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Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial

Summary Background Lowering of LDL cholesterol reduces major vascular events, but whether more intensive therapy safely produces extra benefits is uncertain. We aimed to establish efficacy and safety of more intensive statin treatment in patients at high cardiovascular risk. Methods We undertook a double-blind randomised trial in 12 064 men and women aged 18–80 years with a history of myocardial infarction. Participants were either currently on or had clear indication for statin therapy, and had a total cholesterol concentration of at least 3·5 mmol/L if already on a statin or 4·5 mmol/L if not. Randomisation to either 80 mg or 20 mg simvastatin daily was done centrally using a minimisation algorithm. Participants were assessed at 2, 4, 8, and 12 months after randomisation and then every 6 months until final follow-up. The primary endpoint was major vascular events, defined as coronary death, myocardial infarction, stroke, or arterial revascularisation. Analysis was by intention to treat. This study is registered, number ISRCTN74348595. Findings 6031 participants were allocated 80 mg simvastatin daily, and 6033 allocated 20 mg simvastatin daily. During a mean follow-up of 6·7 (SD 1·5) years, allocation to 80 mg simvastatin produced an average 0·35 (SE 0·01) mmol/L greater reduction in LDL cholesterol compared with allocation to 20 mg. Major vascular events occurred in 1477 (24·5%) participants allocated 80 mg simvastatin versus 1553 (25·7%) of those allocated 20 mg, corresponding to a 6% proportional reduction (risk ratio 0·94, 95% CI 0·88–1·01; p=0·10). There were no apparent differences in numbers of haemorrhagic strokes (24 [0·4%] vs 25 [0·4%]) or deaths attributed to vascular (565 [9·4%] vs 572 [9·5%]) or non-vascular (399 [6·6%] vs 398 [6·6%]) causes. Compared with two (0·03%) cases of myopathy in patients taking 20 mg simvastatin daily, there were 53 (0·9%) cases in the 80 mg group. Interpretation The 6% (SE 3·5%) reduction in major vascular events with a further 0·35 mmol/L reduction in LDL cholesterol in our trial is consistent with previous trials. Myopathy was increased with 80 mg simvastatin daily, but intensive lowering of LDL cholesterol can be achieved safely with other regimens. Funding Merck; The Clinical Trial Service Unit also receives funding from the UK Medical Research Council and the British Heart Foundation.BACKGROUND Lowering of LDL cholesterol reduces major vascular events, but whether more intensive therapy safely produces extra benefits is uncertain. We aimed to establish efficacy and safety of more intensive statin treatment in patients at high cardiovascular risk. METHODS We undertook a double-blind randomised trial in 12,064 men and women aged 18-80 years with a history of myocardial infarction. Participants were either currently on or had clear indication for statin therapy, and had a total cholesterol concentration of at least 3·5 mmol/L if already on a statin or 4·5 mmol/L if not. Randomisation to either 80 mg or 20 mg simvastatin daily was done centrally using a minimisation algorithm. Participants were assessed at 2, 4, 8, and 12 months after randomisation and then every 6 months until final follow-up. The primary endpoint was major vascular events, defined as coronary death, myocardial infarction, stroke, or arterial revascularisation. Analysis was by intention to treat. This study is registered, number ISRCTN74348595. FINDINGS 6031 participants were allocated 80 mg simvastatin daily, and 6033 allocated 20 mg simvastatin daily. During a mean follow-up of 6·7 (SD 1·5) years, allocation to 80 mg simvastatin produced an average 0·35 (SE 0·01) mmol/L greater reduction in LDL cholesterol compared with allocation to 20 mg. Major vascular events occurred in 1477 (24·5%) participants allocated 80 mg simvastatin versus 1553 (25·7%) of those allocated 20 mg, corresponding to a 6% proportional reduction (risk ratio 0·94, 95% CI 0·88-1·01; p=0·10). There were no apparent differences in numbers of haemorrhagic strokes (24 [0·4%] vs 25 [0·4%]) or deaths attributed to vascular (565 [9·4%] vs 572 [9·5%]) or non-vascular (399 [6·6%] vs 398 [6·6%]) causes. Compared with two (0·03%) cases of myopathy in patients taking 20 mg simvastatin daily, there were 53 (0·9%) cases in the 80 mg group. INTERPRETATION The 6% (SE 3·5%) reduction in major vascular events with a further 0·35 mmol/L reduction in LDL cholesterol in our trial is consistent with previous trials. Myopathy was increased with 80 mg simvastatin daily, but intensive lowering of LDL cholesterol can be achieved safely with other regimens. FUNDING Merck; The Clinical Trial Service Unit also receives funding from the UK Medical Research Council and the British Heart Foundation.

Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial.

CONTEXT Blood homocysteine levels are positively associated with cardiovascular disease, but it is uncertain whether the association is causal. OBJECTIVE To assess the effects of reducing homocysteine levels with folic acid and vitamin B(12) on vascular and nonvascular outcomes. DESIGN, SETTING, AND PATIENTS Double-blind randomized controlled trial of 12,064 survivors of myocardial infarction in secondary care hospitals in the United Kingdom between 1998 and 2008. INTERVENTIONS 2 mg folic acid plus 1 mg vitamin B(12) daily vs matching placebo. MAIN OUTCOME MEASURES First major vascular event, defined as major coronary event (coronary death, myocardial infarction, or coronary revascularization), fatal or nonfatal stroke, or noncoronary revascularization. RESULTS Allocation to the study vitamins reduced homocysteine by a mean of 3.8 micromol/L (28%). During 6.7 years of follow-up, major vascular events occurred in 1537 of 6033 participants (25.5%) allocated folic acid plus vitamin B(12) vs 1493 of 6031 participants (24.8%) allocated placebo (risk ratio [RR], 1.04; 95% confidence interval [CI], 0.97-1.12; P = .28). There were no apparent effects on major coronary events (vitamins, 1229 [20.4%], vs placebo, 1185 [19.6%]; RR, 1.05; 95% CI, 0.97-1.13), stroke (vitamins, 269 [4.5%], vs placebo, 265 [4.4%]; RR, 1.02; 95% CI, 0.86-1.21), or noncoronary revascularizations (vitamins, 178 [3.0%], vs placebo, 152 [2.5%]; RR, 1.18; 95% CI, 0.95-1.46). Nor were there significant differences in the numbers of deaths attributed to vascular causes (vitamins, 578 [9.6%], vs placebo, 559 [9.3%]) or nonvascular causes (vitamins, 405 [6.7%], vs placebo, 392 [6.5%]) or in the incidence of any cancer (vitamins, 678 [11.2%], vs placebo, 639 [10.6%]). CONCLUSION Substantial long-term reductions in blood homocysteine levels with folic acid and vitamin B(12) supplementation did not have beneficial effects on vascular outcomes but were also not associated with adverse effects on cancer incidence. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN74348595.

Effects on 11-year mortality and morbidity of lowering LDL cholesterol with simvastatin for about 5 years in 20,536 high-risk individuals: a randomised controlled trial.

Summary Background Findings of large randomised trials have shown that lowering LDL cholesterol with statins reduces vascular morbidity and mortality rapidly, but limited evidence exists about the long-term efficacy and safety of statin treatment. The aim of the extended follow-up of the Heart Protection Study (HPS) is to assess long-term efficacy and safety of lowering LDL cholesterol with statins, and here we report cause-specific mortality and major morbidity in the in-trial and post-trial periods. Methods 20 536 patients at high risk of vascular and non-vascular outcomes were allocated either 40 mg simvastatin daily or placebo, using minimised randomisation. Mean in-trial follow-up was 5·3 years (SD 1·2), and post-trial follow-up of surviving patients yielded a mean total duration of 11·0 years (SD 0·6). The primary outcome of the long-term follow-up of HPS was first post-randomisation major vascular event, and analysis was by intention to treat. This trial is registered with ISRCTN, number 48489393. Findings During the in-trial period, allocation to simvastatin yielded an average reduction in LDL cholesterol of 1·0 mmol/L and a proportional decrease in major vascular events of 23% (95% CI 19–28; p<0·0001), with significant divergence each year after the first. During the post-trial period (when statin use and lipid concentrations were similar in both groups), no further significant reductions were noted in either major vascular events (risk ratio [RR] 0·95 [0·89–1·02]) or vascular mortality (0·98 [0·90–1·07]). During the combined in-trial and post-trial periods, no significant differences were recorded in cancer incidence at all sites (0·98 [0·92–1·05]) or any particular site, or in mortality attributed to cancer (1·01 [0·92–1·11]) or to non-vascular causes (0·96 [0·89–1·03]). Interpretation More prolonged LDL-lowering statin treatment produces larger absolute reductions in vascular events. Moreover, even after study treatment stopped in HPS, benefits persisted for at least 5 years without any evidence of emerging hazards. These findings provide further support for the prompt initiation and long-term continuation of statin treatment. Funding UK Medical Research Council, British Heart Foundation, Merck & Co, Roche Vitamins.

