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GENERAL CARDIOLOGY

Cardiovascular effects of air pollution highlighted

Both short and long-term exposure to air pollution has been associated with an increase in cardiovascular morbidity and mortality, and the WHO estimates that air pollution causes 800 000 premature deaths each year. However, the exact mechanisms for this association remain relatively unexplored.

Mills et al performed a double-blind, randomised, crossover study of the effect of dilute diesel exhaust on 20 men with a previous history of myocardial infarction. In two separate sessions, the men were exposed to dilute diesel exhaust (300 μg per cubic metre) or filtered air for 1 hour during periods of both rest and moderate exercise. During the exposure experiment, continuous 12-lead electrocardiography was used to assess ST-segment changes. Six hours later, vasomotor and fibrinolytic function was assessed by means of intra-arterial agonist infusions.

Exercise-induced ST-segment depression was seen in all patients, but the changes seen were greater during exposure to diesel exhaust (−22 (SD 4) vs −8 (SD 6) millivolt seconds, p<0.001). Although vasomotor dysfunction was not made worse by exposure to diesel exhaust, the acute release of endothelial tissue plasminogen activator was reduced (35% decrease in area under the curve).

Although this study demonstrates the deleterious effects of diesel fumes, it does not allow us to determine exactly which components of the fumes caused the effects seen. Furthermore diesel exhaust forms only one part of ambient air pollution, and the authors thus plan future studies to try to pinpoint exactly which elements are to blame. In the meantime patients with coronary artery disease may well be advised to exercise away from traffic when possible.

Mills NL, Tornqvist H, Gonzalez MC,. Ischemic and thrombotic effects of dilute diesel-exhaust inhalation in men with coronary heart disease. N Engl J Med 2007;357:1075–82.

Mittleman MA. Air pollution, exercise, and cardiovascular risk. N Engl J Med 2007;357:1147–49.

Glitazones and cardiovascular disease– the debate continues

The debate on the safety of the glitazones continues with the publication of two new meta-analyses in the Journal of the American Medical Association.

Dr Sonal Singh and colleagues performed a meta-analysis of the long-term cardiovascular effects of rosiglitazone to look at the incidence of myocardial infarction, heart failure and cardiovascular mortality. Trials involving the drug were selected if they involved diabetic patients on at least 12 months of treatment and provided numerical data on all adverse events, in particular cardiovascular adverse events. Four studies were included after 140 had been screened for cardiovascular events.

Overall the four trials included 14 291 patients, of whom 6421 received rosiglitazone and 7870 received control therapy, with a duration of follow-up of 1–4 years.

Of these patients, those on rosiglitazone had an increased risk of myocardial infarction (94/6421 patients vs 83/7870 patients on control therapy; relative risk, 1.42; p = 0.02). A similar result was found for heart failure (102/6421 vs 62/7870; relative risk, 2.09; p<0.001), but an increase in cardiovascular mortality was not found overall (59/6421 vs 72/7870; relative risk, 0.90; p = 0.53). These findings seemed to be consistent across the trials identified.

A separate study in the same issue evaluated the effect of pioglitazone on ischaemic cardiovascular events. Lincoff et al analysed data from 16 390 patients enrolled in 19 trials, all of whom had been given the study drug for between 4 months and 3.5 years. Death, myocardial infarction or stroke occurred in 375/8554 patients (4.4%) receiving pioglitazone and 450/7836 patients (5.7%) receiving control therapy (hazard ratio, 0.82; p = 0.005), with the time to event curves showing separation after approximately 1 year of therapy. However, serious heart failure was reported in 200 (2.3%) of the pioglitazone-treated patients and 139 (1.8%) of the control patients (hazard ratio, 1.41; p = 0.002), although once again no overall effect on mortality was seen. Thus pioglitazone appeared to have a favourable effect on ischaemic events, and an unfavourable effect on heart failure, regardless of the length of the trials involved, or whether or not patients had established vascular disease.

These studies suggest that pioglitazone may have a slightly better safety profile, at least in terms of ischaemic events, and some are now advocating a head-to-head comparison of the two drugs as the only way to resolve the issue. The controversy over the thiazolidinediones, in many ways reminiscent of the coxib controversy of recent years, highlights the fact that currently drug safety panels have no clear guidance or tools for constructing appropriate risk/benefit analyses. In an accompanying editorial, Dr Daniel Solomon and Wolfgang Winkelmayer from Brigham and Women’s Hospital in Boston suggest that the FDA could develop such methods of assessing risk and stipulate that they be used as part of new drug applications or for the continued marketing of drugs.

