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Cardiogenic shock carries a mortality rate in excess of 50%. Induction of nitric oxide synthase (NOS), leading to the generation of excess nitric oxide, is believed to contribute to the inappropriate vasodilatation seen in cardiogenic shock. Tilarginine acts as an NOS inhibitor and early studies have suggested a potential clinical benefit. The TRIUMPH (Tilarginine Acetate Injection in a Randomized International Study in Unstable MI Patients With Cardiogenic Shock) planned to enrol 658 patients at 130 centres, however the study was terminated early after 398 patients had been enrolled. All patients were in refractory cardiogenic shock after myocardial infarction (MI) despite revascularisation. The primary outcome was all‐cause mortality among patients who received the study drug. Secondary outcomes included shock resolution and duration, NYHA class at 30 days, and 6‐month mortality. Enrolment was stopped in August 2006 and the 6‐month follow‐up completed in February 2007. No difference in 30‐day all‐cause mortality was found between patients who received tilarginine (48%) and those who received placebo (42%; p=0.24). Resolution of shock (66% for tilarginine, 61% for placebo; p=0.31) and duration of shock (156 vs 190 hours; p=0.16) were similar. At 30 days a similar percentage of patients had heart failure (48% tilarginine vs 51% placebo; p=0.51), with a similar percentage of patients in NYHA class I/II (73% tilarginine vs 75% placebo; p=0.27). After 6 months, mortality rates were similar in the two groups (58% tilarginine vs 59% placebo; p=0.80). Tilarginine did not reduce mortality rates in patients with refractory cardiogenic shock complicating MI despite an open infarct artery. It should be borne in mind that in this trial the drug was given late once shock was established; NOS inhibition might still theoretically have an important role if given at an earlier stage.
The TRIUMPH Investigators. Effect of tilarginine acetate in patients with acute myocardial infarction and cardiogenic shock. JAMA 2007;297:1657–66.
An inflammatory response has been postulated as one of the triggering factors for postoperative atrial fibrillation (AF). Therefore, might suppression of this response with corticosteroids decrease the incidence of AF? Halonen et al conducted a double‐blind, randomised multicentre trial in three university hospitals in Finland over the course of 1 year. Two hundred and forty‐one consecutive patients undergoing on‐pump coronary artery bypass grafting, aortic valve replacement, or a combination—none of whom had a prior history of AF or flutter—were randomised to receive either 100 mg hydrocortisone or matching placebo. The first dose was given on the evening of the operative day, then one dose given every 8 hours for the next 8 days. In addition, all patients received oral metoprolol (50–150 mg/day) titrated to heart rate. The main outcome measure was the occurrence of AF during the first 84 hours after surgery. The incidence of postoperative AF was significantly lower in the hydrocortisone group (36/120 (36%) than in the placebo group 58/121 (48%); p=0.004). Patients receiving hydrocortisone did not have higher rates of superficial or deep wound infections, or other major complications, in comparison with those receiving placebo. Patients taking steroids also had less postoperative nausea, vomiting and anorexia. The authors conclude that their promising findings should be backed up by larger‐scale clinical trials.
Halonen J, Halonen P, Jarvinen O, et al. Corticosteroids for the prevention of atrial fibrillation after cardiac surgery. JAMA 2007;297:1562–7.
