drugs and their mechanism and action

1. DR PRAKARSH SHARMA
SR NEUROLOGY

2.  Each year, ≈795 000 individuals in the United States experience a stroke, of
which 87% (690 000) are ischemic and 185 000 are recurrent.
 Approximately 240 000 individuals experience a transient ischemic attack
(TIA) each year.
 The risk of recurrent stroke or TIA is high but can be mitigated with
appropriate secondary stroke prevention.
 In fact, cohort studies have shown a reduction in recurrent stroke and TIA
rates in recent years as secondary stroke prevention strategies have improved.
Heart disease and stroke statistics–2020 update: a report from the American Heart Association.

3.  A meta-analysis of randomized controlled trials (RCTs) of secondary stroke
prevention therapies published from 1960 to 2009 showed a reduction in
annual stroke recurrence from 8.7% in the 1960s to 5.0% in the 2000s,
 with the reduction driven largely by improved blood pressure (BP) control
and use of antiplatelet therapy.
 Due to the complexity of stroke aetiology and diverse mechanisms of
antiplatelet agents, it is essential to select optimal antiplatelet therapy in the
real-world practice.
Declining stroke and vascular event recurrence rates in secondary prevention trials over the past 50 years and consequences for
current trial design.Circulation. 2011; 123:2111–2119. doi:

4.  DAPT
1. NON CARDIOEMBOLIC ISCHEMIC STROKE WITH NIHSS< 3
2. TRANSIENT ISCHEMIC ATTACK WITH ABCD 2 SCORE ≥4
3. ICAD
TRIPLE ANTIPLATELET
.
.
.

5.  Tremendous strides have been made in the management of cerebrovascular
disorders.
 Ischemic stroke is more challenging to treat than coronary artery disease due
to the variety of mechanisms that can lead to cerebral ischemia.
 Stroke subtypes include: 25% due to cardioembolism;
 10% due to extracranial atherosclerotic disease;
 10% due to intracranial atherosclerotic disease (ICAD);
 25% due to small vessel disease (SVD);
 5% from other determined causes;
 Antithrombotic Therapy to Prevent Recurrent Strokes in Ischemic Cerebrovascular Disease: JACC Scientific Expert Panel

6.  The pattern of recurrence varies by stroke subtype, being the highest for large-
artery atherosclerosis (LAA) in the early phase,
 whereas for cardioembolic strokes, the long-term risk is steadily high and is
associated with higher mortality.
 The immediate period after stroke has been the target of time-sensitive
therapies including thrombolysis and endovascular thrombectomy.
 Beyond this stage, therapeutic goals are to reduce the risk of stroke recurrence
and prevent medical complications.
 Antithrombotic agents contribute to preventing recurrent stroke and vascular
events after an ischemic stroke.

7. Epidemiology of ischemic stroke subtypes according to TOAST criteria:Stroke. 2001; 32:2735–2740. doi: 10.1161/hs1201.100209

8. INTRACEREBRAL HEMORRHAGE
Is around 10% contributor of total strokes
The recurrence rate for ICH was 2.4% (95% CI 1.4% to 3. 9%) per year.
SUB ARACHNOID HEMORRHAGE
After SAH, the incidence of a recurrence within the first 10 years is 22 (12 to 38) times
higher than expected in populations with comparable age and sex.
Rate of stroke recurrence in patients with primary intracerebral hemorrhage
•. 2000 Jan;31(1):123-7. doi: 10.1161/01.str.31.1.123.

9. LACUNAR STROKE
 Non cortical infarcts causes by thrombosis or lipohyalonotic occlusion of deep
penetrating branch of large cerebral artery.
 Lacunar syndrome, with normal computed tomography (CT)/magnetic
resonance imaging (MRI) or subcortical stroke measuring <1.5 cm in diameter
on CT or MRI.
 Stroke attributable to small vessel disease: Subcortical stroke measuring <1.5
cm in diameter on CT or MRI without evidence of a concomitant cortical
infarct.

10. CARDIOEMBOLIC STROKE
 : Stroke attributable to arterial occlusion from an embolus that presumably arose in the
heart.
 Clinical and brain imaging findings are similar to those described in large artery
atherosclerosis.
 Evidence of a previous TIA or stroke in >1 vascular territory supports a clinical
diagnosis of cardioembolic stroke.

11. STROKE CAUSED BY LARGE ARTERY
ATHEROSCLEROSIS
 : Ischemic stroke in the vascular distribution of a major intracranial or extracranial
artery with >50% stenosis or occlusion on vascular imaging.
 Clinical findings include those of cerebral cortical involvement or brainstem or
cerebellar dysfunction.
 Cortical and cerebellar lesions and brainstem or subcortical lesions >1.5 cm are
considered potentially caused by large artery atherosclerosis.
 Diagnostic studies should exclude potential sources of cardioembolic embolism.

12. ICADis more prevalent among Asians, Blacks, and Hispanics, thus is likely
the most common vascular lesion in stroke patients worldwide.
 Even with intensive medical management, individuals with ICAD and high-
grade stenosis have a 30-day and 1-year risk of stroke recurrence of 5% and
15%, respectively.
 Extracranial carotid disease is responsible for 10% to 15% of all ischemic
strokes.
 Patients with stroke, TIA, and amaurosis fugax caused by carotid disease often
have recurrent symptoms
P.B. Gorelick, K.S. Wong, H.J. Bae, D.K. Pandey
Large artery intracranial occlusive disease: a large worldwide burden but a relatively neglected frontier
Stroke, 39 (2008), pp. 2396-2399

13. CRYPTOGENIC STROKE:
 An imaging-confirmed stroke with unknown source, despite thorough
diagnostic assessment including, at a minimum:
arterial imaging,
echocardiography,
extended rhythm monitoring,
and key laboratory studies such as a lipid profile and hemoglobin A1c [HbA1c]).
Cryptogenic stroke accounts for 30% to 40% of ischemic stroke.

