ISCHAEMIC HEART DISEASE

Rescue angioplasty: should we or shouldn’t we? ▸

Although primary percutaneous coronary intervention (PCI) is a proven therapeutic approach in ST elevation myocardial infarction (STEMI) and is used increasingly, intravenous thrombolysis remains the first line treatment in 30–70% of cases worldwide. However, thrombolysis results in a grade 3 flow, according to the thrombolysis in myocardial infarction (TIMI) classification system, in only 60% of patients, even with current fibrin specific agents. To date, it has been unclear how best to treat the remaining patients, in whom thrombolysis has not worked. In a randomised trial involving 427 patients with STEMI of < 6 hours’ duration treated with thrombolysis, in whom reperfusion failed to occur (< 50% ST segment resolution) within 90 minutes, patients were randomly assigned to repeated thrombolysis (142 patients), conservative treatment (141 patients), or rescue PCI (144 patients). The primary end point was a composite of death, reinfarction, stroke, or severe heart failure within six months. The rate of event-free survival among patients treated with rescue PCI was 84.6%, as compared with 70.1% among those receiving conservative treatment and 68.7% among those undergoing repeated thrombolysis (overall p  =  0.004). The adjusted hazard ratio for the occurrence of the primary end point for repeated thrombolysis versus conservative treatment was 1.09 (95% confidence interval (CI) 0.71 to 1.67; p  =  0.69), as compared with adjusted hazard ratios of 0.43 (95% CI 0.26 to 0.72; p  =  0.001) for rescue PCI versus repeated thrombolysis and 0.47 (95% 0.28 to 0.79; p  =  0.004) for rescue PCI versus conservative treatment. There were no significant differences in mortality from all causes. Non-fatal bleeding, mostly at the sheath insertion site, was more common with rescue PCI, although mortality related to bleeding was higher in the other two groups. At six months, 86.2% of the rescue PCI group were free from revascularisation, as compared with 77.6% of the conservative treatment group and 74.4% of the repeated thrombolysis group (overall p  =  0.05). These results are considerably more encouraging than those of the Middlesbrough early revascularization to limit infarction (MERLIN) trial, where only repeat revascularisation was reduced despite mortality in the conservative arms being similar. This has generated some debate, but at present, attempting rescue PCI would appear to be a reasonable option.

Fenofibrate in diabetes trial: probably statin first line still ▸

A multinational, randomised controlled trial with 9795 participants aged 50–75 years, with type 2 diabetes mellitus, and not taking statin treatment at study entry, randomly assigned patients (2131 with previous cardiovascular disease and 7664 without) with a total cholesterol concentration of 3.0–6.5 mmol/l and a total cholesterol/high density lipoprotein (HDL) cholesterol ratio of 4.0 or more, or plasma triglyceride of 1.0–5.0 mmol/l, to micronised fenofibrate 200 mg daily (n  =  4895) or matching placebo (n  =  4900). The primary outcome was coronary events (coronary heart disease death or non-fatal myocardial infarction (MI)); the outcome for prespecified subgroup analyses was total cardiovascular events (the composite of cardiovascular death, MI, stroke, and coronary and carotid revascularisation). Analysis was by intention to treat. Over the five years’ study duration, similar proportions in each group discontinued study medication (10% placebo v 11% fenofibrate) and more patients allocated placebo (17%) than fenofibrate (8%; p < 0.0001) commenced other lipid treatments, predominantly statins; 5.9% (n  =  288) of patients on placebo and 5.2% (n  =  256) of those on fenofibrate had a coronary event (relative reduction of 11%; hazard ratio (HR) 0.89, 95% CI 0.75 to 1.05; p  =  0.16). This finding corresponds to a significant 24% reduction in non-fatal myocardial infarction (HR 0.76, 95% CI 0.62 to 0.94; p  =  0.010) and a non-significant increase in coronary heart disease mortality (HR 1.19, 95% CI 0.90 to 1.57; p  =  0.22). Total cardiovascular disease events were significantly reduced from 13.9% to 12.5% (HR 0.89, 95% CI 0.80 to 0.99; p  =  0.035). This finding included a 21% reduction in coronary revascularisation (HR 0.79, 95% CI 0.68 to 0.93; p  =  0.003). Total mortality was 6.6% in the placebo group and 7.3% in the fenofibrate group (p  =  0.18).

