Recommendations

Table 15. Risk of stroke within 2, 7 and 90 days after a TIA (ABCD2 risk table) ^{* 506}

7.3. Hypertension

Key Questions

In patients with a history of an episode of stroke, does antihypertensive treatment reduce the risk of new episodes?

What are the target blood pressure values?

HT is the most important risk factor, after age, for ischemic and hemorrhagic stroke. Amongst modifiable risk factors, HT is the most prevalent, and is present in almost half of the population with risk factors²⁰⁰. The number of trials designed to directly assess if treatment of blood pressure reduces the incidence of new stroke or other vascular episodes is limited⁵²⁷. Most information has been extracted from trials that evidence the importance of treating HT in the prevention of vascular episodes²²⁹.

On the other hand, there is a lack of information on antihypertensive treatment in the acute phase of an ischemic stroke that may present high blood pressure values. Normally a cautious strategy is recommended, given that the time when treatment was initiated is unknown. In this phase, a sharp decrease of blood pressure values could reduce cerebral perfusion and thus increase the area of infarction. Special care should be taken with patients presenting bilateral obstruction of the carotid artery greater than 70%, where a sudden reduction of blood pressure entails a special risk of stroke recurrence⁵²⁸.

There are CPGs that extensively address treatment in the acute phase of an ischemic stroke or TIA⁵²⁹. In any case, antihypertensive treatment should be aimed at gradually reducing blood pressure values and the indication for any treatment should be performed taking each patient’s tolerance and concomitant pathology into consideration.

7.3.1. Risk of a new episode with treatment

A SR of 7 RCTs and 15,527 patients with a history of stroke (ischemic, TIA or hemorrhagic), with and without HT, demonstrated that antihypertensive treatment reduces the risk of having a new episode of stroke by 24% (OR: 0.76; 95% CI: 0.63 to 0.92), a myocardial infarction by 21% and vascular episodes by 21%, even though it does not significantly reduce overall mortality or mortality due to stroke. The benefits reported were mainly a result of SBP management⁵³⁰.

SR of RCT
1++

The results of this SR showed that ACEIs reduce the risk of myocardial infarction (OR: 0.74; 95% CI: 0.56 to 0.98), while diuretics reduce the risk of a new stroke (OR: 0.68; 95% CI: 0.50 to 0.92) and vascular episodes (OR: 0.75; 95% CI: 0.63 to 0.90). Betablockers (atenolol) were not shown to be superior to placebo in individual studies or in the joint analysis of results. They were also a significant source of heterogeneity in the results⁵³⁰. Data for the combination of a diuretic and an ACEI were obtained from one RCT, the PROGRESS trial⁵⁰⁰.

The PROGRESS study, included in the previous version, randomised 6,105 patients with a history of ischemic stroke or TIA with and without HT to three groups that received perindopril (4 mg/d) alone, in combination with indapamide (2.5 mg/d) or placebo. The study had a four year follow-up⁵⁰⁰. The most significant benefits were reported in the group that combined perindopril and indapamide, with a 43% reduction of the risk of having a new episode of stroke (405 events; RR: 0.57; 95% CI: 0.46 to 0.70), a 76% reduction of risk of hemorrhagic strokes and a 40% reduction of risk of vascular episodes. Combined treatment demonstrated a greater reduction of blood pressure values.

RCT
1++

A subsequent analysis of the PROGRESS study for different types of stroke indicated that treatment with an ACEI (perindopril) reduced the risk of recurrent hemorrhagic stroke by 50%; absolute reduction was 1% (111 events) ²⁴⁰.

RCT
1+

The MOSES trial, a RCT conducted after these studies that included 1,045 patients with HT and a history of stroke determined that antihypertensive treatment with eprosartan (600 mg/d), an ARA-II, results in a 25% stroke risk reduction when compared to a calcium antagonist (nitrendipine) (236 events; incidence density ratio [IDR] 0.75; 95% CI: 0.58 to 0.97) and a 21% vascular episode risk reduction. However, the study had an open design, amongst other methodological limitations⁵³¹.

RCT
1-

Different types of antihypertensive treatments reduce blood pressure values. In contrast, benefits in primary or secondary prevention of vascular episodes, including stroke, differ considerably. One possible explanation for this effect is that the renin-angiotensin system has been associated with arteriogenesis and proliferation of the vascular smooth muscle⁵³². Thus, ACEIs and ARA-IIs could have additional benefits aside from the reduction of blood pressure values⁵²⁷.

Lifestyle modifications in patients with HT that have been determined to reduce blood pressure values are smoking cessation, weight loss in patients with obesity, alcohol consumption moderation, regular physical activity, reduced salt intake and increased consumption of fruits and vegetables²⁰⁹. These measures are also useful in the management of other vascular risk factors.

SR of RCT
1++

7.3.2. Blood pressure target values

A SR of cohort studies demonstrated that the risk of stroke decreases lineally and consistently with blood pressure until 115/75 mmHg levels in men and women and for different types of stroke. Risk is reduced by about 30% for every 10mmHg decrease of blood pressure values²²⁹.

SR of cohort studies
2++

With the aim of maximising vascular benefits, more intensive treatment with antihypertensives has been suggested for patients with high vascular risk. In patients with a history of stroke, a later analysis of the PROGRESS study reported a gradual benefit in the recurrence of stroke by managing SBP values up to 120 mmHG⁵³³. Although the benefit obtained with decreased BP values is lineal, some more recent international and national CPGs suggest values below 140/90 mmHg^{201, 202}, 130/80 mmHg^{36, 534, 535} or even 120/80 mmHg⁵³⁶ as the target values in secondary prevention. Other CPGs, on the other hand, emphasise the need to initiate treatment in those hypertense or even normotense patients who have had a stroke or who present some vascular risk, but do not establish target values in their recommendations^{223, 537}.

RCT
1++

Despite the benefits of antihypertensive treatment, a study performed in our setting determined that in people who had had a stroke, the implementation of the recommendations provided by CPGs and the therapeutic objectives of the treatment of vascular risk factors, including HT, were very poor²⁰⁶.

 

Summary of evidence

1++	In patients who have had a stroke or transient ischemic attack, antihypertensive treatment reduces the risk of recurrence or other vascular episodes. The benefit is mainly a result of SBP reduction 530.
1++	The greatest benefits are obtained with the combination of angiotensin converting enzyme inhibitor and a diuretic (4 mg/d of perindopril in combination with 2.5 mg/d of indapamide) 500.
1++	Diuretic monotherapy treatment reduces the risk of having a new stroke and other vascular episodes. Angiotensin converting enzyme inhibitor monotherapy reduces the risk of myocardial infarction. Betablockers have been shown to be beneficial in the secondary prevention of stroke 530.
1-	Treatment with angiotensin II antagonists (eprosartan) could be beneficial in reducing the risk of a recurrent stroke 531.
1++	Antihypertensive treatment is beneficial in patients with blood pressure values within established normal limits 500.
1++	n hypertense patients, lifestyle modifications reduce blood pressure values and other vascular risk factors 209.

Recommendations

√	Blood pressure values of patients who have had an ischemic or hemorrhagic stroke should be closely monitored.
A	In patients with a history of stroke or transient ischemic attack and high or even normal blood pressure values, it is recommended to initiate treatment with antihypertensive drugs, preferably with the combination of an angiotensin converting enzyme inhibitor and a diuretic (4 mg/d of perindopril and 2.5 mg/d of indapamide).
B	Depending on the patient’s tolerance or concomitant pathologies, monotherapy with diuretics, angiotensin converting enzyme inhibitors or angiotensin II antagonists should be considered.
B	Once a patient who has had an ischemic stroke or transient ischemic attack is stabilised, blood pressure values should be gradually decreased with the aim of maintaining levels under 130/80 mmHg, and preferably under 120/80 mmHg.
A	Lifestyle changes should be promoted, aside from pharmacological treatment.

7.4. Dyslipemia

Key Questions

In patients with a history of an episode of stroke, does hypolipemiant treatment reduce the risk of new episodes?

What is the optimal dose of hypolipemiant treatment?