14.  In the Oxford meta-analysis of 4 large population-based studies, the risks of
recurrent stroke after CS were 1.6% at 7 days, 4.2% at 1 month, and 5.6% at 3
months.
 Several possible mechanisms may underlie cryptogenic stroke (CS),
- including but not limited to occult paroxysmal atrial fibrillation (AF) and other
atrial cardiopathies,
-paradoxical embolism through a patent foramen ovale (PFO),
- or substenotic atherosclerosis
Cryptogenic Strokehttps://doi.org/10.1161/CIRCRESAHA.116.308447Circulation Research. 2017;120:527–540

15. ESUS: EMBOLIC STROKE OF
UNDETERMINED SIGNIFICANCE
 A stroke that appears nonlacunar on neuroimaging without an obvious source after a
minimum standard evaluation.
A diagnosis of ESUS implies that the stroke is embolic in origin, given the nonlacunar
location; however, the source of the embolus is unknown.
ESUS 4-5 % recurrent risk per year

17.  (A) Small vessel disease: brain magnetic resonance imaging showing an acute
left internal capsule lacunar infarct (<20 mm) on diffusion-weighted imaging (DWI)
sequence. (B) Intracranial atherosclerotic disease: cerebral angiogram and computed
tomography angiogram showing left middle cerebral artery
stenosis (>90%) (arrow) associated with acute infarct on left insula. (C) Extracranial
atherosclerotic disease: cerebral angiogram showing right middle cerebral artery
occlusion associated with severe stenosis of ipsilateral cervical internal
carotid (arrow). (D) Cardioembolic stroke: left frontal cortical infarct on DWI sequence
associated with atrial fibrillation on electrocardiogram. (E) Other determined causes of
stroke: dissection of the left cervical internal carotid artery (arrows) associated with
ischemic stroke on the left frontal lobe. (F) Cryptogenic stroke: right frontal cortical
infarct on DWI sequence with no definite cardioembolic source based on cardiac
monitoring or echocardiography, and no evidence of large-artery steno-occlusive
disease

18.  stroke is the second-leading cause of death and the third-leading cause of death and
disability combined in 2019 globally.
 Platelets are activated by collagen, ADP and arachnoid acid metabolite thromboxane
A2.
 Activated platelets induce platelet aggregation and blood clot formation, resulting in
acute ischemic stroke (AIS) or transient ischemic attack (TIA).
 Antiplatelet agents inhibit platelet aggregation and reduce the risk of AIS or TIA.
 Aspirin, clopidogrel, dipyridamole/aspirin, cilostazol and ticagrelor are commonly used
antiplatelet agents.
Lancet Neurol 2021;20:795–820.doi:10.1016/S1474-4422(21)00252-0

24.  Aspirin, the oldest and most commonly used drug in the world,
 is the standard medical therapy for preventing stroke in patients with transient cerebral
ischemia and for reducing the risk for recurrent stroke and postoperative strokes after carotid
endarterectomy (CEA).
 Aspirin is effective, inexpensive, and safe if started within 48 hours of acute ischemic stroke
(Chinese Acute Stroke Trial, 1997; International Stroke Trial Collaborative Group, 1997).
 Meta-analyses have shown that aspirin reduces the combined relative risk for stroke, MI, and
vascular death by approximately 25%.
BRADLEY’S TEXTBOOK OF NEUROLOGY

25.  The recommended range of daily doses is between 50 and 325 mg of aspirin. There is a
suggestion that aspirin is also effective in doses as low as 30 mg daily. Higher doses confer
more GI side effects.
 The mechanism of action of aspirin is the irreversible inhibition of platelet function by
inactivation of cyclo-oxygenase (COX).
 Aspirin is a nonselective inhibitor of COX and is therefore able to inhibit both isoforms (COX-
1 and COX-2).

26.  The antiaggregant effect is seen within 1 hour after administration.
 Aspirin is also anti-inflammatory, antioxidant, and may increase fibrinolytic activity up to 4
hours after administration.
 The main side effect of aspirin is gastric discomfort. GI hemorrhage occurs in 1%–5% of cases.

27.  Evidence from several clinical studies favors the use of platelet antiaggregants as the first
line of therapy in patients at high risk for stroke (Antithrombotic Trialists’ Collaboration,
2002; Hankey, 2004).
 The International Stroke Trial (IST) randomised patients to aspirin 300 mg daily, subcuta-
neous heparin, both or neither within 48 hours of ischaemic stroke for up to 2 weeks.
 The aspirin group had significantly fewer recurrent ischaemic stroke (2.8% vs 3.9%, p<0.001)
but equal rates of haemorrhage.
Antiplatelet Trialists' Collaboration. BMJ 1994;308:81–106.
International Stroke Trial Collaborative Group. The Lancet 1997;349:1569–81.

28.  The Chinese Acute Stroke Trial was similar in design except for a different
aspirin dose (160 mg daily) and duration (4 weeks).There were significantly
lower absolute risk of recurrent ischaemic stroke in the aspirin group (1.6% vs
2.1%, p=0.01).
 In a Cochrane systematic review of 8 RCTs with 41 483 participants on oral
antiplatelet therapy for stroke prevention, aspirin 160–300 mg daily, started
within 48 hours of stroke onset, reduced the risk of early recurrent ischaemic
stroke without significant risk of haemorrhagic complications.
CAST: randomised placebo-controlled trial of early aspirin use in 20 000 patients with acute ischaemic stroke. The Lancet
1997;349:1641–9.