High dose statins are safe and effective ▸

Although recent studies, such as the treating to new targets (TNT) trial, had suggested incremental benefit with intensive lipid lowering of low density lipoprotein (LDL) cholesterol to below 100 mg/dl (2.59 mmol/l), concerns had been expressed that the benefit of reduced cardiovascular mortality may be offset by an increase in the number of deaths due to non-cardiovascular causes. The IDEAL (incremental decrease in end points through aggressive lipid lowering) study was a prospective, randomised, open label, blind end point evaluation trial conducted across Northern Europe. A total of 8888 patients were enrolled and followed up over a median period of 4.8 years. All had a history of acute MI. Patients were randomly assigned to receive a high dose of atorvastatin (80 mg/day; n  =  4439) or usual dose simvastatin (20 mg/day; n  =  4449). The main outcome measure was the occurrence of a major coronary event, defined as either a coronary death, confirmed non-fatal acute MI, or cardiac arrest with resuscitation. During treatment, mean LDL cholesterol values were 104 mg/dl (2.69 mmol/l) in the simvastatin group and 81 mg/dl (2.09 mmol/l) in the atorvastatin group. A major coronary event occurred in 463 simvastatin patients (10.4%) and in 411 atorvastatin patients (9.3%) (HR 0.89; p  =  0.07). Non-fatal MI occurred in 321 (7.2%) and 267 (6.0%) in the two groups (p  =  0.02), but no differences were seen in the two other components of the primary end point. Major cardiovascular events occurred in 608 and 533 patients in the two groups, respectively (p  =  0.02), while occurrence of any coronary event was reported in 1059 simvastatin and 898 atorvastatin patients (p < 0.001). Non-cardiovascular death occurred in 156 (3.5%) and 143 (3.2%) in the two groups (p  =  0.47), while death from any cause occurred in 374 (8.4%) in the simvastatin group and 366 (8.2%) in the atorvastatin group (HR 0.98; p  =  0.81). Patients in the atorvastatin group had higher rates of drug discontinuation due to non-serious adverse events, namely transaminase elevation resulted in 43 (1.0%) versus 5 (0.1%) withdrawals (p < 0.001). There were no significant differences in the rates of myopathy and rhabdomyolysis, which were rare in both groups. IDEAL agrees with other trials in showing that aggressive lowering of cholesterol leads to reduced cardiovascular events. For practising physicians, it emphasises that patients must be treated with an appropriate dose of statin, that monitoring LDL values is crucial, and, most importantly, that statin use is safe overall, even at high doses.

HEART FAILURE

Stick to the tablets—even if they are placebo ▸

CHARM was a double blind, randomised, controlled clinical trial, comparing the effects of the angiotensin receptor blocker candesartan with placebo in 7599 patients with chronic heart failure (CHF). Median follow up was 38 months. The proportion of time patients took more than 80% of their study medication was defined as good adherence and 80% or less as poor adherence. Good adherence was associated with lower all cause mortality in all patients (HR 0.65, 95% CI 0.57 to 0.75; p < 0.0001). The adjusted HR for good adherence was similar in the candesartan (0.66, 95% CI 0.55 to 0.81; p < 0.0001) and placebo (0.64, 95% CI 0.53 to 0.78; p < 0.0001) groups. This finding suggests that adherence is a marker for adherence to effective treatments other than study medications, or to other adherence behaviours that affect outcome. Understanding these factors could provide an opportunity for new interventions, including those aimed at improving adherence.

HYPERTENSION

ACE inhibitors and ARBs are the best antihypertensive drugs in renal disease: fact or fantasy? ▸

Conventional wisdom suggests a specific benefit for angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in patients with diabetes or renal disease who have hypertension. Controversially, this article suggests the effects may be overstated, and particularly in diabetes, anything beyond blood pressure control is very speculative. Comparisons of ACE inhibitors or ARBs with other antihypertensive drugs yielded a relative risk (RR) of 0.71 (95% CI 0.49 to 1.04) for doubling of creatinine and a small benefit on end stage renal disease (RR 0.87, 95% CI 0.75 to 0.99). In patients with diabetic nephropathy, no benefit was seen in comparative trials of ACE inhibitors or ARBs on the doubling of creatinine (RR 1.09, 95% CI 0.55 to 2.15), end stage renal disease (RR 0.89, 95% CI 0.74 to 1.07), glomerular filtration rate, or creatinine amounts. However, what they also show is that these drugs are at least safe in renal disease, even if they are not renoprotective.