What are the target blood lipid values?

A SR of patients’ individual data, the result of an international collaboration (CTT [Cholesterol Treatment Trialists] Collaborators), included 14 RCTs and 90,056 patients and a mean 5 year follow-up, with a total of 8,186 deaths and 14,348 major vascular episodes. This study demonstrated that statins reduced the risk of death due to all causes by 12% for every 39 mg/dl (1.0 mmol/l) reduction of LDL cholesterol (RR: 0.88; 95% CI: 0.84 to 0.91) and the risk of a major vascular episode by 21% (myocardial infarction, coronary death, revascularisation and stroke) (RR: 0.79; 95% CI: 0.77 to 0.81).

SR of RCT
1++

Specifically, in the case of fatal and non-fatal strokes (2,957 events), there was a 17% risk reduction (RR: 0.83; 95% CI: 0.78 to 0.88), so for every 39 mg/dl reduction of LDL cholesterol (maintained over five years) there were 8 (95% CI: 4 to 12) episodes less per 1,000 treated patients. The benefit was objectivisable from the first year of treatment.

In this same study, statin treatment reduced the incidence of major vascular episodes at five years by 20% for every 39 mg/dl reduction of LDL cholesterol. This benefit was independent from the initial lipid profile and other characteristics such as the presence of a history of vascular disorders. Absolute benefit for each 39 mg/dl reduction of LDL cholesterol (maintained over 5 years) was 48 (95% CI: 39 to 57) major vascular episodes less per 1,000 patients with a history of coronary disease²⁷⁴. Prior reviews report similar results pointing in the same direction^{273, 278-280}.

A later clinical trial (SPARCL) (4,731 patients, 575 events) assessed the efficacy and safety of atorvastatin (80 mg/d) compared to placebo in patients who had had a recent stroke or TIA (one to six months before) and without prior coronary disease. In these patients, atorvastatin reduced the overall incidence of stroke by 16% (HR 0.84; 95% CI: 0.71 to 0.99; ARR 2.2%), as well as death due to stroke (HR 0.57; 95% CI: 0.35 to 0.95), even though increased hemorrhagic stroke (HR 1.66; 95% CI: 1.08 to 2.55) and increased blood liver enzyme levels were reported. The number of patients who needed to be treated to prevent stroke was 46 (NNT 46; 95% CI: 24 to 243). In regards to hemorrhagic strokes, the number of events was limited (55 in atorvastatin and 33 in placebo), but the percentage of patients included with hemorrhagic stroke was also limited⁵³⁸ .

RCT
1+

With the aim of assessing the possible increased risk of hemorrhagic strokes, a recent SR jointly analysed two RCTs (8,011 patients) that showed results for this event: the SPARCL trial in atorvastatin and the HPS (Heart Protection Study) in simvastatin. Results were consistent and showed a significantly increased risk (120 events; RR: 1.73; 95% CI: 1.19 to 2.50)⁵³⁹.

 

SR of RCT
1+

7.4.1. High doses versus low doses

A SR (27,548 patients, 2,385 events) that compared the efficacy of standard dose statins to high dose statins in secondary prevention (patients with a history of coronary disease) reported that high doses result in a greater decrease of an outcome variable comprised of coronary death or myocardial infarction (OR: 0.84; 95% CI: 0.77 to 0.91)⁵⁴⁰. Higher doses were also more effective at reducing the risk of presenting a variable consisting of coronary death or any vascular episode (OR: 0.84; 95% CI: 0.80 to 0.89). Specifically, high dose statins significantly decreased the risk of stroke (697 events; OR: 0.82 95% CI: 0.71 to 0.96). No significant differences were reported in overall or vascular mortality. A later SR yielded similar results in this population and highlights the absence of evidence to establish LDL cholesterol target values, indicate the use of combinations to reach these objectives or the use of more intense regimens in patients without coronary disease⁵⁴¹.

SR of RCT
1++

7.4.2. Elderly patients

A SR jointly assessed the results of 9 RCTs that included a total of 19,569 elderly patients (65 to 82 years) with a history of coronary disease. Statins, compared to placebo, reduced mortality (overall and coronary), myocardial infarction, the need for revascularisation and stroke. In the specific case of stroke, risk was reduced by 25% (RR: 0.75 95% CI: 0.56 to 0.94). The number of patients who needed to be treated to avoid one death was 28⁵⁴².

SR of RCT
1++

7.4.3. Target values

Despite the fact that many institutions that develop health recommendations include LDL cholesterol values as potential thresholds to obtain benefit, there is very little information available. Specifically, a review on this issue did not identify studies that showed the relationship between LDL cholesterol levels and vascular risk in patients with values below 130 mg/dl⁵⁴³. However, the main international and national institutions agree in recommending values below 100 mg/dl and in some cases even below 70 mg/dl. Even so, the long-term safety and impact of these intensive strategies on available resources remains unknown and therefore, more recent guidelines recommend treatment with statins, reflecting their reservations about establishing target values ^{291, 544, 545}. These CPGs also highlight that there is no evidence concerning the cost-effectiveness in relevant clinical variables of the combination of a statin with other hypolipemiant drugs to achieve LDL cholesterol target values²⁹¹.

 

Summary of evidence

1++	In patients with a history of vascular disorders (including stroke) statin treatment reduces the risk of recurrence and new vascular episodes. Coronary episode risk is decreased more than stroke risk 238, 273, 274, 278-280.
1++	In patients with a history of ischemic stroke or transient ischemic attack, without prior coronary disease, high dose statin treatment reduces the risk of recurrence and other vascular episodes. However, adverse effects are more frequent at higher doses 540, 541.
	There is no direct evidence regarding what the target LDL cholesterol levels in secondary prevention are 543.

Recommendations

A	It is recommended that patients with ischemic stroke or prior atherothrombotic transient ischemic attack be treated with atorvastatin (80 mg/d), regardless of their basal LDL-cholesterol levels.
B	Treatment with other statins (simvastatin 40 mg) is also indicated in patients with ischemic stroke or prior atherothrombotic transient ischemic attack, regardless of their basal LDL-cholesterol levels.
√	Treatment with statins should be jointly assessed with the patient after adequately informing him/her of the benefits and potential risks and taking associated pathologies and concomitant treatments into account. Aside from statin treatment, healthier lifestyles should be adopted.
√	These patients should maintain LDL-cholesterol levels below 100 mg/dl.
√	The combination of statins with other hypolipemiant drugs to reach LDL-cholesterol target values should be avoided.

7.5. Hormone Therapy

Key Questions

In postmenopausal women with a history of stroke, does hormone therapy reduce the risk of new episodes?

HT had been widely used in postmenopausal women to prevent vascular diseases, osteoporosis and dementia up until the publication of the WHI study, which demonstrated that the risks outweighed the benefits³¹¹. Evidence supporting this notion is consistent with results that appeared after the WHI³¹³ and WISDOM³¹⁴ studies. In secondary prevention, however, evidence is more limited.

RCT
1++/1+

A SR in postmenopausal women (7 RCTs, 32,000 women) reported that HT does not modify the risk of death due to any cause, coronary DEATH or non-fatal myocardial infarction. In 5 of these RCTs, the women had a history of vascular disease⁵⁴⁶. The SR evidenced increased risk of stroke in the case of estrogens alone or in combination with progestagens (831 events; RR: 1.29; 95% CI: 1.13 to 1.48). In the only RCT that included women with a history of stroke or TIA, HT was not associated with a differential risk of recurrence versus placebo⁵⁴⁷.

SR of RCT
RCT
1++

Summary of evidence

1++	HT treatment (with estrogens alone or in combination with progestagens) increases the risk of stroke in women with prior vascular disease 546, 547.

Recommendations

A	Hormone therapy (with estrogens alone or in combination with progestagens) is not recommended as secondary prevention of vascular disease in postmenopausal women.

7.6. Thrombofilias

Key Questions

In patients with congenital or acquired thrombofilias who have had an episode of stroke, does antithrombotic treatment reduce the risk of new episodes?