29. DIPYRIDAMOLE
 Dipyridamole is a cyclic nucleotide phosphodiesterase inhibitor that increases the levels of
cyclic adenosine monophosphate.
 The European Stroke Prevention Study 2 (ESPS-2),
 a multicenter randomized, double-blind, factorial, placebo-controlled trial
 , randomized patients with stroke or TIA within the previous 3 months to treatment with
aspirin alone (25 mg twice a day), modified-release dipyridamole alone (200 mg twice a day),
the two agents in combination, or placebo.
 The ESPS-2 investigators concluded that both low-dose aspirin and high-dose dipyridamole in
a modified-release form alone were superior to placebo, and that the combination was
significantly superior to each drug alone.
The European Stroke Prevention Study (ESPS). Principal end-points. The ESPS group. Lancet 1987;2:1351–4.

30.  Benefit was limited to stroke prevention in patients with prior stroke or TIA. There was little
effect on fatal stroke and MI.
 The main side effects in the ESPS-2 study were headaches and GI distress with headache
attributed to dipyridamole, and GI distress attributed to aspirin.
 The PRoFESS study, however, failed to show non-inferiority of extended-release dipyridamole
plus low-dose aspirin compared with clopidogrel in recurrent stroke or a composite outcome of
stroke, MI or death,
 and the rate of headache and hemorrhagic complications was higher in the aspirin plus
dipyridamole group.
the Prevention Regimen for Effectively Avoiding Second Strokes Trial(PRoFESS). CerebrovascDis 2007;23:368-380

31. CLOPIDOGREL
 Clopidogrel is a thienopyridine that blocks ADP receptor P2Y12 and interferes with
platelet cross-linking and aggre-gation.
 The Clopidogrel vs Aspirin in Patients at Risk of Ischaemic Events trial randomised
patients with stroke, myocardial infarction or peripheral vascular disease to either aspirin
325 mg or clopidogrel 75 mg daily.
 The clopidogrel group had a significantly lower annual rate of vascular event than the
aspirin group (5.32% vs 5.83%,p=0.043).
CAPRIE Steering Committee. A randomised, blinded trial of clopidogrel versus aspirin in patients at risk of ischemic events
(CAPRIE). Lancet 1996;348:1329-1339

32.  Of note, the relative risk reduction in patients with prior stroke was 7.3% and not
statistically significant.
 Haemorrhage risks were similar between the two groups.

Therefore, clopidogrel is considered a good option for secondary stroke prevention.

33. CILOSTAZOL
 Cilostazol also inhibits phosphodiesterase and platelet aggregation.
 CSPS randomised patients with recent stroke to cilostazol 100 mg two times daily or placebo.
Cilostazol was associated with a relative stroke risk reduc-tion by 41.7% (p=0.015).
 In CSPS-2 trial, 2757 patients were randomised to receive cilostazol 100 mg two times daily
(n=1379) or aspirin 81 mg daily (n=1378). At mean 29-month follow-up, cilostazol group had a
34% relative risk reduction in cerebral infarction than aspirin group (2.76% vs 3.71%, p=0.0357)
and lower haemorrhagic events (0.77% vs 1.78%; p=0.0004).
CSPS (CSPS for antiplatelet Combination) evaluated the efficacy of cilostazol and either aspirin or
clopidogrel versus either aspirin or clopidogrel mono- therapy.
Cilostazol stroke prevention study: . J Stroke Cerebrovasc Dis 2000;9:147–57.
Cilostazol for preventionof secondary stroke (CSPS 2): Lancet Neurol 2010;9:959–68.

34.  Patients with ischaemic stroke within the previous 6 months were eligible for enrolment if at
least two vascular risk factors were present and at least 50% stenosis of either an extracranial
or intracranial artery.
 Dual-antiplatelet therapy (DAPT) was found to be supe- rior to single-antiplatelet therapy
(SAPT) in annual rate of ischaemic stroke (2.2% vs 4.5%, p=0.001). There was no significant
difference in life-threatening bleeding between the two group.
 In a systemic review and meta- analysis of RCTs,cilostazol was shown to have lower rates of
recurrent ischaemic stroke, haemorrhages or deaths, but higher rates of headache, palpitations
and discontin- uation than placebo, aspirin or clopidogrel.
Of note, essentially all clinical trials on cilostazol were conducted in Asia and results have not
been replicated in other ethnic populations.

Dual antiplatelet therapy using cilostazol for secondary prevention in patients with high-risk ischaemic stroke Lancet Neurol
2019;18:539–48.

35.  Warfarin (4-hydroxycoumarin) inhibits the synthesis of factors II, VII, IX, and X, as well as
proteins C and S.
 Oral anticoagulation with warfarin is indicated for primary and secondary prevention of stroke
in patients with NVAF.
 Six randomized studies evaluated primary and secondary stroke prevention of stroke in the
context of NVAF.
 Three of these studies also evaluated aspirin at daily doses of 75 mg, 300 mg, and 325 mg.
These six studies demonstrated that the RRR for stroke was 68% with the use of warfarin
(Koefoed et al., 1997). The RRR with aspirin therapy was 21% (18%–44%) (Atrial Fibrillation
Investigators, 1997).
*BRADLEY TEXTBOOK OF NEUROLOGY

36.  Advancing age increases the risk for major hemorrhage in patients given warfarin for stroke
prevention; patients older than 75 years are at greater risk for hemorrhagic complications.

