The recurrence of atrial fibrillation (AF) after cardioversion may be partially related to a process known as remodeling - the electrical, mechanical and structural properties of the atrial tissue are altered in a progressive and irreversible manner resulting in a more favourable substrate for AF. From animal models, blockade of the rennin-angiotensin-aldosterone system (RAAS) has been shown to alter the remodeling process in a beneficial manner.

The GISSI-AF (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico-Atrial Fibrillation) study was a prospective, multi-centre, randomised, double-blind, placebo controlled trial. It assessed whether the addition of the AIIRB valsartan to established treatments could reduce the recurrence of AF in patients with a history of arrhythmia. Patients were eligible if they were at least 40 years of age and had had 2 or more episodes of symptomatic atrial fibrillation in the previous 6 months or a successful cardioversion (electrical or pharmacological) 48 hours-14 days before randomisation. Patients had to have been in sinus rhythm for a minimum of 48 hours prior to enrolment. Participants were also required to have been on a stable regimen for treatment for atrial fibrillation or other cardiac conditions for 1 month.

1442 patients were randomly assigned to either valsartan (n=722) or placebo (n=720). Study visits were scheduled at 2, 4, 8, 24 and 52 weeks with follow up concluding at 1 year. An ECG was performed at each visit and to increase the likelihood of AF being detected patients were provided with a transtelephonic device with instructions to activate this if symptoms occurred. Additionally they were to activate this device on a weekly basis - regardless of symptoms - and a 30 second ECG was sent to both the co-ordinating centre and the responsible physician. The study was designed with 2 primary end-points: time to first recurrence of AF and the proportion of patients who had more than 1 episode of AF in the follow up period. Secondary end-points included: total number of episodes of AF/patient, hospitalisation for any reason, hospitalisation for a cardiovascular event, the composite of death and thromboembolic events, number of patients in sinus rhythm at each study visit, duration of and ventricular rate at the first recurrence of AF and a safety profile.

AF recurred in 371/722 patients (51.4%) in the valsartan group compared to375/720 (52.1%) in the placebo group (adjusted hazard ratio (HR) 0.97, 96%CI 0.83-1.14, p = 0.73). 194/722 (26.9%) in the valsartan arm and 201/720 (27.9%) in the placebo arm (adjusted odds ratio 0.89, 99% CI 0.64-1.23, p = 0.34 had more than one episode of AF. The results were similar in all the pre-defined sub-groups including those who were not receiving ACE inhibitors.

These results provide demonstrate that valsartan did not prevent the recurrence of AF in this population. However there are some important caveats. The majority of the study population had reasonably well controlled hypertension (85%), 57% were already taking ACE inhibitors and >70% were taking a Class I or III anti-arrhythmic agent for the prevention of atrial fibrillation. In addition, 88% had undergone cardioversion (either electrical or pharmacological) in the 2 week period preceding randomisation. These factors would suggest that the substrate for AF was well established in the population studied, and that it may have been too late for medication to make a noticeable difference. Previous studies have suggested that patients with LV dysfunction or hypertrophy benefit the most from use of ACE inhibitors or AIIRBs for prevention of AF. However in this study population only 8% of patients had either heart failure or ventricular systolic dysfunction and data on presence of left ventricular hypertrophy were not provided. Finally, this was a study of the secondary prevention of AF and it is possible that the greatest benefit from ACE inhibitors and A II RBs will be in the prevention of new onset AF (‘primary’ prevention) since it may be that these drugs can prevent but not reverse the structural remodelling that acts as a substrate for AF.

The GISSI-AF Investigators. Valsartan for Prevention of Recurrent Atrial Fibrillation. N Engl J Med 2009;360:1606-17

Gillis AM (ed). Angiotensin Receptor Blockers for Prevention of Atrial Fibrillation – A Matter of Timing or Target? N Engl J Med 2009;360:1669-71

Should patients with type 2 diabetes be screened for coronary artery disease if asymptomatic? In the DIAD study (Detection of Ischemia in Asymptomatic Diabetics), 1123 patients with type 2 diabetes and no symptoms of coronary artery disease (CAD) were randomly assigned to be screened with adenosine-stress myocardial perfusion imaging (MPI) or to no screening. The main outcome measure was the incidence of cardiac death or nonfatal myocardial infarction (MI) during long-term follow-up.