7.6.1. Congenital thrombofilia

Several studies with different designs (RCTs, cohort and case-control studies) have evaluated the relationship between different congenital thrombofilias and the risk of stroke, yielding inconsistent results. The relationship with ischemic stroke is weak in adults. In patients with associated pathology and in children it is stronger. The relationship is more consistent for the risk of cerebral venous thrombosis, especially in women who take oral contraceptives. Evidence supporting this relationship does not differ from the evidence described in section 6.12 of primary prevention.

RCT
1+

Observational studies
2++

The issue concerning whether these congenital alterations can increase the risk of recurrent strokes is controversial. In this sense, the POLARIS study, currently in the recruitment phase, aims to study the relationship between different genetic polymorphisms (including factor V Leiden and prothrombin G20210A mutation) and the recurrence of thrombotic episodes, including strokes and TIAs.

7.6.2. Acquired thrombofilia

APS is a clinical condition characterised by recurrent thrombosis and the presence in plasma of antibodies against cell membrane phospholipids. In observational studies the presence of APS has been associated with the first episodes of thrombotic episodes and even stroke, even though the evidence is not yet consistent. The issue of whether APS has a role in recurrent strokes remains controversial. However, in several prospective studies, patients with ischemic stroke and APS presented a higher probability of recurrence³²².

Observational studies
2++

A later clinical trial (SPARCL) (4,731 patients, 575 events) assessed the efficacy and safety of atorvastatin (80 mg/d) compared to placebo in patients who had had a recent stroke or TIA (one to six months before) and without prior coronary disease. In these patients, atorvastatin reduced the overall incidence of stroke by 16% (HR 0.84; 95% CI: 0.71 to 0.99; ARR 2.2%), as well as death due to stroke (HR 0.57; 95% CI: 0.35 to 0.95), even though increased hemorrhagic stroke (HR 1.66; 95% CI: 1.08 to 2.55) and increased blood liver enzyme levels were reported. The number of patients who needed to be treated to prevent stroke was 46 (NNT 46; 95% CI: 24 to 243). In regards to hemorrhagic strokes, the number of events was limited (55 in atorvastatin and 33 in placebo), but the percentage of patients included with hemorrhagic stroke was also limited⁵³⁸ .

RCT
1+

In patients with a history of vascular disease, the prospective observational cohort APASS (Antiphospholipid Antibodies and Stroke Study)⁵⁴⁸ nested in the WARSS⁵⁴⁹ trial, which was stratified according to the presence or absence of APAs, showed that the presence of APAs in patients with ischemic strokes does not entail an increased risk of occlusive vascular episodes at two years follow-up or a different response to aspirin or warfarin.

 

SR of RCT
1+

7.4.1. High doses versus low doses

 

Summary of evidence

1+/2+	There is controversy regarding whether different congenital thrombofilias can increase the risk of having recurrent strokes 305, 306,316, 323.
2++	No relationship has been found between the presence of antiphospholipid antibodies and recurrence of stroke or other occlusive vascular episodes 322.
2++	The presence of antiphospholipid antibodies does not seem to increase the risk of recurrent strokes or to reach a different prognosis depending on the antithrombotic treatment prescribed after an ischemic stroke548.

Recommendations

B	In patients with hereditary thrombofilia and a history of thrombotic episodes, long-term anticoagulant treatment is recommended.
B	In patients with previous ischemic stroke or transient ischemic attack, who have not presented any other alternative cause to the antiphospholipid syndrome, long term treatment with anticoagulants is recommended.

7.7. Hyperhomocysteinemia

Key Questions

In patients with a history of stroke and hyperhomocysteinemia, do vitamin complexes reduce the risk of new episodes?

Different observational studies evidence the association between hyperhomocysteinemia, especially the form linked to the genetic alteration of the MTHFR enzyme, and vascular disease^330-332, including stroke³³⁴.

Observational studies
2++/2+

Two SRs assessed the efficacy of folic acid supplements in patients with or without prior vascular disease according to plasma homocysteine levels, which were not high in all patients. The reviews yielded inconsistent results^{336, 337}. The first review in a population with a history of vascular disease (12 RCTs, 16,958 patients) concluded that the risk of vascular disease, coronary disease, stroke or death in patients who received folic acid supplements or placebo is similar (RR: 0.86; 95% CI: 0.71 to 1.04)³³⁶.

SR of RCT
1+

In another SR (8 RCTs, 16,841 patients) which assessed folic acid supplements, with or without B complex vitamins, an 18% stroke risk reduction was reported (RR: 0.82; 95% CI: 0.68 to 1.00) in favour of supplements versus control. The effect was obtained mainly in trials that lasted longer than 36 months, were conducted in countries that fortify cereals with folic acid and included patients without a prior history of stroke³³⁷.

SR of RCT 1+

The VISP study (3,680 patients), the only one that has been conducted in population with a history of non-cardioembolic stroke and increased plasma homocysteine levels, assessed the effect of treatment with high and low vitamin doses (B6, B12 and folate)⁵⁵⁰. Although homocysteine values were lower by the end of follow-up in the group that received high doses of vitamins, it did not translate into decreased incidence of new episodes of stroke or other vascular outcomes or mortality. Additionally, a gradient between the different outcomes and basal homocysteine levels was evidenced and some authors determine that there is a probable benefit in patients with higher levels and/or a more pronounced decrease of homocysteine levels⁵⁵¹.

RCT
1++

The VITATOPS study, which aims to assess the effect of vitamin B6, B12 and folate supplements in the secondary prevention of stroke, is currently in the recruitment phase⁵⁵². This study will contribute to a collaborative metaanalysis with 52,000 patients which will help to throw light on the effectiveness of this therapeutic option⁵⁵³.

 

 

Summary of evidence

2++	Elevated plasma homocysteine levels are associated with an increased risk of vascular disease and stroke. There is no evidence on whether the reduction of homocysteine levels reduces the risk of stroke recurrence 330-332, 334.
1++/1+	In patients with elevated plasma homocysteine levels and a history of stroke, complex B vitamins and/or folic acid do not seem to reduce the risk of stroke recurrence or other vascular episodes 336, 337, 550.

Recommendations

B	In patients with prior stroke or hyperhomocysteinemia, folic acid and vitamin B complex supplements should be considered with the aim of reducing elevated plasma homocysteine levels.

7.8. Emboligenous cardiopathies

Key Questions

In patients with atrial fibrillation and a history of ischemic stroke or TIA, does antithrombotic treatment reduce the risk of new episodes?

In patients with a prosthetic heart valve who are under adequate antithrombotic treatment and who present an ischemic stroke or TIA, what is the most adequate therapeutic strategy?

In patients with certain cardiopathies such as MS, mitral valve prolapse of permeable foramen ovale and a history of an episode of ischemic stroke or TIA, does antithrombotic treatment or surgery reduce the risk of having new episodes?

7.8.1. Atrial fibrillation

Non-rheumatic atrial fibrillation is a frequent heart rhythm alteration that can be found in 17% of patients with prior stroke^554-558. Annual mortality rate in these patients is 5%⁵⁵⁹.

Antithrombotics

Two SRs that assessed the efficacy of anticoagulant treatment versus placebo and antiaggregants for the prevention of recurrent stroke in patients with atrial fibrillation were identified^{561, 562}.

The first SR jointly analysed the results of two RCTs. Anticoagulant treatment reduced the risk of a new episode of stroke (74 events; OR: 0.36; 95% CI: 0.22 to 0.58) compared to placebo, even though the number of events was limited. Overall vascular events were reduced by 45% in patients treated with anticoagulants. The review showed a significantly increased risk of Severe extracranial hemorrhages for anticoagulant treatment (2.5 to 4 INR) versus the control group (2.8% and 0.7% respectively) according to the data derived from one study⁵⁶¹.

SR of RCT
1++

In the second SR, which also included two RCTs, anticoagulants were superior to antiaggregants in the prevention of recurrent strokes (OR: 0.49; 95% CI: 0.33 to 0.72) and new vascular episodes (OR: 0.67; 95% CI: 0.5 to 0.91). Severe extracranial hemorrhages were more frequent in patients taking anticoagulants, even though the absolute difference was extremely small⁵⁶².