GENERAL CARDIOLOGY

ACE inhibitors are safe in moderate/severe renal impairment ▸

In a trial of over 200 patients, 44 of 108 patients given benazepril (41%) and 65 of 107 patients given placebo (60%) had a doubling of creatinine over a mean of 3.4 years (the primary end point). As compared with placebo, benazepril was associated with a 43% reduction in the risk (p  =  0.005). This benefit did not appear to be attributable to blood pressure control. Benazepril treatment was associated with a 52% reduction in the level of proteinuria and a reduction of 23% in the rate of decline in renal function. This clinical trial demonstrates that ACE inhibitors can be administered in generous doses, even in patients with advanced chronic kidney disease (glomerular filtration rate (GFR) of 15–29 ml/min/1.73 m², a serum creatinine concentration of 265–442 µmol/l). Doing so may mean that end stage renal disease takes twice as long to develop in the group given benazepril as in the control cohort: 7 years instead of 3.5 years. Hou et al used a daily dose of 20 mg of benazepril, half the maximal recommended dose for patients with chronic kidney disease. This choice is remarkable because almost all studies that have demonstrated a renal protective effect of ACE inhibitors used about 15–25% of the maximal recommended dose, and the patients in those studies had GFRs that were 50–100% higher than the rates in the patients studied by Hou et al. Another important difference is that Hou et al used a twice daily dose, a regimen that provides little opportunity for nocturnal recovery from any hyperkalaemia that might have developed during the day as a result of dietary intake. Thus, it is surprising that serious hyperkalaemia was not a major problem in the study. The absence of serious hyperkalaemia might be explained by three factors. First, during the eight week run-in period, about 5% of the patients in group 2 were excluded because of the development of hyperkalaemia or an inordinate increase in serum creatinine concentrations, or because of an adherence rate of less than 80%. Second, potassium intake in these Chinese patients may have been substantially lower than that of most western patients. Third, more than 80% of the patients in group 2 received a diuretic during follow up. With these caveats, at least ACE inhibitors should be strongly considered in patients with advanced renal impairment.

Intensive glucose control reduces the risk of cardiovascular complications ▸

The diabetes control and complications trial (DCCT) randomly assigned 1441 patients with type 1 diabetes to intensive or conventional therapy, treating them for a mean of 6.5 years between 1983 and 1993. Ninety three per cent were subsequently followed until 1 February 2005, during the observational epidemiology of diabetes interventions and complications (EDIC) study. The EDIC trial was a multicentre, longitudinal, observational study designed to use cohort from the DCCT, which compared intensive insulin treatment with conventional insulin regimens in patients with type 1 diabetes. One of the most important goals was the prospective evaluation of the long term effects of differences in prior diabetes treatment (conventional v intensive) during the DCCT on the development and progression of cardiovascular disease in patients with type 1 diabetes. It has been suggested that cardiovascular disease has overtaken diabetic nephropathy as the leading cause of premature death among young adults with diabetes. At year 11 of the EDIC study, intensive insulin treatment was superior to conventional regimens in reducing the risk of cardiovascular disease. Specifically, as compared with conventional therapy, intensive insulin treatment reduced the risk of any cardiovascular disease by 42% and of non-fatal myocardial infarction, stroke, or death from cardiovascular causes by 57%. Improved glycaemic control, as assessed by the decrease in glycosylated haemoglobin values during the DCCT, appeared to account for much of the cardiovascular benefit attributed to intensive insulin treatment. Although the target HbA1c was 6% in DCCT, at the end of the trial the intensive group was at 7.4% v 9.1% in the conventional arm. At 11 years of follow up, in EDIC, the gap had narrowed to 8% and 8.2%, despite all patients trying to follow more intensive regimens. The American Diabetic Association at present suggests HbA1c < 7% as the target.