37.  Factor Xa inhibitors and direct thrombin inhibitors are alternatives to warfarin in patients with
NVAF.
 Dabigatran, a reversible oral thrombin inhibitor, at a dose of 110 mg was associated with rates
of stroke and systemic embolism similar to those associated with warfarin, with lower rates of
major hemorrhage (Connolly et al., 2009).
 Dabigatran at a dose of 150 mg was associated with lower rates of stroke and systemic
embolism but similar rates of major hemorrhage compared with warfarin.
 The oral factor Xa inhibitor rivaroxaban (20 mg daily) was shown to be non-inferior to
warfarin for stroke prevention and systemic embolism in 14,264 patients with NVAF
Bradely textbook of Neurology

38.  Stroke or systemic embolism rates were 1.7% per year for rivaroxaban-treated patients and
2.2% per year for warfarin-treated patients (P < .001 for non-inferiority).
 Major and nonmajor bleeding events were similar for both groups with slightly fewer
intracranial (0.2% absolute reduction, P = .02) and fatal (0.3% absolute reduction, P = .003)
hemorrhages in the rivaroxaban group (Patel et al., 2011).

41.  While the use of dual antiplatelet therapy (DAPT) is well established in cardiology for acute
coronary heart disease , its use in the neurological ambit has been for a long time less proven
and only recently has it been established and codified in guidelines.
 The need for a proper therapy of ischemic stroke and transient ischemic attack (TIA) derives
from the high risk of stroke recurrence.
 This risk has been estimated around 2% at 12 h, 3% at 2 days, 5% at 7 days, and 10% at 14 days
after the acute event.
 With the aim of further reducing the rate of stroke recurrence, DAPT has received increasing
attention in the last years.
Risk of stroke early after transient ischaemic attack: a systematic review and meta-analysis. Lancet Neurol 6(12):1063–1072.

42.  If patients with mild stroke or high-risk TIA are evaluated early after the onset
of their stroke, starting short-term DAPT followed by long-term SAPT is
preferred compared with SAPT according to the reduction of risk of early
recurrent stroke.
 Beyond 90 days after stroke, DAPT is associated with increased risk of
bleeding and no benefit in long-term reduction of recurrent stroke risk.
 For patients not treated until later after their stroke event, use of any SAPT is
indicated to reduce long-term recurrent stroke risk.
(MATCH): randomised, double-blind, placebo-controlled trial.Lancet. 2004; 364:331–337. doi: 10.1016/S0140-6736(04)16721-4

43.  After one earlier studythat was stopped because of the difficulty in recruitment (Fast
Assessment of Stroke and Transient ischemic attackto prevent Early Recurrence, FASTER) ,
 the current knowledge in this field derives from 4 trials. Three studies have been conducted
in patients with minor stroke or TIA:
 - the Clopidogrel in High-Risk Patients with AcuteNondisabling Cerebrovascular Events
(CHANCE) study ,
 -the Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) study ,
 and the Acute Stroke or Transient Ischemic Attack Treated with Tica- grelor and
acetylsalicylic acid for Prevention of Stroke and Death (THALES) study.
(FASTER): a randomised controlled pilot trial. Lancet Neurol 6(11):961–969. https:// doi. org/ 10. 1016/ S1474- 4422(07) 70250-8

44.  In all of them, aspirin was used, while the second antiplatelet agent was clopidogrel in 2 trials and
ticagrelor in the third one.
 An additional study has been performed in patients with intracranial atherosclerotic dis- ease: the
Stenting and Aggressive Medical Managementfor Preventing Recurrent Stroke in Intracranial Stenosis
(SAMMPRIS) study.

45. (CHANCE)
 CHANCE was a randomized, double-blind, placebo-con-trolled trial conducted in 114 centers
in China from October2009 to July 2012.
 The study compared the efficacyof DAPT (aspirin plus clopidogrel for 21 days and clopi-
dogrel alone for other 69 days) versus placebo plus aspirin in reducing the risk of recurrent
stroke at 90 days in patientswith minor ischemic stroke (NIHSS ≤ 3) or high-risk TIA (ABCD2
≥ 4)
 randomized within 24 h from the event.
 The results showed that DAPT reduced the occurrence of stroke(event rate 8.2% DAPT vs.
11.7% aspirin, HR 0.68, NNT 29) in particular of ischemic stroke (event rate 8.4% in DATP vs.
11.9% in placebo, HR 0.67) and did not increase the risk ofsevere bleeding (event rate 0.2% in
both groups).
Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. NEJM Org N EnglJ Med 369(1):11–19. https:// doi. org/ 10.
1056/ NEJMo a1215 340

46.  POINT was the second study that evaluated the efficacy of clopidogrel plus aspirin.
 It was a randomized, inter- national, double-blind, placebo-controlled trial, conducted from
May 2010 to December 2017 in 269 sites in 10 dif- ferent countries (North America, Europe,
Australia, and New Zealand), although 82.8% of the patients were from the USA.
 It randomized 4881 patients within 12 h from non-cardioembolic high-risk TIA (ABCD2 ≥ 4)
or non- cardioembolic minor ischemic stroke
 to receive clopidogrel plus aspirin for 90 days or aspirin plus placebo and evaluated the risk of
a composite outcome of major ischemic event at 90 days (ischemic stroke, myocardial
infarction, death due to an ischemic event).
Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. N EnglJ Med 379(3):215–225. https:// doi. org/ 10. 1056/ nejmo
a1800 410

47.  The study was stopped in August2017 because the major bleeding boundary was exceeded.
 At that time, major ischemic event occurred less frequently in patients treated with DAPT
(event rate 5.0% DAPT vs. 6.5% aspirin, HR 0.75, NNT 66), and the occurrence of ischemic
stroke was reduced in the treatment group (event rate 4.6% DAPT vs. 6.3% aspirin, HR 0.72),
 although the risk of major bleeding was significantly increased (event rate 0.9% DAPT, vs.
0.4% aspirin, HR 2.32, NNH 200).