SR of RCT
1++

Results were similar to those yielded by another SR (29 RCTs, 28,044 patients) that included studies on primary and secondary prevention of vascular episodes. Oral anticoagulants were superior to placebo and antiaggregants at preventing stroke in patients with atrial fibrillation³⁷⁸. Furthermore, a recent multicentre study performed on 973 patients without a history of stroke reported that the benefit of anticoagulant treatment can be applied to elderly patients³⁸⁴.

 

SR of RCT
RCT
1++

The efficacy of anticoagulant treatment to prevent thromboembolic episodes in patients with atrial fibrillation has been consistently evidenced in several RCTs, even when compared to antiaggregant treatment. The optimal intensity of anticoagulant treatment for the secondary prevention of stroke lies between 2 and 3 INR^{563, 564}. Efficacy is reduced for INR values below 2. Anticoagulant treatments have a narrow therapeutic margin and present frequent interactions with other drugs and with certain types of food, requiring frequent monitoring and dose adjustments. All this could contribute to infrautilisation of anticoagulant treatment or use of infratherapeutic doses, which could result in inadequate protection of high risk patients.

 

RCT
1++

No studies have been identified that assess possible therapeutic strategies in patients with atrial fibrillation who suffer a stroke, even when receiving treatment with optimal anticoagulation intensity. The additional benefit of intensifying anticoagulant treatment or adding an antiaggregant to this treatment is therefore unknown. However, the NASPEAF trial assessed the efficacy of combined treatment with anticoagulants and triflusal (600 mg/d) in 1,209 patients with high risk (valvular origin with or without prior embolism) or moderate risk atrial fibrillation. Combined treatment reduced the risk of vascular events (vascular death, TIA, non-fatal stroke or systemic embolism) in 67% of patients with moderate risk (HR 0.33; 95% CI: 0.12 to 0.91) and in 49% of high risk patients (HR 0.51; 95% CI: 0.27 to 0.96), compared to anticoagulant treatment alone. Combined treatment reduced the intensity of anticoagulation. The number of severe bleeding episodes was similar in high risk patients, but the total number of events was limited³⁸³.

 

RCT
1+

Patient perceptions

Patients taking anticoagulants generally do not have enough information on the objectives and risks of this treatment (section 6.18)³⁶⁷. In a significant portion of patients anticoagulation self-management programmes lead to reduced thromboembolic episodes and risk of death^389-392.

SR of RCT
RCT
1++

Results were similar to those yielded by another SR (29 RCTs, 28,044 patients) that included studies on primary and secondary prevention of vascular episodes. Oral anticoagulants were superior to placebo and antiaggregants at preventing stroke in patients with atrial fibrillation³⁷⁸. Furthermore, a recent multicentre study performed on 973 patients without a history of stroke reported that the benefit of anticoagulant treatment can be applied to elderly patients³⁸⁴.

 

SR of RCT
RCT
1++

Bleeding risk stratification systems

There are several models to estimate the risk of severe bleeding in patients who receive anticoagulant treatment^371-373, but all of them present limitations. It is essential to establish a balance between the benefits of anticoagulant treatment in reducing the risk of having a new episode of ischemic stroke or TIA and the risks of a severe bleeding episode. This risk should be evaluated in each patient using one of the currently available models (section 6.14.1)³⁷⁴.

 

Observational studies
2++

 

Summary of evidence

2++	Atrial fibrillation is a risk factor for stroke, especially in elderly patients who have had a prior ischemic stroke 364.
1++	In patients with paroxistic, persistent or permanent atrial fibrillation and a history of stroke, anticoagulant treatment (2 to 3 INR target range) is more effective than antiaggregants at preventing new episodes 378, 562.
1++	Anticoagulants present more hemorrhagic adverse effects than antiaggregants and require strict and periodic follow-up of treatment 378, 562.
	There are no studies that assess possible therapeutic strategies for patients with atrial fibrillation who have a stroke even when receiving treatment with optimal anticoagulation intensity.

Recommendations

√	All patients with atrial fibrillation should be individually assessed in order to establish an adequate benefit-risk balance of anticoagulant treatment.
A	Treatment with oral anticoagulants with an INR target range of 2 to 3 for an indefinite period of time is recommended in patients with paroxistic, persistent or permanent atrial fibrillation who have previously suffered a stroke and who present no formal contraindications to treatment.
√	In cases where anticoagulant treatment is contraindicated, treatment with aspirin (300 mg/d) is an appropriate alternative.
√	Intensification of anticoagulation or combination with antiaggregant treatment (aspirin or triflusal) should be considered in patients with paroxistic, persistent or permanent atrial fibrillation, who receive correct doses of anticoagulant treatment and still present stroke or recurrent transient ischemic attack.

7.8.2. Valve prostheses

There are several types of mechanical prosthetic heart valves. All of them require indefinite anticoagulant treatment. In section 6.14.4 of this guideline recommendations are provided to determine the required intensity of anticoagulant treatment depending on the type of mechanical valve and patient risk factors, following the recommendations formulated by the working group for vascular disease management of the European Society of Cardiology ⁵⁶⁵.

Even with anticoagulant treatment, the risk of presenting a thromboembolic episode in these patients ranges between 1% and 2% annually^{425, 566}. Most of the evidence is indirect, deriving from trials that have assessed the combination of an antiaggregant and anticoagulant treatment, resulting in decreased incidence of thrombotic episodes but also an increased risk of bleeding.

A SR (11 RCTs, 2,428 patients) reported that combining antiaggregant treatment and anticoagulant treatment reduces the risk of thromboembolic episodes by 61% (156 events; OR: 0.39; 95% CI: 0.28 to 0.56) and overall mortality by 45% (173 events; OR: 0.55; 95% CI: 0.40 to 0.77) when compared to anticoagulant treatment alone. Both aspirin at low doses (100 mg) and dipiridamol yield similar results. The risk of major hemorrhagic episodes significantly increased by 66% (151 events; OR: 1.66; 95% CI: 1.18 to 2.34)⁴²⁶.

 

SR of RCT
1++

Summary of evidence

1++

In patients with a mechanical heart valve prosthesis who have an ischemic stroke despite receiving anticoagulant treatment with an INR objective within the recommended range for each type of valve, combined treatment with aspirin at low doses (100 mg) or dipiridamol reduces overall mortality and the risk of thrombotic episodes, even though it also increases the risk of hemorrhagic episodes426.

Recommendations

A	In patients with one or more mechanical prosthetic heart valves who have an ischemic stroke while receiving adequate anticoagulant treatment, it is recommended to add aspirin at low doses (100 mg) or dipiridamol.
√	In patients with contraindications to aspirin, the joint administration of clopidogrel or triflusal and an anticoagulant is a correct strategy.

7.8.3. Other cardiopathies

This guideline does not aim to provide detailed information on the therapeutic management of very specific conditions such as certain cardiopathies that are often found amongst the causes of stroke.

Mitral stenosis

MS due mainly to rheumatic fever is a frequent cause of recurrent systemic embolism. The highest risk corresponds to those patients who have developed atrial fibrillation^{430, 431}.

Observational studies
2+

There are not RCTs that assess the efficacy of anticoagulant treatment to reduce the risk of embolic episode recurrence in patients with MS. Several observational studies have reported reduced incidence of embolic episodes in patients who followed anticoagulant treatment, even though patients with and without prior embolic episodes were combined and in many cases they also had atrial fibrillation^{432, 433, 567, 568}.

Observational studies
2+

When considering antithrombotic treatment, its benefit should always be weighed with the risk of a hemorrhagic stroke. Taking the frequency and permanent sequelae of thromboembolic phenomena into account, the benefits of antithrombotic treatment are superior to the complications derived from hemorrhagic episodes, so in standard practice anticoagulant treatment would be indicated for most patients⁵⁶⁹.

Expert opinions
4

Patients with MS who have developed atrial fibrillation should be considered at high risk of presenting recurrent embolic phenomena. Data extracted from large cohort studies have demonstrated the benefit of anticoagulant treatment in patients with atrial fibrillation and prior thrombotic episodes, even though patients with valvular atrial fibrillation were specifically excluded⁵⁷⁰.