AICD patients should continue antiarrhythmic medication ▸

At total of 412 patients from 39 outpatient automatic implantable cardioverter-defibrillator (AICD) clinical centres located in North America and Europe were randomised to treatment for one year with amiodarone plus β blocker, sotalol alone, or β blocker alone. Primary outcome was ICD shock for any reason. Shocks occurred in 41 patients (38.5%) assigned to β blocker alone, 26 (24.3%) assigned to sotalol, and 12 (10.3%) assigned to amiodarone plus β blocker. A reduction in the risk of shock was observed with use of either amiodarone plus β blocker or sotalol versus β blocker alone (HR 0.44, 95% CI 0.28 to 0.68; p < 0.001). Amiodarone plus β blocker significantly reduced the risk of shock compared with β blocker alone (HR 0.27, 95% CI 0.14 to 0.52; p < 0.001) and sotalol (HR 0.43, 95% CI 0.22 to 0.85; p  =  0.02). There was a trend for sotalol to reduce shocks compared with β blocker alone (HR 0.61, 95% CI 0.37 to 1.01; p  =  0.055). The rates of study drug discontinuation at one year were 18.2% for amiodarone, 23.5% for sotalol, and 5.3% for β blocker alone. Adverse pulmonary and thyroid events and symptomatic bradycardia were more common among patients randomised to amiodarone. Since AICD shocks are painful and psychologically damaging, attempts to avoid them are useful. Amiodarone alone was not tested, but may have been useful.

Amiodarone prophylaxis perioperatively is safe and effective ▸

Atrial tachyarrhythmias after cardiac surgery are associated with adverse outcomes and increased costs. Previous trials of amiodarone prophylaxis, while promising, were relatively small and yielded conflicting results. A double blind randomised controlled trial of 601 patients listed for non-emergent coronary artery bypass graft (CABG) surgery and/or valve replacement/repair surgery was performed. The patients were followed up for one year. Oral amiodarone (10 mg/kg daily) or placebo were administered six days before surgery through to six days after surgery (13 days). Randomisation was stratified for subgroups defined by age, type of surgery, and use of preoperative β blockers. Incidence of atrial tachyarrhythmias lasting five minutes or longer that prompted treatment by the sixth postoperative day was the primary end point. Atrial tachyarrhythmias occurred in fewer amiodarone patients (48/299, 16.1%) than in placebo patients (89/302, 29.5%) overall (HR 0.52, 95% CI 0.34 to 0.69; p < 0.001). This was maintained in all subgroups and was independent of the use of β blockade, or the type of surgery. Postoperative sustained ventricular tachyarrhythmias occurred less frequently in amiodarone patients (1/299, 0.3%) than in placebo patients (8/302, 2.6%) (p  =  0.04). Dosage reductions of blinded treatment were more common in amiodarone patients (34/299, 11.4%) than in placebo patients (16/302, 5.3%) (p  =  0.008), suggesting possible side effects. There were no differences in serious postoperative complications, in-hospital mortality, or readmission to the hospital within six months of discharge or in one year mortality.

Erectile dysfunction as marker of coronary risk is like smoking or family history ▸

Of the men aged 55 years or older who were randomised to the placebo group (n  =  9457) in the prostate cancer prevention trial, 8063 (85%) had no cardiovascular disease at study entry; of these men, 3816 (47%) had erectile dysfunction at study entry. Among the 4247 men without erectile dysfunction at study entry, 2420 men (57%) reported incident erectile dysfunction after five years. After adjustment, incident erectile dysfunction was associated with a hazard ratio of 1.25 (95% CI 1.02 to 1.53; p  =  0.04) for subsequent cardiovascular events during study follow up. For men with either incident or prevalent erectile dysfunction, the hazard ratio was 1.45 (95% CI 1.25 to 1.69; p < 0.001). This risk association was estimated to be in the range of risk associated with current smoking or a family history of myocardial infarction.

