Jordan Fulcher

Impact of renal function on the effects of LDL cholesterol lowering with statin-based regimens: a meta-analysis of individual participant data from 28 randomised trials

BACKGROUND Statin therapy is effective for the prevention of coronary heart disease and stroke in patients with mild-to-moderate chronic kidney disease, but its effects in individuals with more advanced disease, particularly those undergoing dialysis, are uncertain. METHODS We did a meta-analysis of individual participant data from 28 trials (n=183 419), examining effects of statin-based therapy on major vascular events (major coronary event [non-fatal myocardial infarction or coronary death], stroke, or coronary revascularisation) and cause-specific mortality. Participants were subdivided into categories of estimated glomerular filtration rate (eGFR) at baseline. Treatment effects were estimated with rate ratio (RR) per mmol/L reduction in LDL cholesterol. FINDINGS Overall, statin-based therapy reduced the risk of a first major vascular event by 21% (RR 0·79, 95% CI 0·77-0·81; p<0·0001) per mmol/L reduction in LDL cholesterol. Smaller relative effects on major vascular events were observed as eGFR declined (p=0·008 for trend; RR 0·78, 99% CI 0·75-0·82 for eGFR ≥60 mL/min per 1·73 m(2); 0·76, 0·70-0·81 for eGFR 45 to <60 mL/min per 1·73 m(2); 0·85, 0·75-0·96 for eGFR 30 to <45 mL/min per 1·73 m(2); 0·85, 0·71-1·02 for eGFR <30 mL/min per 1·73 m(2) and not on dialysis; and 0·94, 0·79-1·11 for patients on dialysis). Analogous trends by baseline renal function were seen for major coronary events (p=0·01 for trend) and vascular mortality (p=0·03 for trend), but there was no significant trend for coronary revascularisation (p=0·90). Reducing LDL cholesterol with statin-based therapy had no effect on non-vascular mortality, irrespective of eGFR. INTERPRETATION Even after allowing for the smaller reductions in LDL cholesterol achieved by patients with more advanced chronic kidney disease, and for differences in outcome definitions between dialysis trials, the relative reductions in major vascular events observed with statin-based treatment became smaller as eGFR declined, with little evidence of benefit in patients on dialysis. In patients with chronic kidney disease, statin-based regimens should be chosen to maximise the absolute reduction in LDL cholesterol to achieve the largest treatment benefits. FUNDING UK Medical Research Council, British Heart Foundation, Cancer Research UK, European Community Biomed Programme, Australian National Health and Medical Research Council, Australian National Heart Foundation.

Inappropriate sinus tachycardia: focus on ivabradine.

Inappropriate sinus tachycardia (IST) is an incompletely understood condition, characterised by an elevation in heart rate (HR) accompanied by wide ranging symptoms in the absence of an underlying physiological stimulus. The condition often takes a chronic course with significant adverse effects on quality of life. Currently, there is no effective treatment for IST. Beta‐blockers, generally considered the cornerstone of treatment, are often ineffective and poorly tolerated. Ivabradine is a novel sinus node If ‘funny current’ inhibitor, which reduces the HR. It has been approved for the treatment of beta‐blocker refractory chronic systolic heart failure and chronic stable angina but more recently has shown promise in the treatment of IST. This review provides an overview of IST prevalence and mechanisms followed by an examination of the evidence for the role and efficacy of ivabradine in the treatment of IST.