An inappropriate increase of arginine vasopressin has a major role in the fluid retention seen in heart failure. Tolvaptan, an arginine vasopressor V2 receptor blocker, has previously been shown to improve fluid management and haemodynamics; now two articles in the Journal of the American Medical Association report findings from the multicentre Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) clinical trials programme. In the first trial, Konstam and colleagues randomised 4133 patients admitted with heart failure to tolvaptan 30 mg once a day (n=2072) or placebo (n=2061). All patients were randomised within 48 hours of admission and given treatment for a minimum of 60 days; all had NYHA class 3–4 heart failure and a left ventricular ejection fraction <40%. Dual primary end points were all‐cause mortality (superiority and non‐inferiority) and cardiovascular death or hospitalisation for heart failure (superiority only). Secondary end points included changes in dyspnoea, body weight and oedema. Median follow‐up was for 9.9 months; 537 patients (25.9%) in the tolvaptan group and 543 (26.3%) in the placebo group died (p=0.68). The combined number of cardiovascular deaths or hospitalisations for heart failure occurred in 871 (42.0%) tolvaptan group patients and 829 (40.2) placebo group patients (hazard ratio=1.04; 95% CI 0.95 to 1.14; p=0.55). Tolvaptan significantly improved secondary end points of patient‐assessed dyspnoea at day 1, day 1 body weight, and oedema after 7 days. In patients with hyponatraemia, serum sodium levels significantly increased. The Kansas City Cardiomyopathy Questionnaire overall summary score was not improved at outpatient week 1, but body weight and serum sodium effects persisted long after discharge. Long‐term tolvaptan treatment thus had no effect, either favourable or unfavourable, on all‐cause mortality or the combined end point of cardiovascular mortality or subsequent hospitalisation for worsening heart failure. The upper confidence limit for the mortality difference was within the prespecified non‐inferiority margin of 1.25 (p<0.001).
Gheorghiade et al reported on the short‐term effects of the drug on symptom relief in the same patients, but presented this as two trials that were based on location of study centre assigned. Trial A recruited 2048 patients and trial B 2085. The primary end point was a composite of changes in clinical status based on a visual analogue scale and body weight at day 7 (or discharge if earlier). Secondary end points included dyspnoea, global clinical status, body weight and peripheral oedema. Rank sum analysis of the composite primary end point showed greater initial improvement in dyspnoea, orthopnoea, jugular venous distension, rales and oedema with tolvaptan than placebo in both trials. Mean body weight reduction was greater with tolvaptan on day 1 (trial A: −1.71 kg vs −0.99 kg; p<0.001, and trial B: −1.82 kg vs −0.95 kg; p<0.001) and also after 1 week of treatment or at discharge (whichever was earlier). However, no improvements in global clinical status were seen between the groups. More patients receiving tolvaptan (76.7% vs 70.6% for trial A, 72.1% vs 65.3% for trial B; both trials p<0.001) reported an improvement in dyspnoea at day 1. Oedema at day 7 or discharge improved significantly with tolvaptan in trial B but not in trial A. Serious adverse event frequencies were similar between groups, without excess renal failure or hypotension. Overall, these trials tell us that tolvaptan relieves some of the symptoms of acute decompensated heart failure without having any serious adverse effects. However, there was no indication that the drug influenced either heart‐failure‐related hospital admissions or mortality at 1 year.
Yancy CW. Climbing the mountain of acute decompensated heart failure The EVEREST Trials. JAMA 2007;297:1374–6.
Gheorghiade M, Konstam MA, Burnett JC, et al. Short‐term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure JAMA 2007;297:1332–43.
The EVEREST Clinical Status Trials. JAMA 2007;297:1332–43.
Konstam MA, Gheorghiade M, Burnett JC, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST outcome trial. JAMA 2007;297:1319–31.
Can statin treatment cause coronary artery disease to regress? The METEOR (Measuring Effects of Intima–Media Thickness: an evaluation of Rosuvastatin) study was designed to investigate the effect of a 40 mg dose of rosuvastatin on carotid intima–media thickness (CIMT) over the course of 2 years in middle‐aged people with low Framingham risk scores and subclinical atherosclerosis. The study was a randomised, double‐blind, placebo‐controlled trial. Nine hundred and eighty‐four patients were randomised to receive placebo or rosuvastatin 40 mg in a 2:5 ratio. The mean age of participants was 57, and all had modest CIMT thickening (<3.5 mm at all sites), and raised low‐density lipoprotein (LDL) cholesterol (mean 4.0 mmmol/l) at the time of enrolling. Rate of change in maximum CIMT at 12 carotid sites was assessed with B‐mode ultrasound; regression was also assessed, but only in the rosuvastatin‐treated patients. The rosuvastatin group showed a mean reduction in LDL cholesterol of 49%, declining from 4.0 mmol/l to 2.0 mmol/l. The change in maximum CIMT was −0.0014 mm/year for 12 sites in the rosuvastatin group vs 0.0131 mm/year for the placebo group; although similar results were found for individual carotid segments, no overall regression of atherosclerosis burden was seen in this trial. Rosuvastatin 40 mg was well tolerated with few side effects—six participants had eight events over 2 years. Thus although rosuvastatin slowed the progression of CIMT over the 2 years, it did not induce regression. The trial remains significant for demonstrating that, when left untreated, even people at relatively low‐risk such as those studied here can have progressive subclinical atherosclerotic disease. Statins have an important role in slowing disease progression.