48.  The third trial was the THALES, a randomized, placebo-controlled, double-blind trial conducted in 414
sites in 28 countries from January 2018 to October 2019.
 It enrolled 11,073 patients with non-cardioembolic high-risk TIA (ABCD2 ≥ 6) or mild-to-moderate
non-cardioembolic ischemic stroke (NIHSS ≤ 5) within 24 h from onset
 evaluated the efficacy of ticagrelor plus aspirin in reductionof the risk of subsequent stroke or death at
30 days.
 Five thousand five hundred twenty-three patients were assigned to the treatment group (ticagrelor +
aspirin) and 5493 to theaspirin group (aspirin + placebo).
Ticagrelor and aspirin or aspirin alone in acute ischemic stroke or TIA. N EngJ Med 383(3):207–217. https:// doi. org/ 10. 1056/ nejmo
a1916 870

49.  The occurrence of the pri-mary outcome was significantly reduced in the DAPT group(event
rate 5.4% DAPT, 6.5% aspirin, HR 0.83, NNT 92), and so was the occurrence of ischemic
stroke (event rate 5.0% DAPT, 6.2% aspirin, HR 0.79).
 Considering safety, severe bleeding risk was significantly increased in the treat-ment group
(event rate 0.5% DAPT, 0.1% aspirin, HR 3.99,NNH 263), and intracranial hemorrhages or
fatal bleedings were more frequent in patients treated with DAPT (event rate0.4% DAPT, 0.1%
aspirin, HR 3.66).

51. DAPT IN PATIENTS WITH STROKE DUE TO
INTRACRANIAL STENOSIS
Stenting vs Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial
Stenosis (SAMMPRIS) trial compared medical therapy withintracranial stenting.
 Patients with a TIA or stroke attributed to 70%–99% stenosis of an intracranial artery were
randomised to aggressive medical management with aspirin 325 mg and clopidogrel 75 mg daily
for 3 months vs angioplasty and stenting plus aggressive medical management.
The study was stopped early after enrolment of 450 patients due to a higher 30-day rate of stroke
and death in the stenting group (14.7% vs 5.8%, p=0.002) primarily due to periprocedural
complications.
Stroke in Intracranial Stenosis trial. J Stroke Cerebrovasc Dis 20(4):357–368. https:// doi. org/ 10. 1016/j. jstro kecer ebrov asdis.
2011. 05. 001

52. At a median follow-up of 32.4 months, the risk of stroke or death was
23% in the stenting group vs 15%in the medical group.
 These results supported the use of DAPT for 90 days in patients with
symptomatic high- grade intracranial stenosis.

55. Early
ischemic
stroke (IS),
<24 hours
from onset
high-risk
TIA,
ABCD2 score
≥4;
low-risk TIA,
ABCD2 score
<4;
dual
antiplatelet,
acetylsalicylic
acid
(ASA)+clopid
ogrel.

56.  The Italian Stroke Prevention and Educational Awareness Diffusion (SPREAD)
 the European Stroke Association (ESO) and
 the American Heart Association/American Stroke Association (AHA/ASA)
SPREAD Italian guidelines For stroke prevention and management.8th ed. ISO. http:// iso- spread. it. Accessed 15 June
2022
European Stroke Organisation (2021. Eur Stroke J 6(2):CLXXXVII-CXCI. https:// doi.org/ 10. 1177/ 23969 87321 10008 77

58.  Long-term use of DAPT with aspirin and clopidogrel has been shown in 2 secondary
stroke prevention RCTs to have no benefit over SAPT for recurrent stroke prevention
and to have a significantly increased risk of ICH and major bleeding.
 The exact duration of DAPT at which the risk of hemorrhage begins to outweigh the
benefit of stroke prevention is unknown, but meta-analyses report as early as
21, 30,or 90 days.
 Older patients and those with more severe stroke appear to be at higher risk of ICH
with DAPT.
(MATCH): randomised, double-blind, placebo-controlled trial.Lancet. 2004; 364:331–337. doi: 10.1016/S0140-6736(04)16721-
4

59.  Although the optimal time to switch from DAPT to SAPT to maximize benefit
and reduce risk is not entirely clear, benefit in stroke reduction with DAPT
may be maximized as early as the first 21 days after the event.
 There may be other non–stroke-related indications for DAPT beyond 90 days
after stroke (eg, recent drug-eluting cardiac stent placement), but these
indications should be clarified to ensure that DAPT is not continued
indefinitely beyond the clinically recommended time frame.