Advise patients to lose weight as well as giving them pills ▸

Weight loss medications are recommended as an adjunct to a comprehensive programme of diet, exercise, and behaviour therapy, but are typically prescribed with minimal or no lifestyle modification. This practice is likely to limit therapeutic benefits. In this one year trial, 224 obese adults were randomly assigned to receive 15 mg of sibutramine per day alone, delivered by a primary care provider in eight visits of 10–15 minutes each; lifestyle modification counselling alone, delivered in 30 group sessions; sibutramine plus 30 group sessions of lifestyle modification counselling (that is, combined therapy); or sibutramine plus brief lifestyle modification counselling delivered by a primary care provider in eight visits of 10–15 minutes each. All subjects were prescribed a diet of 1200–1500 kcal per day and the same exercise regimen. At one year, subjects who received combined therapy lost a mean (SD) of 12.1 (9.8) kg, whereas those receiving sibutramine alone lost 5.0 (7.4) kg, those treated by lifestyle modification alone lost 6.7 (7.9) kg, and those receiving sibutramine plus brief therapy lost 7.5 (8.0) kg (p < 0.001). Those in the combined therapy group who frequently recorded their food intake lost more weight than those who did so infrequently (18.1 (9.8) kg v 7.7 (7.5) kg; p  =  0.04). The combination of medication and group lifestyle modification resulted in more weight loss than either medication or lifestyle modification alone.

Radiofrequency ablation at the time of mitral valve surgery ▸

More than 40% of patients referred for mitral valve surgery have continuous atrial fibrillation. However, data on the use of left atrial radiofrequency ablation (RFA) in this context are not known. Doukas and colleagues performed RFA of the left atrium on 49 of 97 patients who underwent mitral valve surgery over a two year period. All patients had had at least six months of uninterrupted atrial fibrillation. Follow up lasted 12 months. The primary outcome measure was presence of sinus rhythm at 12 months; secondary measures included patient functional status and exercise capacity, left atrial contraction, plasma concentrations of B type natriuretic peptide, and left atrial and ventricular dimensions and function. Twenty (44.4%) of 45 RFA patients were in sinus rhythm at 12 months, compared to two (4.5%) of 44 controls (p < 0.001). Restoration of sinus rhythm in the RFA group was accompanied by a greater improvement in exercise ability and a greater reduction in B type natriuretic peptide. Postoperative rates of complications and deaths were similar in both groups. The authors therefore suggest that routine use of left atrial RFA during mitral valve surgery is safe and effective at restoring sinus rhythm and improving exercise capacity. This needs to be introduced with proper quality control and safety data if randomised trials prove a benefit.

BASIC SCIENCE

Sinus bradycardia doesn’t mean you are extra fit ▸

Although being fit gives a high vagal tone, and so a relative bradycardia, some patients have pathological reasons for a slow heart rate. In asymptomatic patients, a familial pattern can sometimes be seen. The “funny” current (I_f) causes a sloping depolarisation in the sino-atrial node, before activation occurs. β Adrenergic stimulation accelerates the slope via increasing c-AMP, and thereby increases heart rate. Vagal activity does the reverse. This group screened for mutations in the gene for the pacemaker HCN4 ion channel which make up the mammalian “f” channel, producing the “funny” current. They found a mutation in exon 7, S672R, in an Italian family that correlated with sinus bradycardia. They proved the functional relevance of the mutation by transfecting cells in vitro and assessing their depolarisation characteristics, and confirmed that the change was caused by a negative shift in the activation curve unrelated to c-AMP binding. A similar shift occurs in the wild type channel with vagal stimulation via changes in c-AMP.

Journals scanned

American Journal of Medicine; American Journal of Physiology: Heart and Circulatory Physiology; Annals of Emergency Medicine; Annals of Thoracic Surgery; Archives of Internal Medicine; BMJ; Chest; European Journal of Cardiothoracic Surgery; Lancet; JAMA; Journal of Clinical Investigation; Journal of Diabetes and its Complications; Journal of Immunology; Journal of Thoracic and Cardiovascular Surgery; Nature Medicine; New England Journal of Medicine; Pharmacoeconomics; Thorax

Reviewers

Dr Diana Gorog, Dr Akhil Kapur, Dr Masood Khan, Dr Alistair Lindsay, Dr Andrew Sharp