Crouse JR III, Raichlen JS, Riley WA, et al, for the METEOR study group. Effect of rosuvastatin on progression of carotid intima‐media thickness in low‐risk individuals with subclinical atherosclerosis: the METEOR trial. JAMA 2007;297:1344–53.
A study from New Jersey, USA, has shown that patients' outcomes from myocardial infarction (MI) vary according to the day of the week on which they are admitted. A total of 231364 patients with a first presentation acute MI between 1987 and 2002 were studied. Data were obtained from the Myocardial Infarction Data Acquisition System (MIDAS) database; this contains sociodemographic and clinical data on patients discharged with the diagnosis of acute MI from all non‐federal acute care hospitals in New Jersey. The primary outcome variable was death within 30 days after admission. Both inhospital and cumulative (inpatient or after discharge) mortality rates were examined at various intervals, including up to 1 year from the index event. The primary independent variable was admission at weekends (Saturday or Sunday) versus weekdays. Patients admitted at weekends were less likely to undergo invasive procedures than those admitted on weekdays. The probability of catheterisation by the day after admission was significantly lower for patients admitted at weekends (p<0.001 for all comparisons). In the interval 1999–2002 (59786 admissions), 30‐day mortality was significantly higher for patients admitted at weekends (12.9% vs 12.0%; p=0.006). This difference became significant the day after admission (3.3% vs 2.7%; p<0.001) and persisted at 1 year (1% absolute difference in mortality). When the definition of “weekend” was expanded to include Friday after 17:00, the adjusted 30‐day risk of death was similar to that in the original analysis (hazard ratio=1.054). This study suggests that a hospital working week of Monday to Friday is not optimal for the care of patients with acute MI. The data were collected from 1987 to 2002 and hospital practices may have already changed—the advent of primary percutaneous coronary intervention may have contributed to more uniform staffing patterns. Eliminating the current shortfall in weekend care will require widespread societal change.
Kostis WJ, Demissie K, Marcella SW, et al. Weekend versus weekday admission and mortality from myocardial infarction. N Engl J Med 2007;356:1099–109.
Redelmeier DA, Bell CM. Weekend worriers. N Engl J Med 2007;356:1164–5.
Raised levels of high‐density lipoprotein (HDL) cholesterol are associated with a decreased incidence of coronary heart disease and stroke; thus raising HDL cholesterol is now being targeted as a potential treatment for atherosclerosis. Torcetrapib is an inhibitor of cholesteryl ester transfer protein (CETP) that results in higher HDL cholesterol levels. The ILLUMINATE (Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events) trial involving 15000 patients at high risk for developing coronary artery disease was stopped prematurely after a year because of an excess of deaths, myocardial infarction, angina, revascularisation procedures and heart failure in patients receiving torcetrapib plus atorvastatin compared with those receiving atorvastatin monotherapy. An independent parallel study, ILLUSTRATE (Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclersosis by CETP Inhibition and HDL Elevation) looked at the effect of torcetrapib/atorvastatin treatment versus atorvastatin alone on coronary artery atherosclerotic plaque burden using intravascular ultrasound (IVUS). This prospective multicentre randomised controlled trial ran from 30 October 2003 to 16 August 2004 and incorporated 1188 patients with angiographically documented coronary artery disease; 597 patients were randomised to the atorvastatin monotherapy group and 591 to the torcetrapib/atorvastatin group. Patients were randomly assigned to either a fixed combination of atorvastatin (at the dose established during the run‐in period) with 60 mg torcetrapib or atorvastatin monotherapy with corresponding placebo tablets. After angiography, baseline and 24‐month follow‐up IVUS studies were performed. Nine hundred and ten patients (77%) remained in the study at 24 months—446 (75%) in the atorvastatin monotherapy group and 464 (79%) in the combined therapy arm.