60.  Triple antiplatelet therapy with aspirin, clopidogrel, and dipyridamole was compared with
standard antiplatelet therapy in the TARDIS trial (Triple Antiplatelets for Reducing
Dependency after Ischaemic Stroke), which found no difference in stroke outcomes and a
significantly increased risk of bleeding with triple antiplatelet therapy.
 The incidence and severity of recurrent stroke or TIA did not differ between intensive and
guideline therapy (93 [6%] participants vs 105 [7%]; adjusted common odds ratio [cOR] 0·90,
95% CI 0·67–1·20, p=0·47). By contrast, intensive antiplatelet therapy was associated with
more, and more severe, bleeding (adjusted cOR 2·54, 95% CI 2·05–3·16, p<0·0001)
(TARDIS): a randomised, open-label, phase 3 superiority trial.Lancet. 2018; 391:850–859. doi: 10.1016/S0140-6736(17)32849-0

61. 1.No randomized trials have focused on the question of changing long-term antiplatelet
therapy for the prevention of recurrent stroke.
2.A meta-analysis suggested that, among the 4 studies that examined stroke outcomes,
there was a reduced risk of recurrent stroke (HR, 0.70 [95% CI, 0.54–0.92]) among
patients who switched from 1 antiplatelet agent to another or to DAPT.
3. However, both of the RCTs that specifically examined recurrent stroke used DAPT
rather than switching antiplatelets.
4.A prospective registry study found that maintaining aspirin therapy was associated
with higher recurrent stroke rates (8.0%) compared with switching to another
antiplatelet (6.9%) or adding another antiplatelet (6.6%).
Different antiplatelet strategies in patients with new ischemic stroke while taking aspirin.Stroke. 2016; 47:128–134. doi:
10.1161/STROKEAHA.115.011595

63. EXTRACRANIAL CAROTID
DISEASE
 Beyond the procedural period and among those not eligible for intervention,
antiplatelet therapy with aspirin, clopidogrel, or aspirin-dipyridamole is recommended
indefinitely after CEA and CAS.
 Ticagrelor needs further investigation as an option for those with atherosclerotic
disease.
 DAPT not indicated due to increase chances of bleeding intra operatively.
Guideline on the management of patients with extracranial carotid and vertebral artery disease. J Am Coll Cardiol 2011;57:e16–94.

64. EXTRACRANIAL VERTEBRAL
DISEASE
 Among posterior circulation strokes, 10% to 20% of patients have proximal
atherosclerotic extracranial disease.
 The same medical management recommended for carotid disease is followed for
extracranial vertebral disease.
 Two trials failed to show superiority of stenting over medical management.
 A recent trial, unfortunately discontinued due to funding issues, showed that stenting
was safe and suggested a trend toward better outcomes.
 To date, no data support endovascular intervention for vertebral artery disease.
Guideline on the management of patients with extracranial carotid and vertebral artery disease. J Am Coll Cardiol 2011;57:e16–94.

66. AORTIC ARCH ATHEROSCLEROTIC DISEASE
 studies have identified an association between aortic arch atherosclerosis and
ischemic stroke, particularly when large plaques (>4 mm) are present.
 Compared with other stroke mechanisms, there are relatively scarce data on
antithrombotic treatment for secondary prevention in arch disease.
 the current published reports support as a Class I recommendation treating patients
with aortic arch disease and stroke or TIA with antiplatelet agents.
 There is no evidence that warfarin is useful in this condition.
Atherosclerotic disease of the aortic arch as a risk factor for recurrent schemic stroke. N Engl J Med 1996;334:1216–21.

68. CARDIOGENIC EMBOLISM
 Atrial fibrillation
 Long-term anticoagulation is recommended for secondary stroke prevention in
patients with AF
 DOACs are favored over warfarin in secondary stroke prevention in patients with AF,
except in those with moderate-to-severe mitral stenosis or mechanical heart valve .
 In patients with moderate-to-severe kidney disease, adjusted doses of DOACs are
required,
 whereas in those with end-stage renal disease or requiring dialysis, warfarin is
recommended instead of DOACs.
Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ ACC/HRS guideline for the management of patients
with atrial fibrillation J Am Coll Cardiol 2019;74:104–32.

69. OTHER CARDIOEMBOLIC SOURCES
Mitral stenosis, commonly secondary to rheumatic fever, have a high risk of
systemic embolism and is frequently complicated by AF.
 In the absence of high-quality evidence, there is general consensus that
anticoagulation is indicated in patients with mitral stenosis and previous stroke or AF.
 Patients with moderate-to-severe mitral stenosis long-term VKA therapy (INR 2 to 3) is
recommended.
Mechanical heart valves carry a high stroke risk and life-long therapy with
VKA (INR 2.3 to 3.5) is mandatory.
 Warfarin was superior to dabigatran in patients with mechanical heart valves, both in
terms of efficacy and safety
Antithrombotic and thrombolytic therapy for valvular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American
College of Chest Physicians Evidence-Based ClinicalPractice Guidelines. Chest 2012;141 Suppl:e576S–600S.

70. Bioprosthetic valves have a lower risk of thromboembolism when
compared with mechanical valves.
 For patients with mitral bioprosthetic valves, anticoagulation with VKA (INR 2 to 3) for
3 months followed by antiplatelet therapy is recommended.
 For aortic bioprosthetic valves, including transcatheter aortic valve bioprosthesis,
antiplatelet therapy is suggested over anticoagulation.
 There are no data to support the long-term use of anticoagulation in patients with
bioprosthetic valves.

71. Acute MI can lead to formation of a left ventricular thrombus.
 Anticoagulation with heparin followed by 3 months of VKA is recommended.
 Whether DOACs have a similar efficacy and safety in this situation remains to be
proven.
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.

