Kittipan Rerkasem

Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: a randomised controlled trial

BACKGROUND N-3 polyunsaturated fatty acids (PUFAs) from oily fish protect against death from cardiovascular disease. We aimed to assess the hypothesis that incorporation of n-3 and n-6 PUFAs into advanced atherosclerotic plaques increases and decreases plaque stability, respectively. METHODS We did a randomised controlled trial of patients awaiting carotid endarterectomy. We randomly allocated patients control, sunflower oil (n-6), or fish-oil (n-3) capsules until surgery. Primary outcome was plaque morphology indicative of stability or instability, and outcome measures were concentrations of EPA, DHA, and linoleic acid in carotid plaques; plaque morphology; and presence of macrophages in plaques. Analysis was per protocol. FINDINGS 188 patients were enrolled and randomised; 18 withdrew and eight were excluded. Duration of oil treatment was 7-189 days (median 42) and did not differ between groups. The proportions of EPA and DHA were higher in carotid plaque fractions in patients receiving fish oil compared with those receiving control (absolute difference 0.5 [95% CI 0.3-0.7], 0.4 [0.1-0.6], and 0.2 [0.1-0.4] g/100 g total fatty acids for EPA; and 0.3 [0.0-0.8], 0.4 [0.1-0.7], and 0.3 [0.1-0.6] g/100 g total fatty acids for DHA; in plaque phospholipids, cholesteryl esters, and triacylglycerols, respectively). Sunflower oil had little effect on the fatty acid composition of lipid fractions. Fewer plaques from patients being treated with fish oil had thin fibrous caps and signs of inflammation and more plaques had thick fibrous caps and no signs of inflammation, compared with plaques in patients in the control and sunflower oil groups (odds ratio 0.52 [95% CI 0.24-0.89] and 1.19 [1.02-1.57] vs control; 0.49 [0.23-0.90] and 1.16 [1.01-1.53] vs sunflower oil). The number of macrophages in plaques from patients receiving fish oil was lower than in the other two groups. Carotid plaque morphology and infiltration by macrophages did not differ between control and sunflower oil groups. INTERPRETATION Atherosclerotic plaques readily incorporate n-3 PUFAs from fish-oil supplementation, inducing changes that can enhance stability of atherosclerotic plaques. By contrast, increased consumption of n-6 PUFAs does not affect carotid plaque fatty-acid composition or stability over the time course studied here. Stability of plaques could explain reductions in non-fatal and fatal cardiovascular events associated with increased n-3 PUFA intake.

Systematic Review of the Risks of Carotid Endarterectomy in Relation to the Clinical Indication for and Timing of Surgery

BACKGROUND AND PURPOSE Reliable data on the risk of carotid endarterectomy (CEA) in relation to clinical indication and timing of surgery are necessary to target CEA more effectively, to inform patients, to adjust risks for case mix, and to understand the mechanisms of operative stroke. METHODS We performed a systematic review of all studies published from 1980 to 2000 inclusive that reported the risk of stroke and death resulting from CEA. Pooled estimates of risk by type of presenting ischemic event and time since the last event were obtained by Mantel-Haenszel meta-analysis. RESULTS Of 383 published studies, only 103 stratified risk by indication. Although the operative risk for symptomatic stenosis overall was higher than for asymptomatic stenosis (odds ratio [OR], 1.62; 95% confidence interval [CI], 1.45 to 1.81; P<0.00001; 59 studies), risk in patients with ocular events only tended to be lower than for asymptomatic stenosis (OR, 0.75, 95% CI, 0.50 to 1.14; 15 studies). Operative risk was the same for stroke and cerebral transient ischemic attack (OR, 1.16; 95% CI, 0.99 to 1.35; P=0.08; 23 studies) but higher for cerebral transient ischemic attack than for ocular events only (OR, 2.31; 95% CI, 1.72 to 3.12; P<0.00001; 19 studies) and for CEA for restenosis than primary surgery (OR, 1.95; 95% CI, 1.21 to 3.16; P=0.018; 6 studies). Urgent CEA for evolving symptoms had a much higher risk (19.2%, 95% CI, 10.7 to 27.8) than CEA for stable symptoms (OR, 3.9; 95% CI, 2.7 to 5.7; P<0.001; 13 studies), but there was no difference between early (<3 to 6 weeks) and late (>3 to 6 weeks) CEA for stroke in stable patients (OR, 1.13; 95% CI, 0.79 to 1.62; P=0.62; 11 studies). All observations were highly consistent across studies. CONCLUSIONS Risk of stroke and death resulting from CEA is highly dependent on the clinical indication. Audits of risk should be stratified accordingly, and patients should be informed of the risk that relates to their presenting event.