Singh S, Loke YK, Furberg CD. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. JAMA 2007;298:1189–95.

Lincoff AM, Wolski K, Nicholls SJ,. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: A meta-analysis of randomized trials. JAMA 2007;298:1180–8.

Solomon DH, Winkelmayer WC. Cardiovascular risk and the thiazolidinediones: Déjè vu all over again? JAMA 2007;298:1216–18.

Mild weight gain associated with cardiovascular disease

To what extent is the relationship between obesity and increased cardiovascular risk caused by the adverse effect of increased body weight on blood pressure and cholesterol? Bogers et al aimed to answer this question by performing a meta-analysis of 21 studies encompassing 302 296 participants and 18 000 coronary heart disease (CHD) events. Eligible studies were prospective cohort studies conducted in healthy populations for whom an association between increased BMI and CHD had been reported.

The age-, sex-, physical activity- and smoking-adjusted relative risks for cardiovascular disease were 1.32 for those who were overweight (BMI 25.0–29.9) and 1.81 for those who were obese (BMI>30), although these risks were reduced to 1.17 and 1.49 respectively when additional adjustment was made for blood pressure and cholesterol. An increase in BMI of five units was associated with 29% increased risk of CHD and after adjustment for blood pressure and cholesterol levels this risk remained at 16%.

The authors conclude from their study that adverse effects of being overweight on blood pressure and cholesterol could account for about 45% of the increased risk of CHD, although there is still a significant proportion of that risk that is independent of these effects. Although some confounding factors, such as the effect of diet, cannot be ruled out, these data suggest that merely being overweight (BMI 25.0–29.9), as opposed to obese (BMI>30), causes a significant increase in the risk of CHD. Potential mechanisms for this effect include an altered coagulation profile, chronic low-grade inflammation, or endothelial dysfunction. Although the exact mechanisms are not known, physicians should be aware that in overweight and obese patients optimal blood pressure and cholesterol management is not enough– weight loss must form a central part of any risk-reduction strategy.

Bogers RP, Bemelmans WJ, Hoogenveen RT,. Association of overweight with increased risk of coronary heart disease partly independent of blood pressure and cholesterol levels. A meta-analysis of 21 cohort studies including more than 300 000 persons. Arch Intern Med 2007;167:1720–28.

INTERVENTIONAL CARDIOLOGY

More data on the safety of DES

Recently the long-term safety of drug-eluting stents has been questioned following reports of death, myocardial infarction and late stent thrombosis. However, individual trials have been criticised for low patient numbers, limited follow-up, or poor study design. Stettler and colleagues established a collaborative group of investigators to provide trial data based on standardised definitions of outcomes and then performed a network meta-analysis of all randomised controlled trials comparing either sirolimus-eluting stents (SES) or paclitaxel-eluting stents (PES) with each other or with bare-metal stents (BMS).

Thirty-eight trials involving 18 023 patients were included overall, with triallists and manufacturers providing additional data on the outcomes of 29 trials. Safety outcomes included mortality, myocardial infarction, and definite stent thrombosis, while the effectiveness outcome was target vessel revascularisation. The study found that mortality rates were similar amongst the three groups: SES vs BMS, hazard ratio 1.0; PES vs BMS, hazard ratio 1.03; SES vs PES, hazard ratio 0.96. Overall, SES were associated with the lowest risk of myocardial infarction (hazard ratio, 0.81 vs BMS; 0.83 vs PES). Although there were no differences in the risk of definite stent thrombosis seen, the risk of late definite stent thrombosis (>30 days) was increased with PES (hazard ratio, 2.11 vs BMS; 1.85 vs SES). The reduction in target lesion revascularisation seen with drug-eluting stents compared with BMS was more pronounced with SES than PES (hazard ratio, 0.70).

The authors conclude that sirolimus-eluting stents are clinically better than either bare-metal or paclitaxel-eluting stents, although the risks of mortality associated with all stents are similar. Despite the thoroughness of this analysis, it should be noted that complex patients such as those with diabetes or renal failure are often excluded from clinical trials, and thus meta-analyses also. Nonetheless, an accompanying editorial suggests that this paper is the “best current comparison” of the two main drug-eluting stents available.

Stettler C, Wandel S, Allemann S,. Outcomes associated with drug-eluting and bare-metal stents: a collaborative network meta-analysis. Lancet 2007;370:937–48.

Webster MW, Ormiston JA. Drug-eluting stents and late-stent thrombosis. Lancet 2007;370:914–15.