Cohort studies 2++

Mitral valve prolapse

MVP is a common cardiopathy, with a generally benign prognosis, even though the possibility that it may cause recurrent thromboembolic phenomena continues to be a much discussed issue^{440, 442}. The presence of mitral regurgitation (moderate or severe), increased mitral valve thickness (>5mm) or left ventricle size (> 50 mm) measured by echocardiography are associated with a higher risk of vascular mortality and MVP-related complications^{444, 445}. Patients with a thrombus in the left atrium or atrial fibrillation also have a higher risk of recurrent embolic phenomena.

 

Observational studies
2+

There are no randomised studies that compare the efficacy of different antithrombotic treatments in patients with ischemic stroke or TIA who present this type of valvulopathy. The benefits of antithrombotic treatment should be extrapolated from studies on secondary prevention, serving as a basis for the formulation of recommendations.

 

Permeable foramen ovale

The persistence of a permeable foramen ovale is frequent in the general population. In echocardiographic studies it has been reported in 25.6% of the studied population. The septal aneurysm is less frequent and can affect up to 2% of the general population⁵⁷¹. The possibility that the presence of a permeable foramen ovale may cause stroke is a much discussed issue: its importance is increasingly evident, especially in young patients. A SR of case-control studies showed that patients who had had a stroke presented more permeable foramen ovale and septal aneurysm findings (OR: 3.1; 95% CI: 2.3 to 4.2 and OR: 6.1; 95% CI: 2.5 to 15.2 respectively) ⁵⁷². Later, a case-control study determined the presence of atrial septal aneurysm to be an independent risk factor of stroke⁵⁷³.

 

SR of case-
control studies
2++/


Case-control studies
2+

A SR that included three cohort studies (one of them nested in the WARSS randomised study) did not find increased incidence of recurrent strokes or death (OR: 0.95; 95% CI: 0.62 to 1.44) in patients with permeable foramen ovale and with a history of stroke or TIA⁵⁷⁴. In all these studies, participants received antithrombotic treatment with antiaggregants or anticoagulants. There is insufficient data to estimate the risk for septal aneurysms given that patients who presented a permeable foramen ovale with or without septal aneurysm were combined.

SR of cohort studies
2++/2+

In regards to stroke recurrence, results yielded by different studies differ. One cohort study of 581 participants reported an increased risk of stroke recurrence in patients with permeable foramen (3.8% annually) versus patients without this defect (1.1% annually)⁵⁷⁵. In a previous cohort study of 160 participants, patients with or without permeable foramen showed a similar risk of stroke or TIA recurrence and only those patients with a greater degree of interatrial communication presented higher stroke recurrence⁵⁷⁶.

 

Cohort studies
2++/2+

No differences were found between anticoagulant treatment and antiaggregant treatment in terms of stroke recurrence or death in a subgroup of patients of the WARSS trial⁵⁴⁹ who participated in a prospective cohort^577, even though patients treated with anticoagulants presented more mild bleeding complications.

 

Cohort studies
1-

One therapeutic option consists of the percutaneous closure of the interatrial defect. There are no RCTs that compare medical treatment and surgical treatment. One SR (16 case series) that included 895 patients with medical treatment (antithrombotic) and 1,355 patients with surgical treatment showed that the surgical option can decrease the risk of recurrent episodes. The incidence of recurrent strokes or TIAs at one year for antithrombotic treatment varied between 3.8% and 12%, while in the case of surgical procedure it ranged between 0% and 4.9% even though it was associated to a higher incidence of complications⁵⁷⁸.

 

SR of case series 3

 

Summary of evidence

3	Mitral stenosis due to a rheumatic condition is a frequent cause of recurrent ischemic stroke 430-438.
2+/4	In patients with mitral stenosis who have already had a stroke, the benefits of anticoagulant treatment are superior to the risks derived from suffering a hemorrhagic episode 432, 433, 567, 568, 570.
2+	Mitral valve prolapse can cause recurrent ischemic stroke or transient ischemic attack. Certain conditions such as the presence of mitral regurgitation, increased mitral valve thickness or presence of a thrombus in the left atrium or atrial fibrillation comprise a group that is especially at risk 440, 442, 444, 445.
2++	Persistent foramen ovale and the presence of an atrial septal aneurysm have been associated with an increased incidence of stroke, even though the effect on the risk of recurrence is unclear 571-574.
1-	In patients with persistent foramen ovale, the benefits of anticoagulant or antiaggregant treatment are similar 577.
3	One possible therapeutic option is the percutaneous closure of the interatrial defect 578.

Recommendations

B	All patients with atrial fibrillation should be individually assessed in order to establish an adequate benefit-risk balance of anticoagulant treatment.
B	n patients with previous ischemic stroke or transient ischemic attack who present mitral valve prolapse, antiaggregant treatment (100-300 mg/d of aspirin) is recommended.
C	In patients with previous ischemic stroke or transient ischemic attack who present mitral valve prolapse as the only cause, anticoagulant treatment with an INR target range of 2 to 3 should be considered only in cases of high risk of presenting cardioembolic phenomena.
B	In patients with previous ischemic stroke or transient ischemic attack who present permeable foramen ovale, treatment with antiaggregants (100-300 mg/d of aspirin) is recommended
C	In patients with permeable foramen ovale and previous ischemic stroke or transient ischemic attack, treatment with anticoagulants should be considered if there is an increased risk of cardioembolic episodes (atrial septal aneurysm or associated with large interatrial communication).
√	Surgical procedure via percutaneous closure of the permeable foramen ovale should only be considered in the context of a clinical trial and in cases of repeat strokes.

7.9. Symptomatic carotid artery stenosis

Key Questions

In patients with carotid artery stenosis and a history of an episode of ischemic stroke or TIA, does carotid endarterectomy reduce the risk of new episodes compared to endovascular techniques?

What degree of carotid stenosis benefits most from the performance of these interventions?

Does antithrombotic treatment (antiaggregant/anticoagulant) after the intervention provide additional benefits?

7.9.1. Carotid endarterectomy

The main pathology of supraaortic trunks is stenosis or atherosclerotic occlusion of the carotid artery at the bifurcation level. This arteriopathy can evolve without symptoms, but can cause about 30% of ischemic strokes⁴⁴⁸. There are some specific anatomic features of the carotid lesion that play an essential role in the rupture of the plaque and its distant embolisation such as ulceration of the atheromatous plaque or that embolisation causes the formation of a thrombus⁵⁷⁹.

The benefits of CEA in patients with prior ischemic stroke or TIA and different degrees of carotid artery stenosis have been assessed in three big clinical trials: the NASCET⁵⁸⁰, ECST ⁵⁸¹ and the Veterans Affairs Cooperative Study Program (VACSP)⁵⁸².

The NASCET and ECST trials assessed the degree of carotid artery stenosis using imaging techniques and obtained differential results in regards to the percentage of occlusion. Table 16 shows the corresponding values for both proposals.

It is important to note that the performance of these trials and the potential benefits documented for CEA were prior to the appearance and generalised use of treatments that have been proven to reduce the risk of stroke in patients with prior vascular disease, such as the combination of aspirin and dipiridamol, statins and the generalisation of recommendations on the strict monitoring of blood pressure values. At present there is uncertainty regarding the real absolute benefit of CEA in patients with a more intensive medical treatment for vascular disease.

A SR jointly analysed the results of the NASCET and ECST studies (5,950 patients), even though it did not include the results from the VASCP study, which ended prematurely after the NASCET study results came out⁵⁸³. The benefit of CEA was associated with the degree of stenosis, so the intervention resulted in an overall reduction of the risk of disabling stroke and death in patients with moderate or severe stenosis (NASCET >50%; ECST >70%). Net benefit was moderate for patients with moderate stenosis (NASCET 50 to 69%; ECST 70 to 82%), while lesser degrees of stenosis were harmed by CEA. Table 17 presents a summary of the review’s main results. .