The cumulative cardiac event rate was 2.9% over a mean follow-up of 4.8 years for an average of 0.6% per year. Seven nonfatal MIs and eight cardiac deaths (2.7%) occurred among the screened group, and ten nonfatal MIs and seven cardiac deaths (3.0%) among the group that received no screening (p=.73). However, of the patients who underwent screening, those with normal results (n=409) and those with small MPI defects (n=50) had lower event rates than the 33 with moderate or large MPI defects (0.4% vs 2.4% per year, p=.001).

Therefore screening using SPECT appeared to make no difference to the rate of coronary events in this study, and the event rate overall was low, which translates into a high cost of screening per event prevented. Indeed a low event rate was also seen in the recent ACCORD (Action to Control Cardiovascular Risk in Diabetes), leading some to question whether diabetic patients should truly be labelled as having the same risk as patients who have already had coronary events. For example, the ARIC (Atherosclerosis Risk in the Community) study found a lower mortality rate amongst diabetics than amongst patients with known coronary disease.

· Young LH, Wackers FJ, Chyun DA, et al. Cardiac outcomes after screening for asymptomatic coronary artery disease in patients with type 2 diabetes. JAMA 2009; 301: 1547-1555.

· Wackers FJ, Young LH, Inzucchi SE, et al. Detection of silent myocardial ischemia in asymptomatic diabetic subjects: the DIAD study. Diabetes Care 2004; 27: 1954-1961

It has been calculated that a polypill containing asprin, a beta-blocker, a statin and an angotensin-converting enzyme inhibitor could reduce cardiovascular events in people with cardiovascular disease by about 75%. It has further been suggested that the addition of folic acid, and the use of three separate agents to lower blood pressure (each in low doses), could enable a polypill preparation to reduce cardiovascular disease by more than 80%. The Indian Polycap Study (TIPS) was designed to examine the efficacy of just such a formulation, named the Polycap pill.

2053 patients without cardiovascular disease, all aged 45-80 years but with one cardiovascular risk factor, were randomised to the Polycap (n=412) or to one of eight other groups - each with about 200 patients - of aspirin alone, simvastatin alone, hydrochlorthiazide alone, three different combinations of two blood-pressure lowering drugs, three blood-pressure lowering drugs alone, or three blood-pressure-lowering drugs with aspirin.

Compared with groups not receiving blood pressure drugs, the Polycap reduced systolic blood pressure by 7.4mmHg and diastolic blood pressure by 5.6mmHg. Although the Polycap reduced LDL cholesterol by 0.70mmol/L, this was less than the effect of simvastatin alone (0.83mmol/L; p=0.04). Tolerability of the Polycap was similar to that of other treatments, with no evidence of higher intolerability as the number of active components increased.

This phase II study confirms that a polypill formulation can be tolerated and used to reduced multiple risk factors. Importantly, the study also demonstrates that the effects of a polypill may not necessarily be totally predicted by its components – the weakness of the cholesterol effect demonstrates this. Of course, the trial does not tell us about morbidity and mortality effects, although the authors predict these values and compare them to those projected by another study by Wald and Law (see table). Nonetheless, this study marks an important step in the ongoing development of the polypill.

· The Indian Polycap Study (TIPS). Effects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): a phase II, double-blind, randomized trial. Lancet 2009; DOI:10.1016/S0140-6736(09)60611-5.

· Cannon CP. Can the polypill save the world from heart disease? Lancet 2009; DOI:10.1016/S0140-6736(09)60652-8.

Surgical ventricular reconstruction is a technique which has been developed to reconstruct dysfunctional myocardial segments; it is usually performed in conjunction with coronary artery bypass grafting (CABG). Previous studies of this technique have not been randomised and have been limited to observational studies.