The case for more intensive use of statins

The notion that you cannot have too much of a good thing, coined first by Shakespeare, seems inherently primordial, and has been shared with us from Mae West to Casanova’s memoirs. However true this might appear, things in medicine are rarely black and white, and cardiovascular disease (CVD) management is no exception. Meta-analyses of blood pressure treatment trials have demonstrated the progressive cardiovascular benefits of larger blood pressure reductions. However, the issue of a possible ‘J-point’, whereby lower achieved diastolic blood pressures might be associated with increased mortality, and whether, if true, it is causally related to the blood pressure therapy, is contentious [D’Agostino et al. 1991; Hansson et al. 1998; Boutitie et al. 2002; Wang et al. 2005] In the case of diabetes, the UK Prospective Diabetes Study (UKPDS) found patients with type 2 diabetes receiving intensive glucose therapy compared with conventional therapy achieved significant reductions in microvascular complications over 10 years [UKPDS Group, 1998]. In a legacy follow up of UKPDS participants, significant long-term microvascular, macrovascular and mortality event reductions were borne out despite relative equalization of glycated haemoglobin levels between the two original treatment arms [Holman et al. 2008]. However, in the Action to Control Cardiovascular Risk in Type 2 Diabetes (ACCORD) trial, intensive compared with usual glycaemic management was associated with an increase in mortality [Gerstein et al. 2008], an observation that still remains largely unexplained [Boyko, 2010]. In contrast, combination antiplatelet therapy (such as aspirin and clopidogrel together) has proven to be unequivocally better than aspirin alone in preventing recurrent ischaemic events,[Mehta et al. 2001; Steinhubl et al. 2002], even though higher aspirin doses alone have not been proven better than current standard doses of between 75 and 150 mg daily [Antithrombotic Trialists Collaboration, 2002]. Moreover, there is emerging evidence that higher doses of clopidogrel loading and earlier therapy in patients with acute coronary syndrome undergoing percutaneous coronary intervention (PCI) can reduce major adverse cardiac events [Dangas et al. 2009; Mehta et al. 2010]. Thus, higher dose or more intensive therapy for CVD has clear benefits in some settings, but in others has no proven benefit and even in some cases the possibility of harm. Statin therapy for lipid level control is now widely accepted as a core component of occlusive coronary disease treatment and prevention. Patients with established CVD (secondary prevention) or who have a high (>20%) 10-year risk of CVD (primary prevention) are empirically recommended statin therapy according to US National Cholesterol Education Program (NCEP) guidelines and UK National Institute for Health and Clinical Excellence (NICE) guidelines [NCEP Expert Panel, 2002; Cooper et al. 2008]. ATPIII guidelines suggest consideration of statin therapy in lower risk groups according to baseline low-density lipoprotein (LDL)-cholesterol levels and also offer different targets. For example, they suggest lifestyle modifications and consideration of statin therapy in individuals with moderate (10–20%) 10-year CVD risk with a LDL-cholesterol level greater than 3.36 mmol/liter. In individuals with a low (<10%) 10-year CVD event risk but with two or more risk factors, the recommended LDL-cholesterol level at which to consider intervention is greater than 4.1 mmol/liter [NCEP Expert Panel, 2002]. Prior to the emergence of statins, LDL-cholesterol lowering was far more difficult to achieve due to the lesser efficacy and poor side-effect profiles of earlier available therapies such as bile acid sequestrants [Hou and Goldberg, 2009]. Significant improvements in lipid profiles and CVD prevention have been achieved since. In 2005 the Cholesterol Treatment Trialists’ Collaboration published a prospective meta-analysis of individual patient data from 90,000 people in 14 trials comparing statin therapy with control [Baigent et al. 2005]. In that report, the authors were able to quantify the efficacy of statin therapy according to LDL-cholesterol reduction, and showed that a highly significant proportional relationship exists between the average amount of LDL-cholesterol lowering achieved from statin therapy in each trial and its major vascular event reduction: For each 1 mmol/liter reduction in LDL cholesterol achieved, major vascular events are reduced by about 20%. This applied over 5 years of follow up (dose response trend, p = 0.0002). This led to the next hypothesis to evaluate directly – that more aggressive lowering of LDL cholesterol, either with higher doses of the same statin or the use of newer more potent statins, compared with others should result in even greater reductions in cardiovascular events. More recently a number of trials have been completed comparing the use of more intensive statin therapy with less intensive regimens in patients with established coronary disease, attempting to ascertain if additional cardiovascular benefits can be achieved by aggressively lowering LDL cholesterol to even below ‘normal’ population levels [Armitage et al. 2010; Cannon et al. 2004; De Lemos et al. 2004; Waters et al. 2004; Pedersen et al. 2005]. Only two of the five major trials individually demonstrated a significant reduction in major vascular events with high-dose statin therapy [Larosa et al. 2005; Pedersen et al. 2005], leaving some uncertainty about the additional value of higher dose therapy. However, in late 2010 the Cholesterol Treatment Trialists’ Collaboration incorporated the results of the five major ‘more versus less’ trials in an updated meta-analysis, as well as the data from seven more ‘statin versus control’ trials published since the first analysis with their existing data [Baigent et al. 2010]. This provided information on nearly 130,000 individuals in statin versus control trials and nearly 40,000 individuals in ‘more versus less’ trials. Compared with usual dose statin therapy, high-dose treatment was associated with a highly significant reduction in major vascular events of 28% per mmol/liter LDL-cholesterol reduction achieved. After analysing trial results according to baseline LDL-cholesterol values, it was shown that a significant cardiovascular event reduction of about 20% continues to be achieved per mmol/liter reduction in LDL cholesterol even down to starting levels at less than 2.0 mmol/liter (Figures 1​1–3). On average, the high-dose trials actually lowered LDL cholesterol by an additional 0.5 mmol/liter, effectively offering around 15% greater reduction in CVD risk. Figure 1. Relation between proportional reduction in incidence of major coronary events and major vascular events and mean absolute low-density lipoprotein (LDL) cholesterol reduction at 1 year. Squares represent a single trial plotted against mean absolute LDL ... Figure 2. Effects on any major vascular event in each study. In the left panel, unweighted rate ratios (RRs) for each trial of the comparison of first event rates between randomly allocated treatment groups are plotted along with 99% confidence intervals (CIs). ... Figure 3. Effects on major vascular events per 1.0 mmol/liter reduction in low-density lipoprotein (LDL) cholesterol (LDL-C), by baseline LDL-C concentration on the less intensive or control regimen. Rate ratios (RRs) are plotted for each comparison of first event ... With the efficacy of intensive statin therapy apparent even at levels of LDL cholesterol traditionally considered low, issues of safety would appear to be the only major potential obstacle to an empiric recommendation to routine high-dose statin use. Whilst this will be of major importance to the balance of benefit and harm in individuals at low risk (e.g. <10% 10-year risk of CVD) [Cholesterol Treatment Trialists’ (CTT) Collaborators, 2012] it will be of less concern in those at high risk or with clinically established CVD. To date, the major safety concerns that have emerged relate to an increased risk of myalgias, myositis, symptomatic myopathy, rhabdomyolysis, and very rarely significant liver dysfunction. More recently, evidence of a small absolute increase in risk of new diabetes has been reported and concerns have been raised about an increased risk of intracranial haemorrhage, cognitive impairment and even cancer. Broadly speaking the conclusions of the latest CTT Collaborators analyses were that no particular major adverse effects had been identified with significantly higher frequency using high versus conventional dose statin therapy in spite of the additional lowering of LDL cholesterol [Baigent et al. 2005, 2010]. However, it is helpful to review the data relating to each of these stated individual safety concerns in turn.

