Robert G. Hart

Cardiovascular disease in chronic kidney disease. A clinical update from Kidney Disease: Improving Global Outcomes (KDIGO)

Cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD) is high, and the presence of CKD worsens outcomes of cardiovascular disease (CVD). CKD is associated with specific risk factors. Emerging evidence indicates that the pathology and manifestation of CVD differ in the presence of CKD. During a clinical update conference convened by the Kidney Disease: Improving Global Outcomes (KDIGO), an international group of experts defined the current state of knowledge and the implications for patient care in important topic areas, including coronary artery disease and myocardial infarction, congestive heart failure, cerebrovascular disease, atrial fibrillation, peripheral arterial disease, and sudden cardiac death. Although optimal strategies for prevention, diagnosis, and management of these complications likely should be modified in the presence of CKD, the evidence base for decision making is limited. Trials targeting CVD in patients with CKD have a large potential to improve outcomes.

Embolic strokes of undetermined source: the case for a new clinical construct

Cryptogenic (of unknown cause) ischaemic strokes are now thought to comprise about 25% of all ischaemic strokes. Advances in imaging techniques and improved understanding of stroke pathophysiology have prompted a reassessment of cryptogenic stroke. There is persuasive evidence that most cryptogenic strokes are thromboembolic. The thrombus is thought to originate from any of several well established potential embolic sources, including minor-risk or covert cardiac sources, veins via paradoxical embolism, and non-occlusive atherosclerotic plaques in the aortic arch, cervical, or cerebral arteries. Accordingly, we propose that embolic strokes of undetermined source are a therapeutically relevant entity, which are defined as a non-lacunar brain infarct without proximal arterial stenosis or cardioembolic sources, with a clear indication for anticoagulation. Because emboli consist mainly of thrombus, anticoagulants are likely to reduce recurrent brain ischaemia more effectively than are antiplatelet drugs. Randomised trials testing direct-acting oral anticoagulants for secondary prevention of embolic strokes of undetermined source are warranted.

Cardioembolic vs. Noncardioembolic Strokes in Atrial Fibrillation: Frequency and Effect of Antithrombotic Agents in the Stroke Prevention in Atrial Fibrillation Studies

Background: While atrial fibrillation (AF) increases the risk of cardioembolic stroke, some ischemic strokes in AF patients are noncardioembolic. Objectives: To assess ischemic stroke mechanisms in AF and to compare their responses to antithrombotic therapies. Methods: On-therapy analyses of ischemic strokes occurring in 3,950 participants in the Stroke Prevention in Atrial Fibrillation I–III clinical trials. Strokes were classified by presumed mechanism according to specified neurologic features by neurologists unaware of antithrombotic therapy. Results: Of 217 ischemic strokes, 52% were classified as probably cardioembolic, 24% as noncardioembolic, and 24% as of uncertain cause (i.e., 68% of classifiable infarcts were deemed cardioembolic). Compared to those receiving placebo or no antithrombotic therapy, the proportion of cardioembolic stroke was lower in patients taking adjusted-dose warfarin (p = 0.02), while the proportion of noncardioembolic stroke was lower in those taking aspirin (p = 0.06). Most (56%) ischemic strokes occurring in AF patients taking adjusted-dose warfarin were noncardioembolic vs. 16% of strokes in those taking aspirin. Adjusted-dose warfarin reduced cardioembolic strokes by 83% (p < 0.001) relative to aspirin. Cardioembolic strokes were particularly disabling (p = 0.05). Conclusions: Most ischemic strokes in AF patients are probably cardioembolic, and these are sharply reduced by adjusted-dose warfarin. Aspirin in AF patients appears to primarily reduce noncardioembolic strokes. AF patients at highest risk for stroke have the highest rates of cardioembolic stroke and have the greatest reduction in stroke by warfarin.