 

SR of RCT
1++

A subgroup analysis of this review reported that the greatest benefits of surgery are achieved if the procedure is performed sometime within two weeks and 3 months after a non-disabling ischemic stroke or TIA. The benefit decreases if the procedure is performed more than six months after the acute episode⁵⁸³. Results obtained from later SRs indicate that in these patients there are no data to support delayed surgical procedure ^{584, 585}.

Table 16. Corresponding ECST and NASCET values for assessment of carotid artery stenosis⁵⁸³

ECST	30%	50%	58%	70%	82%	99%	100%
NASCET	-17%	17%	30%	50%	70%	99%	100%

Adapted from: Cina CS, Clase CM, Haynes RB. Carotid endarterectomy for symptomatic carotid stenosis. Cochrane Database of Systematic Reviews. 1999, Issue 3. Art. No.: CD001081

Table 17. Main results of the SR according to degree of stenosis⁵⁸³

% de stenosis		Disabling stroke or death		Disabling stroke or death (30 days)
ECST	NASCET	RRR (IC 95%)*	ARR (IC 95%)**	RR (IC 95%)***	ARR (IC 95%)
82-99	70-99	48% (27 a 63)	6,7% (3,2 a 10)	3,52 (1,11 a 11,13)	2% (1 a 3)
70-81	50-69	27% (5 a 44)	4,7% (0,8 a 8,7)
<70	<50	20% (0 a 44)	2,2% (0 a 4,4)	2,16 (1,36 a 3,44)	1% (1 a 2)

Adapted from: Cina CS, Clase CM, Haynes RB. Carotid endarterectomy for symptomatic carotid stenosis. Cochrane Database of Systematic Reviews. 1999, Issue 3. Art. No.: CD001081.

*RRR (95% CI): Relative risk reduction and its 95% confidence interval.
**ARR (95% CI): Absolute risk reduction and its 95% confidence interval.
***RR (95% CI): Relative risk and its 95% confidence interval.

 

Summary of the Evidence

1++	In patients with a history of ischemic stroke or transient ischemic attack and with a moderate-to-severe degree of carotid artery stenosis (>50% of NASCET values), CEA has been beneficial, especially if performed at an early stage 583.
1++	Treatment with antiaggregants after a CEA results in reduced risk of stroke456
1+	CEA has obtained better results than endovascular procedures in the majority of patients 459-461.

Recommendations

A	Carotid endarterectomy is recommended in patients with ischemic stroke of at least 6 months evolution and significant stenosis of the carotid artery (70% to 99%, NASCET values), if and when the surgical team confirms a perioperative morbimortality of less than 6%.
B	In patients with ischemic stroke of less than 6 months evolution and moderate carotid artery stenosis (50% to 69%, NASCET values), carotid endarterectomy should be considered depending on factors such as sex, age and the presence of other comorbidities.
A	In patients with mild carotid artery stenosis (less than 50%, NASCET values), carotid endarterectomy is not recommended.
B	In patients with ischemic stroke or non-disabling transient ischemic attack and surgical indication, it is recommended to perform the procedure within the first two weeks following the episode.
A	In patients who are not candidates for intervention, treatment with antiaggregants is recommended after carotid endarterectomy, as well as intensive intervention on other vascular risk factors.
B	The use of endovascular techniques with stent implantation is not routinely recommended. Indications should be individualised in patients with high surgical risk if there are technical difficulties for performing carotid endarterectomy or within the context of a clinical trial.

Note:

Note: The information regarding the safety of CEA, antiaggregant treatment after the procedure and endovascular treatment do not differ from what has been presented in the section on asymptomatic carotid artery stenosis. The evidence presented in the aforementioned section should be used for the synthesis of the evidence and the elaboration of the following recommendations.

7.10. Antithrombotic treatment in the secondary prevention of stroke

Key Questions:

In patients with a history of an episode of non-cardioembolic ischemic stroke or TIA, does antiaggregant treatment reduce the risk of new episodes?

Does the combination of two antiaggregant treatments provide an additional benefit versus treatment with only one antiaggregant?

Has anticoagulant treatment been proven to be superior to antiaggregant treatment?

7.10.1. Antiaggregant treatment

Antiaggregants have proven to reduce the risk of vascular episodes such as myocardial infarction, stroke or vascular death in patients with high vascular risk in a SR (287 RCTs). Specifically, in patients with a history of ischemic stroke or TIA, antiaggregants showed a 25% reduction for new episodes of stroke and a 20% increase for hemorrhagic strokes. Absolute difference favoured antiaggregant treatment, with a subsequent 2.7% reduction of any stroke. Absolute reduction of vascular episodes was 3.6% (Table 18). Most evidence was for the use of aspirin. 75 mg to 150 mg per day aspirin doses were as effective as higher doses and presented fewer adverse effects, even though the risk of severe bleeding was similar. The review concludes that there is insufficient evidence to determine that any other antiaggregant treatment is superior to aspirin, even though most studies were small⁴⁰³.

SR of RCT
1++

The direct comparison of clopidogrel and aspirin was carried out in the CAPRIE trial, which included over 19,000 patients. In this RCT clopidogrel (75 mg/d) reduced the risk for a combined variable comprised of ischemic stroke, myocardial infarction and vascular death versus aspirin (325 mg/d) in a population with prior vascular disease. The absolute difference of risk was 0.5% annually. There were no differences between both treatments in the subgroup of patients with a history of stroke and the differences were mainly due to patients with peripheral arteriopathy. The incidence of adverse effects was similar, while gastrointestinal tolerance could be better for clopidogrel⁵⁸⁶.

RCT
1++

Tioclipidin is an active ingredient structurally similar to clopidogrel which has not been proven superior to aspirin and presents frequent adverse effects such as diarrhea (12%), skin rash or, less frequently, neutropenia (2%, severe neutropenia <1%)^{403, 587, 588}.

RCT
1+

Two RCTs specifically assessed the efficacy of triflusal in the secondary prevention of stroke ^{589, 590}. The TACIP trial, which included 2,113 patients with prior ischemic stroke or TIA, did not show differences for a combined variable comprised of vascular episodes (including stroke) between triflusal (600 mg/d) and aspirin (325 mg/d). Results for non-fatal strokes were also similar. The overall incidence of hemorrhagic episodes was significantly higher for aspirin (25.2% versus 16.7%)⁵⁸⁹. Additionally, results of a previous trial (TAPIRSS) were similar⁵⁹⁰. A recent SR (4 RCTs, 2,994 patients) did not show differences between treatment with triflusal and aspirin (>300 mg/d) for the secondary prevention of vascular episodes, including stroke and TIA (596 events). In patients with prior ischemic stroke or TIA, triflusal was superior to aspirin in reducing recurrence of fatal episodes (253 events). The risk of hemorrhagic episodes, including severe ones, was lower for triflusal, with a 1.7% absolute reduction⁵⁹¹.

ECA
1++

RS de ECA
1+

The benefit of introducing aspirin treatment (160 to 300 mg/d) is produced immediately (within the first 48 hours) after the clinical suspicion of ischemic stroke, according to the joint analysis of two big RCTs in which 40,000 patients participated. The relative reduction of recurrent strokes was 30%. 1.5% of patients treated with aspirin and 2.3% of the control group had a recurrent ischemic stroke (777 events), which corresponds to a 0.7% absolute reduction. In contrast, the risk of having hemorrhagic strokes or hemorrhagic transformation of the stroke was 1% and 0.8% for aspirin and the control group, respectively. With all this, aspirin reduced the risk of having any type of stroke or death in the hospital in 9 out of every 1,000 patients. It should be noted that in most patients hemorrhagic stroke was ruled out by means of neuroimaging before continuing treatment. Benefits were observed within the first four weeks, which was the maximum duration of the studies included⁵⁹².