Systematic Review of the Operative Risks of Carotid Endarterectomy for Recently Symptomatic Stenosis in Relation to the Timing of Surgery

Background and Purpose— Reliable data on the risk of carotid endarterectomy (CEA) in relation to timing of surgery are necessary to plan CEA most effectively, to adjust risks for case-mix, and to understand the mechanisms of operative stroke. Methods— We performed a systematic review of all studies published from 1980 to 2008 inclusive that reported the risk of stroke and death due to CEA in relation to the time between presenting symptom and surgery. Pooled estimates of risk by the time since the last event were obtained by Mantel–Haenszel meta-analysis. Results— Of 494 published operative series, only 47 stratified risk by timing of surgery. The pooled absolute risks of stroke and death after urgent CEA were high in patients with stroke-in-evolution (20.2%, 95% CI 12.0 to 28.4) and in patients with crescendo TIA (11.4%, 6.1 to 16.7), with no trends toward reduced risks in more recent studies. However, there was no significant difference between early and later CEA in neurologically stable patients with recent TIA or nondisabling stroke (<1 week versus ≥1 week, OR=1.2, 0.9 to 1.7, P=0.17; <2 weeks versus ≥2 weeks, OR=1.2, 0.9 to 1.6, P=0.13). Conclusions— Emergency endarterectomy for stroke-in-evolution has a high operative risk, but the risk may be somewhat lower in patients with crescendo TIA. Surgery in the first week in neurologically stable patients with TIA or minor stroke is not associated with a substantially higher operative risk than delayed surgery. More data are required on the risk and benefit of more urgent surgery for TIA and minor stroke and for early versus delayed surgery in patients with major nondisabling stroke.

A Systematic Review of the Associations between Age and Sex and the Operative Risks of Carotid Endarterectomy

Background: Randomized trials of carotid endarterectomy (CEA) for both symptomatic and asymptomatic carotid stenosis have demonstrated that benefit is decreased in women, due partly to a high operative risk, which is independent of age. However, it is uncertain whether these trial-based observations are generalisable to routine clinical practice. Methods: We performed a systematic review of all publications reporting data on the association between age and/or sex and procedural risk of stroke and/or death following CEA from 1980 to 2004. Results: 62 eligible papers reported relevant data. Females had a higher rate of operative stroke and death (25 studies, OR = 1.31, 95% CI = 1.17–1.47, p < 0.001) than males, but no increase in operative mortality (15 studies, OR = 1.05, 95% CI = 0.81–0.86, p = 0.78). Compared with younger patients, operative mortality was increased at ≧75 years (20 studies, OR = 1.36, 95% CI = 1.07–1.68, p = 0.02), at age ≧80 years (15 studies, OR = 1.80, 95% CI = 1.26–2.45, p < 0.001) and in older patients overall (35 studies, OR = 1.50, 95% CI = 1.26–1.78, p < 0.001). In contrast, risk of non-fatal stroke did not increase with age and so the combined perioperative risk was only slightly increased at age ≧75 years (21 studies, OR = 1.18, 95% CI = 0.94–1.44, p = 0.06), at age ≧80 years (10 studies, OR = 1.14, 95% CI = 0.92–1.36, p = 0.34) and in older patients overall (36 studies, OR = 1.17, 95% CI = 1.04–1.31, p = 0.01). Conclusions: The effects of age and sex on the operative risk of CEA in published case series are consistent with those observed in the trials. Operative risk of stroke is increased in women and operative mortality is increased in patients aged ≧75 years.