75. SMALL VESSEL DISEASE
 Cerebral SVD is responsible for 25% of all ischemic strokes and the annual risk of
recurrence is 2-7%.
 long-term efficacy of DAPT was specifically studied in the SPS3 (Secondary
Prevention of Small Subcortical Strokes) study.
 stroke recurrence was not reduced by DAPT and the risk of hemorrhage was
increased.
 These findings were concordant with the MATCH trial, which found no benefit of
DAPT versus clopidogrel monotherapy
 Due to its pleiotropic properties such as arteriolar vasodilation and protection of
the vascular endothelium,
 cilostazol is potentially effective for preventing cerebral injury among patients with
SVD.
Cilostazol alleviates cerebral small vessel pathology and white-matter lesions in stroke-prone spontaneously hypertensive rats. Brain
Res 2008;1203:170–6.

77. CRYPTOGENIC STROKE
Embolic stroke of undetermined source
 Cryptogenic strokes that are nonlacunar,
 have no definite cardioembolic source,
 and no evidence of LAA are thought to have an embolic mechanism.
 These patients are classified as ESUS, and represent 10% to 21% of all ischemic
strokes.
 ESUS patients are relatively young (65 years of age average), and the rate of
recurrence is about 5% annually.
Prevalence and patient features in the ESUS Global Registry. Int J Stroke 2016;11:526–33.

78.  Under the assumption of an embolic mechanism, 4 RCTs were initiated comparing
anticoagulation with aspirin after ESUS.
 In conclusion, anticoagulation with DOACs has not been superior to aspirin for stroke
prevention in patients with ESUS
Cryptogenic stroke and patent foramen ovale
 Paradoxical embolism through a patent foramen ovale (PFO) may be implicated in a
proportion of patients with cryptogenic stroke.
 Secondary prevention strategies in these patients include PFO closure, antiplatelet
agents, or anticoagulant agents.
Patent foramen ovale closure for stroke prevention and other disorders. J Am HeartAssoc 2018;7:e007146.

79.  A pooled analysis of 6 RCTs comparing PFO closure plus antiplatelet therapy versus
any antithrombotic agent (antiplatelet and/or anticoagulation) showed significant
stroke reduction in the closure group compared with controls (risk ratio = 0.39;
p = 0.01),
 A sub-analysis of 2 studies comparing PFO closure to antiplatelet agents showed that
the former remained more effective in preventing stroke recurrence (risk ratio = 0.36;
p = 0.01).
 Another study compared PFO closure versus anticoagulation (VKA or DOACs), and
no significant benefit was found.
 Finally, 3 RCTs that compared anticoagulation versus antiplatelet agents showed
fewer ischemic strokes in patients assigned to anticoagulation; however, none found a
significant difference.
Patent foramen ovale closure or anticoagulation versus antiplatelets after stroke. N Engl J Med 2017;377: 1011–21.

80.  In summary, PFO closure plus long-term antiplatelet therapy is superior to antiplatelet
agents alone in carefully selected patients (i.e., younger than 60 years of age).
 PFO closure and anticoagulation may have similar efficacy in preventing stroke
recurrence, but available data are less robust.
 When PFO closure is contraindicated, the benefit of anticoagulation over antiplatelet
therapy is unclear.

82. OTHER DETERMINED
ETIOLOGIES
Cervical arterial dissection
 Cervical arterial dissection (CAD) is a common cause of stroke in the young.
 Stroke recurrence is generally low; however, the first few weeks after presentation
represents a high-risk time period.
 Therefore, 3 to 6 months of antithrombotic agents after diagnosis are recommended.
 The CADISS (Cervical Artery Dissection In Stroke Study) is the only RCT of
antithrombotic agents in CAD.
 Patients received either antiplatelet agents or anticoagulation for 3 months after
diagnosis of CAD. The infrequency of endpoint occurrence precludes any definitive
conclusion.
Antithrombotic drugs for carotid artery dissection. Cochrane Database Syst Rev 2010;10:CD000255.

83.  Carotid web is a thin, circumferential shelf-like filling defect that arises from the posterior wall
of the ICA bulb visualized on CTA or carotid angiography.
 Pathologically, carotid web is a variant of fibromuscular dysplasia and can be classified as
focal or multifocal.
 Platelet deposition can occur in the corrugations of carotid web, forming a nidus for potential
blood flow stagnation and thromboembolism.
 Carotid web is a known cause of ischemic stroke in young patients <65 years of age; it is
detected in up to 9.5% of patients <65 years of age with anterior circulation stroke of unknown
cause.

85. Fibromuscular Dysplasia
FMD is a nonatherosclerotic segmental disease of small or medium-sized
arteries that can result in arterial stenosis, occlusion, intraluminal thrombus,
aneurysm, or dissection.
Multiple fibrous webs can serve as a nidus for platelet deposition or obstruct
flow, resulting in thromboembolic TIA or ischemic stroke.
It can involve the extracranial carotid, vertebral. and renal arteries.

87. HYPERCOAGULABLE STATES
Inherited thrombophilias
 A causal relationship between stroke and inherited thrombophilias (factor V
Leiden, prothrombin G20210A mutation, methylenetetrahydrofolate reductase C677T
mutation, protein C deficiency, protein S deficiency, and antithrombin III deficiency) remains
poorly established, and routine testing is not advised .
 Long-term anticoagulation with VKA or heparin products is recommended for patients with
unprovoked venous thrombosis and an underlying thrombophilia.
 Current guidelines recommend that anticoagulation should be considered in the setting of
recurrent cryptogenic strokes and known inherited thrombophilia.
The Euro-Phospholipid project: epidemiology of the antiphospholipid syndrome in Europe. Lupus 2009;18:889–93.