HEART FAILURE

Latest on ventricular assist devices

The Heart-Mate II ventricular assist device (VAD) represents an important step in the evolution of VAD technology as it uses continuous flow rotatory pump technology, as opposed to the pulsatile devices that have existed to date. In addition, its small size allows the potential for implantation in a greater number of patients and it has greater mechanical reliability due to its simplified design.

To investigate the efficacy of the Heart-Mate II, a prospective multi-centre study was performed in the United States between March 2005 and May 2006. One hundred and thirty-three patients from 26 centres were included. All had end-stage heart failure (NYHA Class IV) and were on the waiting list for transplantation– there was no concurrent control group. The principal outcome was the proportion of patients who by 180 days had undergone cardiac transplantation, had cardiac recovery or had ongoing mechanical support whilst remaining eligible for transplantation. Secondary outcomes included overall survival, survival while receiving device support, survival after transplantation, frequency of adverse events, assessment of functional status (6-minute walk test and NYHA Class) and quality of life (Minnesota Living with Heart Failure and Kansas City Cardiomyopathy questionnaires).

The principal outcome occurred in 100 patients (75%). The median duration of support was 126 days (range 1–600). Of these, 56 underwent heart transplantation, 43 continued to receive support and remained eligible for transplantation and one had the device explanted after recovery of cardiac function. The survival rate during support was 75% at 6 months and 68% at 12 months. At 3 months, device therapy was associated with a significant improvement in both functional status and quality of life. Major adverse events included postoperative bleeding (requiring surgery in 31% of cases, and transfusion requirements >2 units in 53%), stroke (6% ischaemic, 2% haemorrhagic), right heart failure and percutaneous lead infection. Pump thrombosis occurred in two patients. The causes of death in the first 180 days after device implantation included sepsis (n = 5), ischaemic stroke (5), multi-system organ failure (4), haemorrhagic stroke (3), anoxic brain injury (2), right heart failure (2) and miscellaneous (4).

The results suggest that the Heart-Mate II is an effective therapy that can provide haemodynamic support for at least 6 months and lead to an improvement in quality of life and functional assessment; however, there are still challenges to be overcome. There is a risk of thrombosis and thromboembolic complications requiring high levels of antithrombotic therapy, which in itself may pose a further risk. Other concerns include infection risk and mechanical durability. The device was not compared with any other device or with medical therapy alone and therefore the comparative benefits of this therapy cannot be ascertained.

Miller LW, Pagani FD, Russell SD,. Use of a continuous-flow device in patients awaiting heart transplantation. N Engl J Med 2007;357:885–96.

In: Baughman KL, Jarcho JA, eds. Bridge to life– cardiac mechanical support. N Engl J Med 2007;357: 846–9.

ELECTROPHYSIOLOGY

Minimising ventricular pacing to reduce atrial fibrillation

The optimal pacing strategy for patients with symptomatic bradycardia due to sinus node disease has not yet been defined. Although atrial pacing is known to be associated with a lower incidence of atrial fibrillation than ventricular pacing it does not eliminate the risk from the subsequent development of atrio-ventricular block. On the other hand, whilst dual chamber pacing prevents syncope during atrio-ventricular block and has a slightly reduced risk of atrial fibrillation when compared with ventricular pacing, it does not reduce mortality and only slightly reduces the risk of stroke and heart failure.

The Search AV Extension and Managed Ventricular Pacing for Promoting Atrioventricular Conduction (SAVE PACe) trial was a prospective randomised controlled trial of 1065 patients at 72 centres in the United States and Canada which compared a strategy of conventional dual chamber pacing (n = 535) with dual chamber minimal ventricular pacing (n = 530) in patients with sinus node disease. The primary end point was the time to persistent atrial fibrillation which was defined as any of the three following circumstances: (i) two consecutive visits in which atrial fibrillation was present, (ii) at least 22 hours of atrial fibrillation for 7 consecutive days, (iii) at least 22 hours of atrial fibrillation for <7 consecutive days if interruption by either pharmacological or electrical cardioversion occurred. Additionally two expert cardiologists who were unaware of the treatment assignment reviewed all catheter ablation procedures for evidence of persistent atrial fibrillation. Secondary end points included hospitalisations for heart failure and the percentage of atrial and ventricular paced beats over time.

The mean (SD) follow-up period was 1.7 (1.0) years, at which time the primary end point was met. The median percentage of ventricular beats that were paced was lower in dual chamber minimal ventricular pacing than in the conventional arm (9.1% vs 99.0%, p<0.001). The percentage of atrial beats that were paced was similar for the two groups (71.4% vs 70.4%, p = 0.96). Persistent atrial fibrillation developed in 110 patients: 42 (7.9%) in the minimal ventricular pacing arm and 68 (12.7%) in the conventional treatment group. The hazard ratio for development of persistent atrial fibrillation in patients with minimal as compared with conventional dual chamber pacing was 0.60 (95% CI 0.41–0.88, p = 0.009) indicative of a 40% reduction in relative risk. The absolute risk reduction was 4.8%. Mortality rate was similar in the two groups (conventional therapy 5.4%, minimal ventricular pacing 4.9%, p = 0.54).