Differences in Matrix Metalloproteinase-1 and Matrix Metalloproteinase-12 Transcript Levels Among Carotid Atherosclerotic Plaques with Different Histopathological Characteristics

Background and Purpose— Previous studies have shown that atherosclerotic lesions express a number of matrix metalloproteinases (MMPs). Here we investigated whether transcript levels of MMP-1, -3, -7, -9, and -12 in carotid atherosclerotic plaques were correlated with histological features and clinical manifestations. Methods— Atherosclerotic plaques (n=50) removed from patients undergoing carotid endarterectomy were classified histologically using a system proposed by Virmani et al, and MMP-1, -3, -7, -9, and -12 transcript levels in these tissues were quantified by real-time reverse-transcriptase polymerase chain reaction. Results— Compared to plaques with a thick fibrous cap, those with a thin cap had a 7.8-fold higher MMP-1 transcript level (P=0.006). MMP-3, -7, and -12 were 1.5-fold, 1.8-fold, and 2.1-fold, respectively, higher in thin cap plaques, but the differences did not reach statistical significance. MMP-12 transcript levels were significantly increased in ruptured plaques compared with lesions without cap disruption (P=0.001). MMP-9 transcript levels were similar among the different types of lesion. MMP-1 and -12 transcript levels were significantly higher in plaques from patients with amaurosis fugax, than in those from asymptomatic patients (P=0.029 and P=0.008 for MMP-1 and MMP-12, respectively), than in those from patients with stroke (P=0.027 and P=0.001, respectively), and than in those from patients with transient ischemic attack (P=0.046 and P=0.008, respectively). Conclusions— These data support a role of MMP-1 and -12 in determining atherosclerotic plaque stability.

Time Trends in the Published Risks of Stroke and Death due to Endarterectomy for Symptomatic Carotid Stenosis

Background: Large randomised trials performed in the 1980s and early 1990s showed that carotid endarterectomy (CEA) is beneficial for patients with recently symptomatic severe stenosis. Some surgeons have argued that the operative risk of stroke and death has fallen over the last decade due to refinements in operative technique, and that the indications for surgery should therefore now be broadened. Yet, studies of routinely collected data report higher operative mortality than in the trials, and surgical case series without independent post-operative assessment by a neurologist may not provide reliable data on stroke risk. Methods: We performed a systematic review of all studies published between 1994 and 2001 inclusive that which reported the risks of stroke and death for symptomatic carotid stenosis, and compared the reported risks and patient characteristics with those in the ECST and NASCET and with our previous review of studies published prior to 1995. Pooled estimates of the operative risk of stroke and death were obtained by Mantel-Haenszel meta-analysis. Results: Of 383 studies published between 1994 and 2001, only 45 reported operative risks for patients with symptomatic stenosis separately. The pooled operative risk of stroke and death reported in studies published by surgeons only (4.2%, 95% CI = 2.9–5.5, 34 studies) was significantly lower (p < 0.0001) than that in the ECST and NASCET combined (7.0%, 95% CI = 6.2–8.0), whereas the pooled risk reported in studies that involved neurologists was similar (6.5%, 95% CI = 4.3–8.7, 11 studies, p = 0.6). In contrast, operative mortality in ECST and NASCET was significantly lower than in other studies published between 1994 and 2001. By comparison with our previous review, when stratified according to involvement of neurologists, we found no evidence of a reduction in published risks of death or stroke and death due to CEA between 1985 and 2001. Conclusions: There is no evidence of a systematic reduction over the last decade in the published risks of stroke and death due to CEA for symptomatic stenosis. Operative risks in studies with comparable outcome assessment are similar to ECST and NASCET. The surgical data from the large trials are still likely therefore to be applicable to routine clinical practice.

Meta‐analysis of small randomized controlled trials in surgery may be unreliable

Meta‐analysis of randomized controlled trials (RCTs) should provide reliable evidence about the effects of interventions. This may be less reliable when only small trials are available.

Temporal trends in the risks of stroke and death due to endarterectomy for symptomatic carotid stenosis: an updated systematic review.

OBJECTIVES To determine whether there is any evidence of a systematic reduction in the operative risk of carotid endarterectomy (CEA) for symptomatic stenosis in recent years. METHODS We performed a systematic review of all studies published between 2000 and 2008 inclusive that reported the risks of stroke and death for symptomatic carotid stenosis. We compared the reported risks with our previous review of studies published prior to 2001 and between studies that were reported by surgeons alone and studies that included neurologists or stroke physicians as assessors/authors, with particular reference to the proportion of operative strokes to operative deaths. RESULTS Of 494 studies, only 53 reported operative risks for patients with symptomatic stenosis separately. In keeping with the findings of our previous review, the pooled operative risk of stroke and death reported in studies published by surgeons alone (3.9%, 95% confidence interval (CI): 3.4-4.3) was significantly lower (p<0.001) than that reported in studies that involved neurologists (5.6%, 95% CI: 5.1-6.2). The pooled ratio of operative stroke:operative death was 4.0 (range: 3.6-4.5) in studies involving neurologists or stroke physicians and 2.7 (range: 2.1-3.9) in studies involving only surgeons (p=0.002). We found no evidence of a reduction in published risks of death or stroke and death due to CEA for symptomatic carotid stenosis between 1985 and 2008. Indeed, the 1.4% (range: 1.2-1.6%) pooled operative mortality in studies published during 2001-2008 was significantly higher than that reported in ECST and NASCET (1.0%, 95% CI: 0.9-1.1%). However, the average age of patients having CEA has continued to increase during this period. CONCLUSIONS There is no evidence of a systematic reduction over the last decade in the published risks due to CEA for symptomatic stenosis. The lower proportion of non-fatal operative strokes in surgeon-only studies suggests that some minor operative strokes have been missed.