Predictors of successful chronic total occlusion percutaneous coronary interventions: a systematic review and meta-analysis

Objective The aim of this study was to identify positive and negative predictors of technical and clinical success for percutaneous coronary intervention (PCI) of chronic total occlusions (CTO). Methods We conducted a systematic review and meta-analysis of studies published between 2000 and 2016 analysing rates of CTO PCI success with respect to demographic and angiographic characteristics. Crude ORs and 95% CIs for each predictor were calculated using a random effects model. Predictors of technical and clinical success were assessed among 28 demographic and 31 angiographic variables. Clinical success was defined as technical success without major adverse cardiac events. Results A total of 61 studies, totalling 69 886 patients were included in this analysis. The major demographic characteristics associated with a 20% or greater reduction in the odds of technical and clinical success were a history of myocardial infarction, PCI, coronary artery bypass grafting, stroke/transient ischaemic attack and peripheral vascular disease. Angiographic factors were generally stronger predictors of reduced technical and clinical success. Those associated with >20% odds reduction included non-left anterior descending CTOs, multivessel disease, presence of bridging collaterals, moderate-to-severe calcification, >45 degree vessel bending, tortuous vessel, blunt stump and ostial lesions. Of these, novel predictors included prior PCI, prior stroke, peripheral vascular disease, presence of multivessel disease and bridging collaterals. Conclusion The present study has identified strong negative predictors for clinical success for CTO PCI, which will aid in patient selection for this procedure.