Status update and interim results from the asymptomatic carotid surgery trial-2 (ACST-2).

OBJECTIVES ACST-2 is currently the largest trial ever conducted to compare carotid artery stenting (CAS) with carotid endarterectomy (CEA) in patients with severe asymptomatic carotid stenosis requiring revascularization. METHODS Patients are entered into ACST-2 when revascularization is felt to be clearly indicated, when CEA and CAS are both possible, but where there is substantial uncertainty as to which is most appropriate. Trial surgeons and interventionalists are expected to use their usual techniques and CE-approved devices. We report baseline characteristics and blinded combined interim results for 30-day mortality and major morbidity for 986 patients in the ongoing trial up to September 2012. RESULTS A total of 986 patients (687 men, 299 women), mean age 68.7 years (SD ± 8.1) were randomized equally to CEA or CAS. Most (96%) had ipsilateral stenosis of 70-99% (median 80%) with contralateral stenoses of 50-99% in 30% and contralateral occlusion in 8%. Patients were on appropriate medical treatment. For 691 patients undergoing intervention with at least 1-month follow-up and Rankin scoring at 6 months for any stroke, the overall serious cardiovascular event rate of periprocedural (within 30 days) disabling stroke, fatal myocardial infarction, and death at 30 days was 1.0%. CONCLUSIONS Early ACST-2 results suggest contemporary carotid intervention for asymptomatic stenosis has a low risk of serious morbidity and mortality, on par with other recent trials. The trial continues to recruit, to monitor periprocedural events and all types of stroke, aiming to randomize up to 5,000 patients to determine any differential outcomes between interventions. CLINICAL TRIAL ISRCTN21144362.

Antiplatelet Therapy in Carotid Artery Stenting and Carotid Endarterectomy in the Asymptomatic Carotid Surgery Trial-2.

OBJECTIVE Strokes are infrequent but potentially serious complications following carotid intervention, but antiplatelet therapy can reduce these risks. There are currently no specific guidelines on dose or duration of peri-procedural antiplatelet treatment for patients undergoing carotid intervention. Within the ongoing Asymptomatic Carotid Surgery Trial-2 (ACST-2), this study aimed at assessing the current use of antiplatelet therapy before, during, and after CEA and CAS in patients with asymptomatic carotid stenosis. METHODS Questionnaires were sent to ACST-2 collaborators seeking information about the use of antiplatelet therapy during the pre-, peri-, and post-operative periods in patients undergoing carotid intervention at 77 participating sites and also whether sites tested for antiplatelet therapy resistance. RESULTS The response rate was 68/77 (88%). For CAS, 82% of sites used dual antiplatelet therapy (DAPT) pre-operatively and 86% post-operatively with a mean post-procedural duration of 3 months (range 1-12), while 9% continued DAPT life-long. For CEA only 31% used DAPT pre-operatively, 24% post-operatively with a mean post-procedural duration of 3 months (range 1-5), while 10% continued DAPT life-long. For those prescribing post-procedural mono antiplatelet (MAPT) therapy (76%), aspirin was more commonly prescribed (59%) than clopidogrel (6%) and 11% of centres did not show a preference for either aspirin or clopidogrel. Eleven centres (16%) tested for antiplatelet therapy resistance. CONCLUSION There appears to be broad agreement on the use of antiplatelet therapy in ACST-2 patients undergoing carotid artery stenting and surgery. Although evidence to help guide the duration of peri-procedural antiplatelet therapy is limited, long-term treatment with DAPT appears similar between both treatment arms.