RCT
1+

Combinations

The strategy of adding an antiaggregant that acts on platelet aggregation via a different route could yield an additional benefit. Two SRs have assessed the combination of aspirin at different doses and dipiridamol in patients with a history of vascular disorders. The most recent SR (6 RCTs and 7,648 patients) only included secondary prevention studies. The dose of aspirin (30-1,300 mg/d) and dipiridamol (150-400 mg/d) varied, as well as the immediate- or sustained-release pharmaceutical presentation. The combination of aspirin and dipiridamol, when compared to aspirin, reduces the risk of a new episode of non-fatal stroke by 23% (675 events; RR: 0.77; 95% CI: 0.67 to 0.89). Only the studies that used sustained release dipiridamol (2 RCTs) were associated with a significant benefit for the prevention of new strokes (549 events) or other vascular episodes (934 events) ⁵⁹³.

SR of RCT
1++

Another SR, without the results of the ESPRIT study, determined that the combination of dipiridamol and aspirin significantly reduces 10% of vascular episodes in a combined variable⁵⁹⁴.

SR of RCT
1++

The ESPRIT study demonstrated that treatment with sustained release dipiridamol (400 mg/d) and aspirin, compared to aspirin alone, reduced a variable comprised of vascular-related death, stroke or non-fatal myocardial infarction and major hemorrhagic episode by 20% (389 events; HR 0.80; 95% CI: 0.66 to 0.98) in patients with a presumably arterial ischemic stroke or TIA. Headache was a frequent cause (26%) of dipiridamol treatment discontinuation⁵⁹⁵. Additionally, the ESPRIT trial compared the efficacy of anticoagulant treatment (2 to 3 INR) versus aspirin (30-325 mg/d) in 1,068 patients with a history of ischemic stroke or TIA. The trial ended early after results confirmed the efficacy of combined dipiridamol and aspirin. Anticoagulant treatment was not superior to aspirin at reducing the risk of vascular episodes or at the secondary prevention of new episodes of ischemic stroke and was associated with a higher risk of severe bleeding⁵⁹⁶.

RCT
1+

The combination of aspirin and clopidogrel was assessed in two big studies (CHARISMA and MATCH) in high vascular risk patients or patients with established vascular disease^{597, 598}. Combined treatment was not more effective than aspirin or clopidogrel monotherapy and was associated with an increased risk of severe bleeding. Only one fourth of patients had a history of stroke. A later analysis of the CHARISMA study indicated a reduction of the variable comprised of vascular death, myocardial infarction and stroke in patients with an established vascular disease (763 events; HR 0.83; 95% CI: 0.72 to 0.96)⁵⁹⁹.

RCT
1++

The efficacy and safety of long-term clopidogrel treatment compared to the combination of aspirin and dipiridamol is being assessed in the ProFESS trial (Prevention Regimen for Effectively Avoiding Second Strokes Trial)⁶⁰⁰.

Bleeding risk

A case-control study analysed the risk of digestive bleeding for different antiaggregants. Aspirin and ticlopidin increased the risk of bleeding (OR: 4.0; 95% CI: 3.2 to 4.9 and OR: 3.1; 95% CI: 1.8 and 5.1 respectively), while clopidogrel, dipiridamol and triflusal did not show this association⁴⁶⁸.

Case-control studies
2++

7.10.2. Anticoagulant treatment

A SR (5 RCTs, 4,076 patients) that compared the efficacy of anticoagulant treatment, at different intensities, to antiaggregation in patients with a history of non-cardioembolic stroke, did not report differences in the risk of presenting a new episode. No differences were found between anticoagulants (INR up to 2.6) and antiaggregants in terms of deaths due to vascular causes or overall mortality. However, intense anticoagulant treatment (3 to 4.5 INR) was associated with a significant increase of overall mortality and severe bleeding episodes (RR: 9.0; 95% CI: 3.9 to 2.1)⁶⁰¹.

SR of RCT
1++

Table 18. Estimators of relative and absolute risk of antiaggregants versus control in the prevention of vascular episodes in patients with high vascular risk⁴⁰³

	Relative effect (number of events)	Absolute effect
Overall vascular episodes	-22 % (17.207 eventos)	-2,5%
Vascular episodes in patients with prior stroke/TIA	-22% (4.509 eventos)	-3,6%
Ischemic strokes in patients with prior stroke/TIA	-25% (1.780 eventos)	-2,4%
Hemorrhagic strokes in patients with prior stroke/TIA	+20% (115 eventos)	+0,08%
Any stroke in patients with prior stroke/TIA	-23% (2.807 eventos)	-2,7%

Adapted from: Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71-86.

Summary of the Evidence

1++	In patients with high vascular risk, antiaggregants (aspirin, clopidogrel and triflusal) reduce the risk of vascular episodes such as stroke, myocardial infarction and vascular death403.
1+	The combination of aspirin and sustained release dipiridamol results in increased efficacy versus aspirin monotherapy for the prevention of recurrent stroke or other vascular episodes 593.
1++	The combination of aspirin and clopidogrel is not more effective than monotherapy for the prevention of recurrent stroke and is associated with increased severe bleeding 586.
1++	Antiaggregant treatment with triflusal has similar efficacy to aspirin for the secondary prevention of vascular episodes, with fewer bleeding adverse effects 589, 590.
1+	Aspirin treatment within the first 48 hours of determining the clinical suspicion of ischemic stroke has been beneficial 592.
1++	Anticoagulant treatment is not more effective than antiaggregants at reducing the recurrence of non-cardioembolic stroke and is associated with an increased risk of bleeding episodes 601.

Recommendations

A	In patients with non-cardioembolic ischemic stroke or transient ischemic attack, platelet antiaggregation with aspirin (100-300 mg/d), combination of aspirin and sustained release dipiridamol (50 and 400 mg/d), triflusal (600 mg/d) or clopidogrel (75 mg/d) are recommended.
A	Long term use of combined aspirin and clopidogrel is not recommended due to the increased risk of bleeding complications.
A	In patients with ischemic stroke or transient ischemic attack, the systematic use of anticoagulant treatment to prevent recurrent strokes is not recommended.
A	It is recommended to initiate treatment with aspirin within the first 48 hours of the clinical suspicion of ischemic stroke and after ruling out hemorrhagic stroke.
√	In the case of presenting recurrent strokes despite adequate antiaggregant treatment, underlying causes should be carefully reviewed and the management of risk factors prioritised.

7.11. Cerebral venous thrombosis

Key Questions:

In patients with cerebral venous thrombosis, does anticoagulant treatment reduce the risk of new episodes?

What is the optimal duration of anticoagulant treatment?

Cerebral venous thrombosis is an uncommon cause of stroke. Its incidence in adults is unclear, given that there are no population-based epidemiological studies that address this issue. Its most frequent presentation is in young adults, especially women in a ratio of 3 men per each 10 affected women⁶⁰². In children, incidence is estimated to be between 6 and 7 cases per one million, half of them newborns⁶⁰³. Diagnosis is often difficult to make or delayed due to the wide spectrum of clinical signs and symptoms that include headache, focal neurologic deficits, convulsions, mental status disorders, intracranial hypertension or papiledema, amongst others. Although the main diagnosis is based on neuroimaging, often it shows non-specific lesions⁶⁰⁴.

Observational studies
2+

There are several factors that have been associated with a greater incidence of cerebral venous thrombosis, such as certain congenital or acquired thrombofilias (congenital mutations of the coagulation factor V Leiden), pregnancy and the postnatal period, use of oral contraceptives and certain infections in areas close to the brain sinuses, even though in the majority of cases is has a multifactorial etiology and it is possible to identify more than one factor³⁰⁶.

Observational studies
2+

The objective of the initial treatment is to achieve recanalization of the sinus or thrombosed vein and also to prevent recurrence or future episodes of thrombosis in other territories. Treatment with anticoagulants is also controversial because cerebral venous thrombosis can spontaneously result in hemorrhagic stroke⁶⁰⁵. Three RCTs have been located that assess non-fractioned and low molecular weight heparin treatment after the diagnosis of cerebral venous and sinus thrombosis^606-608. One SR showed the combined results of two of them for a total of 79 patients⁶⁰⁹. There were no differences between heparin treatment and placebo in terms of death or dependence at three months, even though the number of events was very limited. Seven deaths were reported in the group that received placebo and two in the active treatment group. Neither study properly assessed new thromboembolism cases. In spite of this, two probable cases were reported, both in the control group.