After 24 months, as compared with atorvastatin monotherapy, the effect of torcetrapib/atorvastatin treatment was an approximate 61% increase in HDL cholesterol and a 20% relative decrease in low‐density lipoprotein (LDL) cholesterol, reaching a ratio of LDL to HDL cholesterol of <1.0. Importantly, torcetrapib was also associated with an increase in systolic blood pressure of 4.6 mm Hg. The percentage atheroma volume (the primary efficacy measure) increased by 0.19% in the atorvastatin monotherapy group and 0.12% in the torcetrapib/atorvastatin arm but was not significant (p=0.72). A secondary measure, change in normalised atheroma volume, demonstrated a favourable effect for torcetrapib (p=0.02), but no significant difference was shown in the change in atheroma volume in the most diseased vessel segment.
The lack of significant difference in the primary end point means that the adverse clinical outcome observed in ILLUMINATE cannot be attributed solely to a worsening of atherosclerotic plaque burden in the coronary arteries. Other possible factors include off‐target toxic effects of torcetrapib. In the ILLUSTRATE trial torcetrapib was associated with a 4.6 mm Hg increase in mean systolic blood pressure, a greater rise than was seen in phase 2 clinical trials. This effect is probably not related to the mechanism of action of the drug because it is not seen in patients with a genetic CETP deficiency, nor has it been seen in trials of other CETP inhibitors. It may be indicative of a unique adverse effect of torcetrapib, possibly through vasospasm or activation of the renin–angiotensin system. Further analysis from the ILLUMINATE trial may be successful in identifying the mechanism. Although lowering of LDL cholesterol by CETP inhibition is likely to be anti‐atherogenic, it remains to be seen whether there are additional benefits in increasing HDL cholesterol by this mechanism. CETP inhibition remains an interesting approach, but perhaps less so than before.
Nissen SE, Tardif JC, Nicholls SJ, et al. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med 2007;356:1304–116.
Tall AR. CETP Inhibitors to increase HDL cholesterol levels. N Engl J Med 2007;356:1364–6.
The COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) Trial was a multicentre randomised study involving 2287 patients who had objective evidence of myocardial ischaemia and stable coronary artery disease. Patients with stable coronary artery disease were randomly assigned to undergo percutaneous coronary intervention (PCI) and optimal medical treatment (PCI group, n=1149) or optimal medical treatment alone (n=1138). The primary outcome was death from any cause and non‐fatal myocardial infarction during a follow‐up period of 2.5–7 years (median 4.6). Two hundred and eleven primary events were recorded in the PCI group compared with 202 in those prescribed medical treatment alone, a statistically non‐significant difference. The median cumulative primary event rates were 19.0% in the PCI group compared with 18.5% for medical treatment (hazard ratio (HR) for the PCI group 1.05, 95% CI 0.87 to 1.27; p=0.62). No significant differences were seen between the two groups in the composite of death, myocardial infarction and stroke, PCI vs medical treatment, respectively (20% vs 19.5%, HR=1.05, 95% CI 0.87 to 1.27; p=0.62), hospitalisation for acute coronary syndrome (12.4% vs 11.8%, HR=1.07, 95% CI 0.84 to 1.37; p=0.56) or non‐fatal myocardial infarction (13.2% vs 12.3%, HR=1.13, 95% CI 0.89 to 1.43, p=0.33). From this the authors concluded that as an initial management strategy in patients with stable coronary artery disease, PCI did not reduce the risk of death, myocardial infarction or other major cardiovascular events when added to optimal medical treatment. A number of factors may have influenced this finding. First, randomisation to the different arms did not occur until after angiography had been performed and may have led to bias. Second, in the medical treatment arm 32.6% required revascularisation by the median 4.6 years of follow‐up and in the PCI arm 21.1% underwent a further revascularisation procedure. Third, drug‐eluting stents had not been approved until the final 6 months of the study and therefore the study is not reflective of current interventional practice—only 2.6% in the PCI arm received these, compared with the current “norm” of 50–60% in the UK. Fourth, of those enrolled, 43% had little or no angina—in the UK conventional practice is for stable patients to undergo PCI only if they are experiencing angina while receiving medical treatment. Lastly, PCI has never (to date) been shown to affect mortality or reduce the incidence of myocardial infarction in stable coronary disease and therefore the choice of primary end point is difficult to understand. It should be remembered that most PCI is still undertaken for patients with unstable syndromes or poorly controlled symptoms.