88. ANTIPHOSPHOLIPID SYNDROME
 Antiphospholipid syndrome (APLS) is an antibody-induced thrombophilia
characterized by recurrent thrombosis (venous and arterial) and pregnancy morbidity.
 In the Euro-Phospholipid Project, 20% of the patients with APLS presented with
ischemic stroke and 11% with TIAs.
 Conversely, it is estimated that 1 in 5 strokes in all young patients (<50 years of age)
are associated with APLS, although all ages can be affected .
 A systematic review showed that APLS patients with previous stroke had high
thrombosis recurrence despite being on antiplatelet agents or standard
anticoagulation
 , and found that <4% of all events occurred with an INR >3.0, thus advocating for an
aggressive therapeutic target in high-risk patients.
A systematic review of secondary thromboprophylaxis in patients with antiphospholipid antibodies. Arthritis Rheum
2007;57:1487–95.

90. STROKE AND MALIGNANCY
 Ischemic stroke is common among cancer patients.
 Cancer may lead to stroke via hypercoagulability,
 paradoxical emboli,
 nonbacterial endocarditis,
 tumor embolization, and local tumor compression, or alternatively, by treatment-
related complications such as radiation-related large-vessel arteriopathy.
 Anticoagulation with either low-molecular-weight heparin (LMWH) or DOACs may be
recommended for cancer-associated thrombosis.
 The mechanism of injury as well as the overall prognosis should be considered when
selecting antithrombotic therapy.
Evaluation and treatment of a patient with recurrent stroke in the setting of active malignancy. Stroke 2018;50:e9–11.

91. Evaluation and treatment of a patient with recurrent
stroke in the setting of active malignancy.
Stroke 2018;50:e9–11.

92. CEREBRAL VENOUS THROMBOSIS
 Although not from an arterial occlusion, ischemic or hemorrhagic infarctions may
occur due to cerebral venous thrombosis (CVT).
 On the basis of 2 RCTs, anticoagulation with heparin products is recommended for
acute CVT, regardless of the presence of intracranial hemorrhage.
 LMWH has been associated with lower mortality, fewer hemorrhagic complications,
and better long-term functional outcome when compared with unfractionated heparin.
 After the acute phase, guidelines recommend anticoagulation with VKA for a variable
period of time (3 to 12 months).
 The optimal duration, as well as the effectiveness of DOACs, is uncertain.
Anticoagulation for cerebral venous sinus thrombosis. Cochrane Database Syst Rev 2011;8: CD002005.

93. ANTITHROMBOTIC THERAPY AFTER
INTRACRANIAL HEMORRHAGE
 Antithrombotic agent–associated ICH is associated with larger hematoma volume, hematoma
expansion, and worse outcomes.
 All antithrombotic agents should be discontinued at presentation, and rapid reversal of
anticoagulation is recommended.
 After bleeding cessation, early use of low-dose heparin is considered safe and effective in
preventing deep venous thrombosis and pulmonary embolism.
 A systematic review evaluated anticoagulation resumption among 5,306 ICH patients with
AF, prosthetic heart valves, previous venous thrombosis, and previous ischemic stroke. With a
median time for restarting anticoagulation of 10 to 39 days, resumption was associated with
lower risk of thromboembolic events (6.7% vs. 17.6%), and no significant risk of ICH
recurrence (8.7% vs. 7.8%) during a mean follow-up ranged from 12 to 43 months.
Oral anticoagulant-associated intracerebral hemorrhage. J Neurol 2012;259:212–24.

94.  restarting antithrombotic agents after ICH should be considered, particularly in high-risk
thromboembolic conditions.
 It has been suggested that avoidance of antithrombotic agents for 2 to 4 weeks after ICH is
reasonable ( sophie’s choice).
 However, given the observational nature of published data, there is a lack of evidence-based
recommendations.
 Numerous ongoing RCTs target this clinical situation.
Timing of Antiplatelet Resumption After Intracerebral Hemorrhage: A Sophie’s Choice

95.  The RESTART (Restart or Stop Antithrombotics Randomised Trial) study is a multicenter RCT
comparing starting versus avoiding antiplatelet drugs after a antithrombotic agent–associated
ICH .
 The results of this trial indicate that resuming antiplatelet therapy at a median of 2.5 months
after symptomatic intracerebral hemorrhage does not increase the risk of recurrent intracerebral
bleeding compared with avoiding antiplatelet agents.
 Several other trials aim to investigate the safety of restarting anticoagulation in patients with
AF after a spontaneous ICH.
Restarting anticoagulant therapy after intracranial hemorrhage: a systematic review andmeta-analysis.
Stroke 2017;48:1594–600.

97.  To date, most DAPT trials have used aspirin and clopidogrel in combination for 21 to
90 days, but whether the duration of treatment should be 21 days, 90 days, or some
other amount of time is not fully established.
 Similarly, whether other combinations of medications are equally or more beneficial is
not known.
 The risk of DAPT among patients with stroke who may be more likely to experience
hemorrhagic transformation of the ischemic stroke or other bleeding complication such
as those with large stroke or microhemorrhages remains uncertain.

98. • Optimal combination of medications, timing of initiation, and duration of DAPT.
• Effectiveness and potential harm of DAPT among specific subgroups of patients
according to stroke characteristics, laboratory or genetic tests, or other factors.
• Effectiveness/selection of a given antiplatelet agent over another in specific subgroups
of patients with noncardioembolic stroke.
• Benefit of switching antiplatelet agent for patients already taking 1 antiplatelet
medication at the time of stroke.
• Effectiveness of DOACs compared with or in combination with antiplatelet therapy for
secondary stroke prevention among patients with noncardioembolic ischemic stroke.

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