This study demonstrates that new technological developments for dual chamber pacing are superior to older pacemaker technologies. Importantly this trial prospectively links a reduction in clinical events (persistent atrial fibrillation) to a reduction in ventricular pacing. The reduction in atrial fibrillation burden led to fewer invasive ablation procedures and a reduction in hospitalisations for heart failure in post hoc analyses. Further studies will aim to show a reduction in clinically important end points and cost in order for this new technique to catch on.

Sweeney MO, Bank AJ, Nsah E,. Minimizing ventricular pacing to reduce atrial fibrillation in sinus-node disease. N Engl J Med 2007;357:1000–8.

The end for amiodarone?– EURIDIS and ADONIS

Dronedarone is a benzofuran derivative with a similar electropharmacological profile to amiodarone. There are structural differences in the molecule which are intended to eliminate the effects on pulmonary and thyroid function. It also has a shorter half-life of 1–2 days compared with 30–55 days for amiodarone.

The European Trial in Atrial Fibrillation or Flutter Patients Receiving Dronedarone for the Maintenance of Sinus Rhythm (EURIDIS) and the American–Australian–African Trial with Dronedarone in Atrial Fibrillation or Flutter Patients for the Maintenance of Sinus Rhythm (ADONIS) were two identical, parallel, multi-centre, double-blind, randomised, placebo-controlled trials. The European arm involved 12 countries and the non-European arm the United States, Canada, Australia, South Africa and Argentina.

Eligibility criteria were age >21 years, at least one episode of atrial fibrillation in the preceding 3 months (documented on electrocardiography, ECG) and sinus rhythm for at least 1 hour before randomisation. Eligible patients who were not in sinus rhythm could be enrolled if they underwent successful cardioversion and maintained sinus rhythm for at least 1 hour. Patients with permanent atrial fibrillation (>12 months) were excluded from the trial, but those who had previous treatment with amiodarone were allowed and patients could be enrolled immediately post discontinuation.

After a 7-day screening period, eligible patients were assigned in a 2:1 ratio to receive either 400 mg of oral dronedarone daily or a matching placebo and a 12-lead ECG and vital signs were measured. The primary end point was defined as the time from randomisation to the first documented recurrence of atrial fibrillation (episode lasting for at least 10 minutes and confirmed by two consecutive ECG recordings). The main secondary end points were symptoms related to atrial fibrillation and mean ventricular rate during the first recurrence.

In total 828 patients received dronedarone 400 mg twice daily and 409 patients received placebo. In the European Trial, median times to recurrence of arrhythmia were 41 days in the placebo group and 96 days in the dronedarone group (p = 0.01). The corresponding data for the non-European Trial were 59 and 158 days respectively (p = 0.002). In both trials, heart rate was slower in the treatment arm when AF recurred. No significant increase in pulmonary toxic effects or liver or thyroid dysfunction was documented in the patients taking dronedarone. There was a higher incidence of elevated creatinine in the dronedarone group compared with placebo (2.4% vs 0.2%, p = 0.004). In both trials dronedarone therapy extended the time to recurrence of atrial fibrillation by a factor greater than two.

However, there are two important limitations to note. Firstly, dronedarone was only compared with placebo– the critical comparison would be against amiodarone, since the latter is known to be highly efficacious in this setting and because the aim was to provide an agent with similar efficacy but fewer side effects. Secondly, all patients in this study had an approximate LVEF 58% (SD 11). A previous study, the ANDROMEDA (Antiarrhythmic Trial with Dronedarone in Moderate to Severe Congestive Heart Failure Evaluating Morbidity Decrease) Trial was discontinued early due to an interim analysis suggesting a potential increase in death in the treatment arm. Whilst this study dealt with a different (higher-risk) population it raises an important concern and further studies will be necessary to evaluate this further.

Singh BN, Connolly SJ, Crijns HJGM,. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med 2007;357:987–99.

In: Ezekowitz MD, ed. Maintaining sinus rhythm: making treatment better than the disease. N Engl J Med 2007;357:1039–41.

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 Alistair C Lindsay, Dr Katie Qureshi

Footnotes

  • 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

  • Dr Alistair C Lindsay, Dr Katie Qureshi