Incidence, outcome, risk factors, and long-term prognosis of cryptogenic transient ischaemic attack and ischaemic stroke: a population-based study

Abstract

Background: A third of transient ischaemic attacks (TIAs) and ischaemic strokes are of undetermined cause (ie, cryptogenic), potentially undermining secondary prevention. If these events are due to occult atheroma, the risk-factor profile and coronary prognosis should resemble that of overt large artery events. If they have a cardioembolic cause, the risk of future cardioembolic events should be increased. We aimed to assess the burden, outcome, risk factors, and long-term prognosis of cryptogenic TIA and stroke.

Methods: In a population-based study in Oxfordshire, UK, among patients with a first TIA or ischaemic stroke from April 1, 2002, to March 31, 2014, we compared cryptogenic events versus other causative subtypes according to the TOAST classification. We compared markers of atherosclerosis (ie, risk factors, coronary and peripheral arterial disease, asymptomatic carotid stenosis, and 10-year risk of acute coronary events) and of cardioembolism (ie, risk of cardioembolic stroke, systemic emboli, and new atrial fibrillation [AF] during follow-up, and minor-risk echocardiographic abnormalities and subclinical paroxysmal AF at baseline in patients with index events between 2010 and 2014).

Findings: Among 2555 patients, 812 (32%) had cryptogenic events (incidence of cryptogenic stroke 0·36 per 1000 population per year, 95% CI 0·23-0·49). Death or dependency at 6 months was similar after cryptogenic stroke compared with non-cardioembolic stroke (23% vs 27% for large artery and small vessel subtypes combined; p=0·26) as was the 10-year risk of recurrence (32% vs 27%; p=0·91). However, the cryptogenic group had fewer atherosclerotic risk factors than the large artery disease (p<0·0001), small vessel disease (p=0·001), and cardioembolic (p=0·008) groups. Compared with patients with large artery events, those with cryptogenic events had less hypertension (adjusted odds ratio [OR] 0·41, 95% CI 0·30-0·56; p<0·0001), diabetes (0·62, 0·43-0·90; p=0·01), peripheral vascular disease (0·27, 0·17-0·45; p<0·0001), hypercholesterolaemia (0·53, 0·40-0·70; p<0·0001), and history of smoking (0·68, 0·51-0·92; p=0·01), and compared with small vessel and cardioembolic subtypes, they had no excess risk of asymptomatic carotid disease (adjusted OR 0·64, 95% CI 0·37-1·11; p=0·11) or acute coronary events (adjusted hazard ratio [HR] 0·76, 95% CI 0·49-1·18; p=0·22) during follow-up. Compared with large artery and small vessel subtypes combined, patients with cryptogenic events also had no excess of minor-risk echocardiographic abnormalities (cryptogenic 37% vs 45%; p=0·18) or paroxysmal AF (6% vs 10%; p=0·17) at baseline or of new AF (adjusted HR 1·23, 0·78-1·95; p=0·37) or presumed cardioembolic events (1·16, 0·62-2·17; p=0·64) during follow-up.

Interpretation: The clinical burden of cryptogenic TIA and stroke is substantial. Although stroke recurrence rates are comparable with other subtypes, cryptogenic events have the fewest atherosclerotic markers and no excess of cardioembolic markers.

Funding: Wellcome Trust, Wolfson Foundation, UK Stroke Association, British Heart Foundation, Dunhill Medical Trust, National Institute for Health Research, Medical Research Council, and the NIHR Oxford Biomedical Research Centre.

Figure 1

Number of atherosclerotic risk factors and frequency of comorbid atherosclerotic disease in different transient ischaemic attack and ischaemic stroke subtypes Frequencies of risk factors and comorbid disease are shown (A) overall and for (B) females and (C) males. Data on smoking status were missing in four patients with cardioembolic events and two patients with cryptogenic events. Risk factors were male sex, hypertension, diabetes, hypercholesterolaemia, and history of smoking. Male sex was not taken into account in the stratification analysis by sex (ie, B and C). p values are for heterogeneity among all subtypes using the χ² test. ESUS=embolic strokes of undetermined source. LAD=large artery disease. PVD=peripheral vascular disease. SVD=small vessel disease. *Asymptomatic carotid stenosis ≥50% at bifurcation.

Figure 2

Severity of stenosis at the asymptomatic carotid bifurcation in different transient ischaemic attack and ischaemic stroke subtypes Carotid events were calculated as carotid stenosis (%) at the asymptomatic side; posterior circulation events were calculated as mean carotid stenosis (%) of both carotid arteries at the bifurcation. p values are for the difference of stenosis distribution between cryptogenic and other subtypes.

Figure 3

10-year absolute risks of acute coronary events, cardioembolic events, and recurrent ischaemic stroke TIA=transient ischaemic attack. *Consisted of recurrent cardioembolic stroke, acute embolic limb ischaemia, and acute embolic visceral embolisation caused by presumed cardioembolism.