Neurologic complications of infective endocarditis

Neurologic syndromes often complicate the management of infective endocarditis (IE). We retrospectively reviewed 166 episodes of native valve endocarditis to assess the occurrence and implications of nonfocal encephalopathy, meningitis, salient headache, back pain, and brain abscess. Neurologic complications occurred in 35% (58/166) of patients: 41% (54/133) of mitral or aortic valve IE and 12% (4/33) of tricuspid valve IE. Of 133 cases of mitral or aortic valve IE, encephalopathy occurred in 14%, meningitis in 5%, and salient headache in 3%. All neurologic complications occurred more often with Staphylococcus aureus infection (67%) than with viridans streptococci (22%), including encephalopathy (22% versus 7%), meningitis (17% versus 0%), stroke (39% versus 16%), and death (39% versus 9%). Encephalopathy was associated with virulent organisms, increased patient age, and uncontrolled infection. Clinical, radiologic, and neuropathologic data all suggest that infective microemboli are often etiologic in IE-related encephalopathy. There were no macroscopic brain abscesses clinically identified. Meningitis occurred only with virulent organisms. While many clinical aspects of IE have changed in recent years, the frequency and gravity of neurologic complications have not.

Prevention of stroke in patients with nonvalvular atrial fibrillation

Objective: To review the risk and pathogenesis of stroke associated with nonvalvular atrial fibrillation (AF) and the efficacies and risks of stroke prevention strategies. Background: About 16% of ischemic strokes are associated with AF; AF is an independent risk factor for stroke. Methods: Review of the literature, focusing on 13 randomized trials of antithrombotic therapy. Results: The overall risk of stroke in AF patients averages about 5%/y, but with wide variation depending on the presence of coexistent thromboembolic risk factors. AF patients with low (about 1% per year), moderate (about 3% per year), and high (about 6% per year) stroke risks have been identified, but the generalizability of risk stratification schemes to clinical practice has not been fully assessed. AF patients with prior stroke or transient ischemic attack, even if remote, are at highest risk (about 12% per year). Adjusted-dose warfarin (target International Normalized Ratio [INR] 2-3) is highly efficacious for preventing stroke in AF patients (about 70% risk reduction) and is safe for selected patients, if carefully monitored. Aspirin has a modest effect on reducing stroke (about 20% risk reduction). The numbers of AF patients that would need to be treated with warfarin instead of aspirin for 1 year to prevent one ischemic stroke are about 200, 70, and 20 for those with low, moderate and high risk, respectively. Conclusions: Many patients with nonvalvular AF have substantial rates of ischemic stroke. Stratification of stroke risk identifies AF patients who benefit most and least from lifelong anticoagulation. Warfarin is recommended for high-risk AF patients who can safely receive it. Aspirin may be indicated for those with a low stroke risk and for those who cannot receive warfarin. For AF patients considered to have a moderate risk of stroke, individual bleeding risk during anticoagulation and patient preference should particularly influence the choice of antithrombotic prophylaxis.

The CHA2DS2-VASc score identifies those patients with atrial fibrillation and a CHADS2 score of 1 who are unlikely to benefit from oral anticoagulant therapy

AIMS The CHA(2)DS(2)-VASc score is a modification of the CHADS(2) score that aims to improve stroke risk prediction in patients with atrial fibrillation (AF) by adding three risk factors: age 65-74, female sex, and history of vascular disease. Whereas previous evaluations of the CHA(2)DS(2)-VASc score included all AF patients, the aim of this analysis was to evaluate its discriminative ability only in those patients for whom recommendations on antithrombotic treatment are uncertain (i.e. CHADS(2) score of 1). METHODS AND RESULTS We selected all patients with a CHADS(2) score of 1 from the AVERROES and ACTIVE trials who were treated with acetylsalicylic acid with or without clopidogrel and calculated the incidences of ischaemic or unspecified stroke or systemic embolus (SSE) according to their CHA(2)DS(2)-VASc score. Of 4670 patients with a baseline CHADS(2) score of 1, 26% had a CHA(2)DS(2)-VASc score of 1 and 74% had a score of ≥ 2. After 11 414 patient-years of follow-up, the annual incidence of SSE was 0.9% (95% CI: 0.6-1.3) and 2.1% (95% CI: 1.8-2.5) for patients with a CHA(2)DS(2)-VASc score of 1 and ≥ 2, respectively. The c-statistic of the CHA(2)DS(2)-VASc score was 0.587 (95% CI: 0.550-0.624). Age 65 to <75 years was the strongest of the three new risk factors in the CHA(2)DS(2)-VASc score. CONCLUSION The CHA(2)DS(2)-VASc score reclassifies 26% of patients with a CHADS(2) score of 1 to a low annual risk of SSE of 1%. This risk seems low enough to consider withholding anticoagulant treatment.