Beta-blocker, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, nitrate-hydralazine, diuretics, aldosterone antagonist, ivabradine, devices and digoxin (BANDAID2): an evidence-based mnemonic for the treatment of systolic heart failure

Heart failure causes significant morbidity and mortality, with recognised underutilisation rates of guideline‐based therapies. Our aim was to review current evidence for heart failure treatments and derive a mnemonic summarising best practice, which might assist physicians in patient care. Treatments were identified for review from multinational society guidelines and recent randomised trials, with a primary aim of examining their effects in systolic heart failure patients on mortality, hospitalisation rates and symptoms. Secondary aims were to consider other clinical benefits. MEDLINE and EMBASE were searched using a structured keyword strategy and the retrieved articles were evaluated methodically to produce an optimised reference list for each treatment. We devised the mnemonic BANDAID 2, standing for beta‐blocker, angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker, nitrate‐hydralazine (or potentially neprilysin inhibitor), diuretics, aldosterone antagonist, ivabradine, devices (automatic implantable cardioverter defibrillator, cardiac resynchronisation therapy or both) and digoxin as a representation of treatments with strong evidence for their use in systolic heart failure. Treatment with omega‐3 fatty acids, statins or anti‐thrombotic therapies has limited benefits in a general heart failure population. Adoption of this mnemonic for current evidence‐based treatments for heart failure may help improve prescribing rates and patient outcomes in this debilitating, high mortality condition.

BANDAID2 – An evidence based mnemonic for the treatment of systolic heart failure

Heart failure causes significant morbidity and mortality, with recognised underutilisation rates of guideline‐based therapies. Our aim was to review current evidence for heart failure treatments and derive a mnemonic summarising best practice, which might assist physicians in patient care. Treatments were identified for review from multinational society guidelines and recent randomised trials, with a primary aim of examining their effects in systolic heart failure patients on mortality, hospitalisation rates and symptoms. Secondary aims were to consider other clinical benefits. MEDLINE and EMBASE were searched using a structured keyword strategy and the retrieved articles were evaluated methodically to produce an optimised reference list for each treatment. We devised the mnemonic BANDAID 2, standing for beta‐blocker, angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker, nitrate‐hydralazine (or potentially neprilysin inhibitor), diuretics, aldosterone antagonist, ivabradine, devices (automatic implantable cardioverter defibrillator, cardiac resynchronisation therapy or both) and digoxin as a representation of treatments with strong evidence for their use in systolic heart failure. Treatment with omega‐3 fatty acids, statins or anti‐thrombotic therapies has limited benefits in a general heart failure population. Adoption of this mnemonic for current evidence‐based treatments for heart failure may help improve prescribing rates and patient outcomes in this debilitating, high mortality condition.

Is it time to repair a Fairly Fast SAAB Convertible? Testing an evidence-based mnemonic for the secondary prevention of cardiovascular disease.

OBJECTIVES Optimising secondary prevention of cardiovascular disease has the greatest potential to reduce recurrent events, yet despite major guidelines there are ongoing treatment gaps. FFSAABC (Fish oils, Fibrates, Statins, Aspirin, Angiotensin converting enzyme inhibitors or angiotensin 2 receptor antagonists, Beta blockers and Clopidogrel) is one mnemonic previously adopted to assist clinicians in remembering medications for use in secondary prevention. The aim of this narrative review is to examine the current evidence base for medications recommended for patients with established cardiovascular disease and the current applicability of this, or a revised mnemonic for their use. STUDY DESIGN Randomised controlled trials and systematic reviews were sought examining Fish oils, Fibrates, Statins, Aspirin, Angiotensin converting enzyme inhibitors or angiotensin 2 receptor antagonists, Beta blockers or Clopidogrel vs placebo in secondary prevention. The emerging evidence base for other contemporary therapies including the P2Y12 inhibitors (ticagrelor and prasugrel) and aldosterone antagonists was also reviewed. RESULTS Definitive evidence supports the use of statins, aspirin, angiotensin converting enzyme inhibitors or angiotensin 2 receptor antagonists, and P2Y12 antagonists (clopidogrel, ticagrelor or prasugrel) for the secondary prevention of cardiovascular disease. Aldosterone antagonists have strong evidence in the presence of systolic heart failure. There is a weaker evidence base for the routine use of omega-3 fatty acid supplementation although this therapy carries minimal harms. Fenofibrate reduces cardiovascular events in dyslipidaemic patients, with additional benefits in patients with diabetes. CONCLUSIONS Mnemonic upgrading from a Fairly Fast SAAB Convertible to a Fairly Fast SA(2)A(2)B (Fish oils, Fibrate, Statin, Antiplatelets (Aspirin+Other), ACE/ARB, Aldosterone Antagonist, Beta-blocker) may help to ensure patients receive best practice evidence-based pharmacotherapies for the secondary prevention of cardiovascular disease.