Ten-year risk of stroke in patients with previous cerebral infarction and the impact of carotid surgery in the Asymptomatic Carotid Surgery Trial

Background Silent brain infarcts are common in patients at increased risk of stroke and are associated with a poor prognosis. In patients with asymptomatic carotid stenosis, similar adverse associations were claimed, but the impact of previous infarction or symptoms on the beneficial effects of carotid endarterectomy is not clear. Our aim was to evaluate the impact of prior cerebral infarction in patients enrolled in the Asymptomatic Carotid Surgery Trial, a large trial with 10-year follow-up in which participants whose carotid stenosis had not caused symptoms for at least six months were randomly allocated either immediate or deferred carotid endarterectomy. Methods The first Asymptomatic Carotid Surgery Trial included 3120 patients. Of these, 2333 patients with baseline brain imaging were identified and divided into two groups irrespective of treatment assignment, 1331 with evidence of previous cerebral infarction, defined as a history of ischemic stroke or transient ischemic attack > 6 months prior to randomization or radiological evidence of an asymptomatic infarct (group 1) and 1002 with normal imaging and no prior stroke or transient ischemic attack (group 2). Stroke and vascular deaths were compared during follow-up, and the impact of carotid endarterectomy was observed in both groups. Results Baseline characteristics of patients with and without baseline brain imaging were broadly similar. Of those included in the present report, male gender and hypertension were more common in group 1, while mean ipsilateral stenosis was slightly greater in group 2. At 10 years follow-up, stroke was more common among participants with cerebral infarction before randomization (absolute risk increase 5.8% (1.8–9.8), p = 0.004), and the risk of stroke and vascular death was also higher in this group (absolute risk increase 6.9% (1.9–12.0), p = 0.007). On multivariate analysis, prior cerebral infarction was associated with a greater risk of stroke (hazard ratio = 1.51, 95% confidence interval: 1.17–1.95, p = 0.002) and of stroke or other vascular death (hazard ratio = 1.30, 95% confidence interval: 1.11–1.52, p = 0.001). At 10 years, greater absolute benefits from immediate carotid endarterectomy were seen in those patients with prior cerebral infarction (6.7% strokes immediate carotid endarterectomy vs. 14.7% delayed carotid endarterectomy; hazard ratio 0.47 (0.34–0.65), p = 0.003), compared to those lower risk patients without prior cerebral infarction (6.0% vs. 9.9%, respectively; hazard ratio 0.61 (0.39–0.94), p = 0.005), though it must be emphasized that the first Asymptomatic Carotid Surgery Trial was not designed to test this retrospective and non-randomized comparison. Conclusions Asymptomatic carotid stenosis patients with prior cerebral infarction have a higher stroke risk during long-term follow-up than those without prior cerebral infarction. Evidence of prior ischemic events might help identify patients in whom carotid intervention is particularly beneficial.

A Randomized Trial of Early Endovenous Ablation in Venous Ulceration

BACKGROUND Venous disease is the most common cause of leg ulceration. Although compression therapy improves venous ulcer healing, it does not treat the underlying causes of venous hypertension. Treatment of superficial venous reflux has been shown to reduce the rate of ulcer recurrence, but the effect of early endovenous ablation of superficial venous reflux on ulcer healing remains unclear. METHODS In a trial conducted at 20 centers in the United Kingdom, we randomly assigned 450 patients with venous leg ulcers to receive compression therapy and undergo early endovenous ablation of superficial venous reflux within 2 weeks after randomization (early‐intervention group) or to receive compression therapy alone, with consideration of endovenous ablation deferred until after the ulcer was healed or until 6 months after randomization if the ulcer was unhealed (deferred‐intervention group). The primary outcome was the time to ulcer healing. Secondary outcomes were the rate of ulcer healing at 24 weeks, the rate of ulcer recurrence, the length of time free from ulcers (ulcer‐free time) during the first year after randomization, and patient‐reported health‐related quality of life. RESULTS Patient and clinical characteristics at baseline were similar in the two treatment groups. The time to ulcer healing was shorter in the early‐intervention group than in the deferred‐intervention group; more patients had healed ulcers with early intervention (hazard ratio for ulcer healing, 1.38; 95% confidence interval [CI], 1.13 to 1.68; P=0.001). The median time to ulcer healing was 56 days (95% CI, 49 to 66) in the early‐intervention group and 82 days (95% CI, 69 to 92) in the deferred‐intervention group. The rate of ulcer healing at 24 weeks was 85.6% in the early‐intervention group and 76.3% in the deferred‐intervention group. The median ulcer‐free time during the first year after trial enrollment was 306 days (interquartile range, 240 to 328) in the early‐intervention group and 278 days (interquartile range, 175 to 324) in the deferred‐intervention group (P=0.002). The most common procedural complications of endovenous ablation were pain and deep‐vein thrombosis. CONCLUSIONS Early endovenous ablation of superficial venous reflux resulted in faster healing of venous leg ulcers and more time free from ulcers than deferred endovenous ablation. (Funded by the National Institute for Health Research Health Technology Assessment Program; EVRA Current Controlled Trials number, ISRCTN02335796.)