Antithrombotic therapy for atrial fibrillation

Atrial fibrillation is the commonest sustained disorder of cardiac rhythm. Although patients often present with symptoms caused by haemodynamic disturbance associated with the rhythm itself, the condition carries an increased risk of arterial thromboembolism and ischaemic stroke due to embolisation of thrombi that form within the left atrium of the heart. Presence of the arrhythmia confers about a fivefold increase in stroke risk, an absolute risk of about 4.5% a year, although the precise annual stroke risk ranges from 12%, according to the presence or absence of certain clinical and echocardiographically identifiable risk factors. ![][1] Severely damaged left atrial appendage endocardial surface with thrombotic mass in a patient with atrial fibrillation and mitral valve disease From trial data, patients with paroxysmal atrial fibrillation seem to carry the same risk as those with persistent atrial fibrillation. The same criteria can be used to identify high risk patients, although it is unclear whether the risk is dependent on the frequency and duration of the paroxysms. Randomised controlled trials have shown the benefit of warfarin and, to a lesser extent, aspirin in reducing the incidence of stroke in patients with atrial fibrillation without greatly increasing the risk of haemorrhagic stroke and extracranial haemorrhage. However, anticoagulant therapy is still underprescribed in patients with atrial fibrillation, particularly in elderly patients, who stand to benefit most It is well established that antithrombotic therapy confers thromboprophylaxis in patients with atrial fibrillation who are at risk of thromboembolism. A recent meta-analysis of antithrombotic therapy in atrial fibrillation showed that adjusted dose warfarin reduced stroke by about 60%, with absolute risk reductions of 3% a year for primary prevention and 8% a year for secondary prevention (numbers needed to treat for one year to prevent one stroke of 33 and 13, respectively). In contrast, aspirin reduced stroke by … [1]: /embed/graphic-1.gif

Apixaban versus aspirin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a predefined subgroup analysis from AVERROES, a randomised trial

BACKGROUND In the AVERROES study, apixaban, a novel factor Xa inhibitor, reduced the risk of stroke or systemic embolism in patients with atrial fibrillation who were at high risk of stroke but unsuitable for vitamin K antagonist therapy. We aimed to investigate whether the subgroup of patients with previous stroke or transient ischaemic attack (TIA) would show a greater benefit from apixaban compared with aspirin than would patients without previous cerebrovascular events. METHODS In AVERROES, 5599 patients (mean age 70 years) with atrial fibrillation who were at increased risk of stroke and unsuitable for vitamin K antagonist therapy were randomly assigned to receive apixaban (5 mg twice daily) or aspirin (81-324 mg per day). The mean follow-up was 1·1 years. The primary efficacy outcome was stroke or systemic embolism; the primary safety outcome was major bleeding. Patients and investigators were masked to study treatment. In this prespecified subgroup analysis, we used Kaplan-Meier estimates of 1-year event risk and Cox proportional hazards regression models to compare the effects of apixaban in patients with and without previous stroke or TIA. AVERROES is registered at ClinicalTrials.gov, number NCT00496769. FINDINGS In patients with previous stroke or TIA, ten events of stroke or systemic embolism occurred in the apixaban group (n=390, cumulative hazard 2·39% per year) compared with 33 in the aspirin group (n=374, 9·16% per year; hazard ratio [HR] 0·29, 95% CI 0·15-0·60). In those without previous stroke or TIA, 41 events occurred in the apixaban group (n=2417, 1·68% per year) compared with 80 in the aspirin group (n=2415, 3·06% per year; HR 0·51, 95% CI 0·35-0·74). The p value for interaction of the effects of aspirin and apixaban with previous cerebrovascular events was 0·17. Major bleeding was more frequent in patients with history of stroke or TIA than in patients without (HR 2·88, 95% CI 1·77-4·55) but risk of this event did not differ between treatment groups. INTERPRETATION In patients with atrial fibrillation, apixaban is similarly effective whether or not patients have had a previous stroke or TIA. Given that those with previous stroke or TIA have a higher risk of stroke, the absolute benefits might be greater in these patients. FUNDING Bristol-Myers Squibb and Pfizer.