Boden WE, O'Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease (the COURAGE Trial Research Group). N Engl J Med 2007;356:1503–16.
Hochman JS, Steg PG, eds. Does preventive PCI work? N Engl J Med 2007;356:1572–4.
Three studies in this month's BMJ re‐ignite the stent versus surgery debate. Two meta‐analyses compare the clinical effectiveness and cost effectiveness of revascularisation of isolated left anterior descending (LAD) coronary artery disease by either method, while a third study examines the cost effectiveness of medical treatment, stenting and surgery in multivessel disease. Aziz et al performed a meta‐analysis of 12 studies (including 1952 patients) comparing percutaneous stenting with minimally invasive left internal thoracic artery bypass surgery for isolated lesions of the LAD. A higher rate of recurrence of angina (odds ratio (OR)=2.62), major adverse coronary and cerebral events (OR=2.86) and repeat revascularisation (OR=4.63) were found with percutaneous stenting. No significant difference was found in myocardial infarction, stroke or mortality at maximum follow‐up between interventions. The same group also examined the cost effectiveness of surgery vs stenting for isolated LAD lesions in a separate paper. Decision analytical modelling and Markov simulation were used to model medium‐ and long‐term costs, quality of life, and cost effectiveness after either intervention. The results indicated that in the first 2 years stenting was generally more effective and less expensive than surgery. By the third year after intervention, however, bypass surgery became more effective, although it remained expensive. By the fifth year the incremental cost effectiveness ratio began to compare favourably with other interventions.
In a final, separate, paper by Griffin et al consecutive, unselected, patients from three tertiary referral centres in London were followed up and the cost per quality adjusted life year (QALY) calculated over a 6‐year follow‐up period. Percutaneous coronary intervention (PCI) cost £30000 per QALY, and compared unfavourably with coronary artery bypass grafting (£22000) and medical treatment (£19000). In patients suitable only for PCI or medical treatment the cost per QALY compared with medical management was £47000. The authors suggest that the benefits of PCI may not be sufficient to justify the cost. It is important to emphasise that no mortality differences were found in the studies, and that drug‐eluting stent trials were not included in the meta‐analysis by Aziz. On the other hand, where appropriate and feasible, minimally invasive surgery can be a highly effective procedure. The upcoming SYNTAX and FREEDDOM trials will provide important fresh data on this highly controversial area of cardiology.
Aziz O, Rao C, Panesar SS, et al. Meta‐analysis of minimally invasive internal thoracic artery bypass versus percutaneous revascularisation for isolated lesions of the left anterior descending artery. BMJ 2007;334:617.
Rao C, Aziz O, Panesar SS, et al. Cost effectiveness analysis of minimally invasive internal thoracic artery bypass versus percutaneous revascularisation for isolated lesions of the left anterior descending artery. BMJ 2007;334:621.
Griffin SC, Barber JA, Manca A, et al. Cost effectiveness of clinically appropriate decisions on alternative treatments for angina pectoris: prospective observational study. BMJ 2007;334:624.
Taggart DP. Coronary revascularisation. BMJ 2007;334:593–4.
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; JAMA; Journal of Clinical Investigation; Journal of Diabetes and its Complications; Journal of Immunology; Journal of Thoracic and Cardiovascular Surgery; Lancet; Nature Medicine; New England Journal of Medicine; Pharmacoeconomics; Thorax
Dr Alistair Lindsay, Dr Katie Qureshi