Optical coherence tomography for serial in vivo imaging of aortic plaque in the rabbit: a preliminary experience

Background In this pilot feasibility study, we aimed to establish a reproducible means of performing serial optical coherence tomography (OCT) procedures in the abdominal aorta of the cholesterol-fed rabbit. Methods Eight cholesterol-fed New Zealand White rabbits were assigned to abdominal aortic balloon injury at baseline (n=6) or as controls (n=2). Three of the balloon injured rabbits received statins from weeks 6 to 12 post balloon injury. OCT of the abdominal aorta in each rabbit was performed at baseline±week 6±week 12 via alternate vascular access points (left or right femoral artery or left carotid artery). OCT sequences were analysed to derive an indexed plaque volume and other OCT measures of plaque complexity, and results were compared between groups. Histopathological correlations with OCT images were made following terminal procedures. Results Of the 16 OCT procedures in these rabbits (6 at baseline, 4 at 6 weeks, 6 at 12 weeks), excellent and analysable images were obtained on 15 occasions (94%). Inability to obtain adequate arterial access for the OCT catheter was the major experimental limitation encountered in the early part of our experience. Balloon injured rabbits developed larger volume and more complex plaque than non-balloon injured rabbits on all OCT indices measured (eg, both mean plaque volume and lumen stenosis were approximately double in the balloon injured group, p<0.0001). A significant correlation between 12 week measures of plaque area by OCT and histology was demonstrated (Pearson correlation coefficient: 0.992, p<0.0001). Conclusions Our preliminary experience suggests that serial OCT of the abdominal aorta in the New Zealand White rabbit is feasible and a potentially promising means of performing serial studies of aortic atherosclerosis.

The role of statin therapy in patients with lower vascular risk.

he th dis T re is no doubting the fundamental role of statin erapy in patients with established cardiovascular ease. However, its role in primary prevention, particularly among patients with lower absolute cardiovascular risk, has been uncertain.1 In 2010, in a meta-analysis of data from 170 000 individual patients with or without cardiovascular disease, the Cholesterol Treatment Trialists’ Collaboration (CTTC) showed that each 1 mmol/L reduction in low-density lipoprotein (LDL)-cholesterol level was associated with a reduction in the incidence of major vascular events of about 20% over 5 years, even among those with starting LDL-cholesterol levels less than 2.0 mmol/L.2 But is this benefit equally applicable to subgroups of patients who have no history of cardiovascular disease and those who have a lower absolute cardiovascular risk? As at least half of all vascular events occur among the latter patient group,3 resolving this uncertainty is important. Recently, the CTTC conducted a further meta-analysis according to risk of vascular disease,3 using their protocol for meta-analysis that prospectively describes study entry criteria, analytical methods and common end points, and thus has greater validity than a protocol formulated posthoc. The CTTC also has access to patient-level data, which provides more reliable estimates of treatment effects than a standard meta-analysis. Patients were stratified at baseline into five arbitrary whole-number categories of 5-year risk of a major vascular event: < 5%; 5% to < 10%; 10% to < 20%; 20% to < 30%; or 30%. The reduction in major vascular events among each group was similar to the overall reduction of 21% for each 1 mmol/L reduction in LDL-cholesterol level. Among patients with no history of vascular disease, those in the two lowest-risk groups who received treatment had significant proportional reductions in the risk of a major vascular event, which were at least as large as ts in higher-risk groups. duced by 15% (and overall patients with diabetes or cluded from the analysis. ncidence and cancer mor-