RCT
1++/1+

No randomised studies that assess the efficacy of oral anticoagulant treatment have been identified, while two SRs of observational studies did not yield conclusive evidence for the use of thrombolysis^{610, 611}.

SR of observational studies
2+

The ISCVT observational study showed the results in 624 patients with cerebral vein and sinus thrombosis with a 16-month follow-up. 2.2% of patients had a new episode of cerebral vein thrombosis, while 4.3% of patients had another type of thromboembolic episode. More than half the patients with new episodes did not follow anticoagulant treatment. Mean duration of anticoagulant treatment was 7.7 months. This study proposed mental status disorder (a certain degree of coma) and the presence of thrombosis in other deep vein territories as poor prognostic factors⁶⁰⁵.

Cohort studies
2+

The optimal duration of anticoagulant treatment is unknown. In patients older than 65 years, the probability of thrombotic episodes is greater, worsening prognosis ⁶¹².

Other guidelines have addressed diagnosis and treatment of patients with cerebral vein and sinus thrombosis is detail ⁶¹³.

Summary of the Evidence

2+	Cerebral venous thrombosis may occasionally cause recurrent ischemic and hemorrhagic strokes 602-604.
1++/1+	Anticoagulant treatment, first with heparin and later with oral anticoagulants, seems beneficial, but the evidence is very limited 606-608.

Recommendations

D	In patients who have had cerebral venous thrombosis, initial treatment with heparin and later with oral anticoagulants over a period of three to six months is recommended
D	In patients with congenital or acquired thrombofilias and in patients over the age of 65 or with other factors that favour thrombotic phenomena, treatment with oral anticoagulants up to twelve months is recommended.

7.12. Antithrombotic treatment after intracerebral hemorrhage

Key Questions:

What therapeutic approach should be adopted in a patient who presents intracerebral hemorrhage during treatment with antithrombotics?

The use of antithrombotics (antiaggregants or anticoagulants) in patients who have had an ICH is a complex clinical situation. Most of the evidence has been extracted from case series of patients who were receiving anticoagulant treatment due to a mechanical heart valve prosthesis or for the treatment of atrial fibrillation and had an ICH during this time. The detailed management of this situation has been addressed in other CPGs²³⁷.

Anticoagulant treatment, still within a 3 to 2 INR therapeutic target range, entails a two-fold increased risk of presenting ICH. The incidence of this complication is estimated to be approximately 0.3% annually^{365, 614}. Similarly, treatment with antiaggregants can increase the risk of ICH up to 80%615. Table 19 shows the incidences of ICH in different clinical conditions⁶¹⁶.

RCT
SR of RCT
1++

There are situations in which the risk of presenting ICH during treatment with anticoagulants increases, such as elderly age (generally >75 years), high blood pressure (SBP >160 mmHg), prior strokes or anticoagulation intensity^617-619.

Observational studies
2++/2+

7.12.1. Use of anticoagulants

Although there is no data on the efficacy and safety of interrupting anticoagulant treatment, in standard clinical practice, in a patient with ICH or SAH, anticoagulant treatment is interrupted with the aim of normalising INR values as soon as possible, aside from initiating treatment with heparin inhibitors or vitamin K²³⁷.

Expert opinions
4

Several case series have described the clinical evolution after stopping anticoagulant treatment. The risk of having an ischemic stroke or other embolic episode during the period of anticoagulant treatment discontinuation (between 10 and 20 days) is, in theory, relatively low. Hence, in a case series with 28 patients who had mechanical heart valve prostheses, no embolic episodes were reported after a period of two weeks without anticoagulant treatment⁶²⁰. In another case series of 141 patients with ICH, the risk of presenting an ischemic stroke depended on the indication of anticoagulation. In patients with a heart valve prosthesis, risk was 2.9% and, finally, 4.8% in patients with a history of ischemic stroke or TIA ⁶²¹.

Case series
3

A decision analysis assessed the approach that should be adopted after ICH in patients who presented indication for anticoagulant treatment, specifically atrial fibrillation. The study concludes that anticoagulant treatment cannot be recommended after an ICH unless there is a risk of ischemic stroke higher than 6.5% in one year. Aspirin is preferable in cases in which the risk of ischemic stroke is lower than 6.5% annually⁶²². Results would be applicable in those cases in which ICH has been caused by a prior anticoagulant treatment as well as other causes.

Observational studies
2+

7.12.2. Use of antiaggregants

A SR (9 RCTs, 2,043 patients) that assessed the safety of antiaggregant treatment after suffering ICH or SAH demonstrated that antiaggregant treatment does not increase the risk of a new episode. However, the study presents certain limitations. In the trials included to estimate the risk of recurrence of a SAH, patients underwent mostly surgical treatment of an aneurysm. Additionally, the fact that antiaggregant treatment was interrupted in half of the patients after diagnosis of ICH should be taken into⁶²³.

SR of RCT
1-

7.12.3. Use of low molecular weight heparins

Deep venous thrombosis and pulmonary embolisms are a cause of morbimortality in patients who have had an ICH. To avoid this complication, one of the therapeutic options available is low molecular weight heparins, but the risk of bleeding should be acknowledged. A RCT performed in a limited number of patients showed that the introduction of low molecular weight heparins after the first two days of an ICH significantly reduced thrombotic complication versus a later administration. Re-bleeding did not increase in either group⁶²⁴.

RCT
1-

Table 19. ICH absolute risks ⁶¹⁶

General population (mean age: 70 years)	0,15%/year
Aspirin (any dose)
Atrial fibrillation	0,2%/year
Cerebrovascular disease	0,3%/year
Aspirin plus clopidogrel
Atrial fibrillation	0,3%/year
Cerebrovascular disease	0,4%/year
Anticoagulation (INR 2.5)
Atrial fibrillation	0,3%-0,6%/year
Cerebrovascular disease	0,4%-1,0%/year
Anticoagulation (INR 2.5) plus aspirin	0,5%-1,0%/year

Adapted from: Hart RG, Tonarelli SB, Pearce LA. Avoiding central nervous system bleeding during antithrombotic therapy: recent data and ideas. Stroke. 2005;36:1588-93.

Summary of the Evidence

2+	The risk of presenting intracerebral hemorrhaging during anticoagulant treatment is superior in certain clinical situations such as elderly age, high blood pressure, prior stroke or anticoagulation intensity 617- 619.
2+	The risk of initiating anticoagulant treatment after intracerebral hemorrhaging outweighs, overall, the benefit in patients who do not present a very high risk of embolic ischemic episodes 620-622.
4	The decision to initiate or resume anticoagulant treatment should be individualised acknowledging the risk of a new intracerebral hemorrhage 237.

Recomendaciones

B	Generalised introduction of anticoagulant or antiaggregant treatment is not recommended after an intracerebral hemorrhage.
√	In patients who require anticoagulant treatment due to a previous condition, restoration of treatment should be individually assessed.
C	Anticoagulant treatment should be considered seven to ten days after an intracerebral hemorrhage only in patients with very high risk (>6.5% annually) of presenting ischemic stroke.
C	Treatment with low molecular weight heparins should be considered two days after intracerebral hemorrhage with the aim of reducing the risk of deep venous thrombosis or pulmonary embolism.
C	In patients who, after intracerebral hemorrhage, present indication for antithrombotic treatment and in those for whom anticoagulant treatment is not advisable, treatment with antiaggregants is an alternative.

 

 

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Figuras y Tablas

Table 15. Risk of stroke within 2, 7 and 90 days after a TIA (ABCD2 risk table) (pdf, 21 Kb)

Table 16. Corresponding ECST and NASCET values for assessment of carotid artery stenosis (pdf, 24 Kb)

Table 17. Main results of the SR according to degree of stenosis (pdf, 26 Kb)

Table 18. Estimators of relative and absolute risk of antiaggregants versus control in the prevention of vascular episodes in patients with high vascular risk (pdf, 26 Kb)

Table 19. ICH absolute risks (pdf, 20 Kb)