A Clinical Rule (Sex, Contralateral Occlusion, Age, and Restenosis) to Select Patients for Stenting Versus Carotid Endarterectomy Systematic Review of Observational Studies With Validation in Randomized Trials

Background and Purpose— Compared with carotid endarterectomy (CEA), carotid angioplasty and stenting (CAS) is associated with a higher risk of procedural stroke or death especially in patients with symptomatic stenosis. However, after the perioperative period, risk is similar with both treatments, suggesting that CAS could be an acceptable option in selected patients. Methods— We performed systematic reviews of observational studies of procedural risks of CEA or CAS and extracted data on 9 predefined risk factors (age, contralateral carotid occlusion, coronary artery disease, diabetes mellitus, sex, hypertension, peripheral artery disease, and type and side of stenosis). We calculated pooled relative risks of procedural stroke or death. Factors with differential effects on risk of CAS versus CEA were identified by interaction tests and used to derive a rule. The rule was tested using individual patient data from randomized trials of CAS versus CEA from the Carotid Stenting Trialists’ Collaboration (CSTC). Results— We identified 170 studies. The effects of sex, contralateral occlusion, age, and restenosis (SCAR) on the procedural risk of stroke or death differed. Patients with contralateral occlusion or restenosis and women <75 years were at relatively low risk for CAS (SCAR negative), with all others being high risk (SCAR positive). Among the 3049 patients in the CSTC validation, 694 (23%) patients were SCAR negative. The pooled RR of procedural stroke and death with CAS versus CEA was 0.93 (0.49–1.77; P=0.83) in SCAR-negative and 2.41 (1.68–3.45; P<0.0001) in SCAR-positive patients (P [interaction]=0.05). Conclusions— The SCAR rule is potentially useful to identify patients in whom CAS has a similar risk of perioperative stroke or death to CEA.

Systematic Review of Randomized Controlled Trials of Patch Angioplasty Versus Primary Closure and Different Types of Patch Materials During Carotid Endarterectomy

OBJECTIVE Patch angioplasty during carotid endarterectomy (CEA) can reduce the risk of perioperative stroke or late carotid artery recurrent stenosis and subsequent ischaemic stroke. We aimed to update our previous systematic review of randomized controlled trials (RCTs) of routine or selective carotid patch angioplasty compared with CEA with primary closure, and of different materials used for carotid patch angioplasty. METHODS We identified new RCTs published during 2002-2010 by searching Medline, Embase and the Cochrane Stroke Group Trials Register. We also hand-searched six relevant journals. Pooled estimates of treatment effects combined with our previous review (1966-2001) were calculated on the basis of a weighted estimate of the odds ratio (OR) with the Peto method. RESULTS Twenty-three eligible RCTs were identified in both periods. Ten RCTs involving 2,157 operations compared primary closure with routine patch closure. Patch closure significantly reduced the combined risk of perioperative stroke and later stroke during long-term follow-up [OR = 0.49, 95% confidence interval (CI) = 0.27-0.90, p = 0.001; 7 RCTs]. Patching also reduced the risks of perioperative arterial occlusion (OR = 0.18, 95% CI = 0.08-0.41, p < 0.0001; 7 RCTs) and recurrent stenosis during long-term followup (OR = 0.24, 95% CI = 0.17-0.34, p < 0.001; 8 RCTs). CONCLUSION Meta-analysis of relatively small RCTs suggests that carotid patch angioplasty reduces the combined perioperative and long-term risk of stroke and the risk of restenosis. More data are needed.