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.................................................................................................................... 6.3. Cerebrovascular diseases Interventions for cerebrovascular diseases depend on the type of event, i.e. ischaemic or haemorrhagic.732,733 Ischaemic events are mainly caused by atherothrombosis, cardiac embolism, or small vessel disease.734 Other mechanisms (e.g. arterial dissection, patent foramen ovale, thrombophilia, inherited diseases) are relatively rare. Intracerebral haemorrhage is mostly caused by hypertensive angiopathy and/or cerebral amyloid angiopathy.735 Bleeding can be precipitated by surges in BP values, use of anticoagulants, or diseases impairing coagulation.733,735

In patients with ischaemic stroke or TIA, antithrombotics prevent further vascular events. Cardioembolic ischaemia, which occurs mainly in AF, requires anticoagulation (see sections 3.4.3 and 6.6).736742 In non-cardioembolic mechanism, platelet inhibitors are recommended.619,620,743753 In non-cardioembolic ischaemic stroke, aspirin is the most studied antithrombotic drug. Aspirin 75150 mg/day reduces the risk of recurrent ischaemic stroke and serious vascular events.619,743 Clopidogrel shows slight superiority to aspirin.620 In patients with ischaemic stroke or TIA and ipsilateral carotid stenosis, ticagrelor added to aspirin compared to aspirin alone reduced the risk of stroke or death at 1 month, without an increase of severe bleeding.754 Adding aspirin to clopidogrel was associated with a non-significant reduction in major vascular events and an increased long-term bleeding risk.747749 However, in patients with minor ischaemic stroke or TIA, a short course of DAPT with aspirin and clopidogrel is beneficial.750,751 Similarly, ticagrelor and aspirin vs. aspirin alone reduces stroke or death at 30 days after mild-to-moderate ischaemic stroke or TIA not treated with thrombolysis or thrombectomy. However, DAPT with ticagrelor and aspirin did not improve the incidence of disability and contributed to severe bleeding.755 DAPT with dipyridamole plus aspirin also showed superiority over aspirin alone.744 In patients with ischaemic stroke, however, dipyridamole plus aspirin vs. clopidogrel alone showed similar rates of recurrent stroke, including haemorrhagic stroke,745 but more major haemorrhagic events. In patients with noncardioembolic ischaemic stroke, oral vitamin K antagonists are not superior to aspirin and carry a higher bleeding risk.752,753 In the absence of a definite cause of ischaemia and a presumed occult cardioembolic

An MRA is recommended for patients with HFrEF already treated with an ACE inhibitor (or an ARNI) and a beta-blocker, to reduce the risk of HF hospitalization and death.718,719 I A Sacubitril/valsartan is recommended as a replacement for an ACE inhibitor to reduce the risk of HF hospitalization and death in patients with HFrEF.707,730 I B An ARB is recommended to reduce the risk of HF hospitalization or CV death in symptomatic patients with HFrEF who are unable to tolerate an ACE inhibitor and/or ARNI (patients should also receive a beta-blocker and an MRA).706 I B Dapagliflozin or empagliflozin are recommended, in addition to optimal treatment of an ACE inhibitor (or ARNI), a beta-blocker, and an MRA, for patients with HFrEF to reduce the risk of HF hospitalization and death.600,601,730 I A Vericiguat may be considered in patients with symptomatic HFrEF who have experienced HF worsening despite treatment with an ACE inhibitor (or an ARNI), a beta-blocker, and an MRA, to reduce the risk of HF hospitalization or CV death.722 IIb B Diuretics are recommended in patients with HFrEF with signs and/or symptoms of congestion to reduce the risk of HF hospitalization.723,724 I C Ivabradine should be considered in symptomatic patients with LVEF <_35%, in sinus rhythm, and with a resting heart rate >_70 bpm despite treatment with an evidence-based dose of a beta-blocker (or maximum tolerated dose below that), an ACE inhibitor (or an ARNI), and an MRA, to reduce the risk of HF hospitalization or CV death.725 IIa B Ivabradine should be considered in symptomatic patients with LVEF <_35%, in sinus rhythm, and with a resting heart rate >_70 b.p.m. who are unable to tolerate or have contraindications for a beta-blocker to reduce the risk of HF hospitalization or CV death. Patients should also receive an ACE inhibitor (or ARNI) and an MRA.726 IIa C Hydralazine and isosorbide dinitrate should be considered in self-identified black patients with LVEF <_35% or with LVEF <45% combined with a dilated LV in NYHA class IIIIV despite treatment with an ACE inhibitor (or ARNI), a betablocker, and an MRA, to reduce the risk of HF hospitalization and death.731 IIa B Hydralazine and isosorbide dinitrate may be considered in patients with symptomatic HFrEF who cannot tolerate ACE inhibitors, ARBs, or ARNIs (or if they are contraindicated), to reduce the risk of death.728 IIb B

Continued Digoxin may be considered in patients with

symptomatic HFrEF in sinus rhythm despite treatment with an ACE inhibitor (or ARNI), a beta-blocker, and an MRA, to reduce the risk of hospitalizations (all-cause and HF).729 IIb B

ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor neprilysin inhibitor; b.p.m. = beats per minute; CR = cardiac rehabilitation; CV = cardiovascular; EBCR = exercise-based cardiac rehabilitation; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; LV = left ventricle; LVEF = left ventricular ejection fraction; MRA = mineralocorticoid receptor antagonist; NYHA = New York Heart Association. aClass of recommendation. bLevel of evidence. cApplies to all patients with HF, regardless of LVEF. For implantable cardioverter-defibrillator and cardiac resynchronization recommendations, see 690

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