The Secondary Prevention of Small Subcortical Strokes (SPS3) study.

Background Small subcortical strokes, also known as lacunar strokes, comprise more than 25% of brain infarcts, and the underlying vasculopathy is the most common cause of vascular cognitive impairment. How to optimally prevent stroke recurrence and cognitive decline in S3 patients is unclear. The aim of the Secondary Prevention of Small Subcortical Strokes study (Trial registration: NCT00059306) is to define strategies for reducing stroke recurrence, cognitive decline, and major vascular events. Methods Secondary Prevention of Small Subcortical Strokes is a randomised, multicentre clinical trial (n=3000) being conducted in seven countries, and sponsored by the US NINDS/NIH. Patients with symptomatic small subcortical strokes in the six-months before and an eligible lesion on magnetic resonance imaging are simultaneously randomised, in a 2 × 2 factorial design, to antiplatelet therapy – 325 mg aspirin daily plus 75 mg clopidogrel daily, vs. 325 mg aspirin daily plus placebo, double-blind – and to one of two levels of systolic blood pressure targets –‘intensive’ (<130 mmHg) vs. ‘usual’ (130–149 mmHg). Participants are followed for an average of four-years. Time to recurrent stroke (ischaemic or haemorrhagic) is the primary outcome and will be analysed separately for each intervention. The secondary outcomes are the rate of cognitive decline and major vascular events. The primary and most secondary outcomes are adjudicated centrally by those unaware of treatment assignment. Conclusions Secondary Prevention of Small Subcortical Strokes will address several important clinical and scientific questions by testing two interventions in patients with recent magnetic resonance imaging-defined lacunar infarcts, which are likely due to small vessel disease. The results will inform the management of millions of patients with this common vascular disorder.

Perindopril-Based Blood Pressure–Lowering Reduces Major Vascular Events in Patients With Atrial Fibrillation and Prior Stroke or Transient Ischemic Attack

BACKGROUND AND PURPOSE Patients with atrial fibrillation have a high risk of stroke and other vascular events even if anticoagulated. The primary objective here is to determine whether routine blood pressure-lowering provides additional protection for this high-risk patient group. METHODS This study was a subsidiary analysis of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS)--a randomized, placebo-controlled trial that established the beneficial effects of blood pressure--lowering in a heterogeneous group of patients with cerebrovascular disease. A total of 6105 patients were randomly assigned to either active treatment (2 to 4 mg perindopril for all participants plus 2.0 to 2.5 mg indapamide for those without an indication for or a contraindication to a diuretic) or matching placebo(s). Outcomes are total major vascular events, cause-specific vascular outcomes, and death from any cause. RESULTS There were 476 patients with atrial fibrillation at baseline, of whom 51% were taking anticoagulants. In these patients, active treatment lowered mean blood pressure by 7.3/3.4 mm Hg and was associated with a 38% (95% confidence interval [CI], 6 to 59) reduction in major vascular events and 34% (95% CI, -13 to 61) reduction in stroke. The benefits of blood pressure-lowering in patients with atrial fibrillation were achieved irrespective of the use of anticoagulant therapy (P homogeneity=0.8) or the presence of hypertension (P homogeneity=0.4). CONCLUSIONS For most patients with atrial fibrillation, routine blood pressure-lowering is likely to provide protection against major vascular events additional to that conferred by anticoagulation.