Post-trial follow-up methodology in large randomized controlled trials: a systematic review protocol

BackgroundClinical trials typically have a relatively short follow-up period, and may both underestimate potential benefits of treatments investigated, and fail to detect hazards, which can take much longer to emerge. Prolonged follow-up of trial participants after the end of the scheduled trial period can provide important information on both efficacy and safety outcomes. This protocol describes a systematic review to qualitatively compare methods of post-trial follow-up used in large randomized controlled trials.Methods/designA systematic search of electronic databases and clinical trial registries will use a predefined search strategy. All large (more than 1000 adult participants) randomized controlled trials will be evaluated. Two reviewers will screen and extract data according to this protocol with the aim of 95% concordance of papers checked and discrepancies will be resolved by a third reviewer. Trial methods, participant retention rates and prevalence of missing data will be recorded and compared. The potential for bias will be evaluated using the Cochrane Risk of Bias tool (applied to the methods used during the in-trial period) with the aim of investigating whether the quality of the post-trial follow-up methodology might be predicted by the quality of the methods used for the original trial.DiscussionPost-trial follow-up can provide valuable information about the long-term benefits and hazards of medical interventions. However, it can be logistically challenging and costly. The aim of this systematic review is to describe how trial participants have been followed-up post-trial in order to inform future post-trial follow-up designs.Systematic review registrationNot applicable for PROSPERO registration.

LDL cholesterol targets--how low to go?

Purpose of review Lowering LDL cholesterol (LDL-C) reduces vascular risk. Current guidelines recommend initiating statin therapy in patients with a yearly coronary heart disease risk of around 1.5–2%, and most clinicians prescribe standard statin regimens (e.g. 40 mg simvastatin daily). However, there is some uncertainty about whether patients at somewhat lower vascular risk should receive lipid-lowering therapy and also how intensive statin treatment should be. Recent findings Lowering LDL-C by around 1 mmol/l reduces vascular mortality and major morbidity by about one-fifth, and more recent randomized trials comparing intensive versus standard statin regimens confirm that a further LDL-C reduction of 0.5 mmol/l results in an additional 15% reduction in the risk of a major vascular event. Furthermore, statin therapy significantly reduces vascular mortality and morbidity in patients with less than 1% annual risk of a major vascular event. In general, statins are safe and well tolerated, but 80 mg simvastatin is associated with an unacceptably high risk of statin-induced myopathy. Summary Lipid-lowering therapy with statins is cost-effective for a wider range of patients than currently recommended. Intensive statin therapy is associated with larger reductions in vascular risk, and lower LDL-C targets (particularly for higher-risk individuals) should help reduce vascular mortality and major vascular morbidity substantially.

Evidence-Based Carotid Interventions for Stroke Prevention: State-of-the-art Review

Carotid artery stenosis is responsible for between 10–20% of all ischaemic strokes. Interventions, such as carotid end-arterectomy and carotid stenting, effectively reduce the risk of stroke in selected individuals. This review describes the history of carotid interventions, and summarises reliable evidence on the safety and efficacy of these interventions gained from large randomised clinical trials. Early trials comparing carotid endarterectomy to medical therapy alone in symptomatic patients, and asymptomatic patients, demonstrated that endarterectomy halved the risk of stroke and perioperative death in these two unique populations. The absolute risk reduction was smaller in the asymptomatic carotid trials, consistent with their lower absolute stroke risk. More recent trials in symptomatic patients, suggest that carotid stenting has similar long term durability to carotid endarterectomy, but possibly has higher procedural hazards dominated by non-disabling strokes. The Asymptomatic Carotid Surgery Trial-2, along with individual patient data meta-analysis of all asymptomatic trials, will provide reliable evidence for the choice of intervention in asymptomatic patients in whom a decision has been made for carotid revascularisation. Given improvements in effective cardiovascular medical therapy, in particular lipid-lowering medications, there is renewed uncertainty as to whether carotid interventions still provide meaningful net reductions in stroke risk in asymptomatic populations. Four large trials in Europe and the US are currently underway, and are expected to report longterm results in the next decade. It is essential that surgeons, interventionalists, and physicians continue to randomise large numbers of patients from around the world to clarify current uncertainty around the management of asymptomatic carotid stenosis.