STICH (Surgical Treatment for Ischaemic Heart Failure Trial) was a multi-centre, non-blinded, randomised trial conducted at 127 sites in 26 countries. There were 2 major hypotheses. The Hypothesis 1 substudy compared medical therapy and CABG with medical therapy alone and has not yet reported. The Hypothesis 2 substudy compared CABG alone with the combined procedure of CABG and ventricular reconstruction. 1000 patients were recruited from 96 medical centres in 23 countries. Patients were required to have coronary disease amenable to CABG, LVEF <35% and a dominant area of anterior myocardial akinesia or dyskinesia that was suitable for treatment with surgical ventricular reconstruction. All patients received standard medical and device therapy for heart failure.

Major peri-operative events and specified end-points were recorded at discharge or 30 days for patients still in hospital. The primary outcome was time to death from any causes or hospitalisation for cardiac causes. Secondary outcomes included death from any cause at 30 days, hospitalisation for any cause and for cardiovascular causes, myocardial infarction and stroke.

499 patients underwent CABG and 501 underwent the combined procedure of CABG and ventricular reconstruction. The median follow up was for 48 months. Surgical ventricular reconstruction reduced the end systolic volume index by 19% as compared with a reduction of 6% with CABG alone. Cardiac symptoms and exercise tolerance improved form baseline to a similar degree in the two groups. No significant difference was seen in the primary outcome which occurred in 292 (59%) patients undergoing CABG and 289 (58%) undergoing CABG with surgical ventricular reconstruction (hazard ratio for the combined approach 0.99, 95%CI 0.84-1.17, p = 0.90).

This large trial had some key strengths including the use of up-to-date surgical techniques and an attempt to standardise heart failure therapies according to guidelines throughout the entire study population. However there are some important limitations. Whilst the authors state that use of evidence based pharmacological and device therapies was monitored throughout the study, no information is given about rates of use of these over the time of the study. There was a greater reduction in the end systolic volume index with the combined procedure (16ml/m² body surface area) compared to CABG alone (5ml/m² body surface area) but these data were only obtained from 373 patients at baseline and at 4 months. More complete and longitudinal information on the end systolic volume index might have provided supporting evidence as to whether ongoing ventricular modelling did occur. Potential explanations for the lack of added efficacy of the combined procedure include the fact that the available heart failure therapies are effective at limiting adverse remodelling. Revascularisation with CABG may enhance this process resulting in a lack of any additional benefit being seen with surgical ventricular reconstruction. When the Hypothesis 1 substudy reports it is hoped that this will provide further insights into the benefits of medical therapies.

• Jones RH, Velazquez EJ, Michler RE et al. Coronary Bypass Surgery with or without Surgical Ventricular Reconstruction. N Engl J Med 2009;360:1705-17
• Eisen HJ (ed). Surgical Ventricular Reconstruction for Heart Failure. N Engl J Med 2009;360:1781-4

Depressive symptoms are prominent in elderly hospitalized patients with heart failure and have been associated with decreased functional status, increased hospital readmissions and greater mortality. However, little is known about the characteristics of heart failure patients prone to depression and their treatment.

In this analysis of the OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) study, a multi-centre registry based in the US of some 48,612 patients at 219 hospitals, a history of depression was present in 10.6% of individuals. Depression was significantly more common in females, whites and those with concomitant diseases such as COPD and insulin-dependent diabetes. Patients with depression were much less likely to receive coronary interventions or cardiac devices or to be referred to outpatient disease management programs.

Due to the retrospective nature of the study, the authors are unable to comment on the reasons for these seeming disparities but these factors may go some way towards explaining the poorer outcomes of some patient groups. The randomized controlled trial MOOD-HF investigating the use of SSRIs in depressed heart failure patients will provide evidence based recommendations for management, but in the meantime an increased awareness of the impact of depression may provide an opportunity to improve outcomes in heart failure patients.

Nancy M. Albert, Gregg C. Fonarow, William T. Abraham et al. Depression and Clinical Outcomes in Heart Failure: An OPTIMIZE-HF Analysis. The American Journal of Medicine (2009) 122, 366-373

Among patients undergoing coronary artery bypass graft surgery (CABG), those with a history of previous myocardial infarction (PMI) have poorer post-operative cardiovascular outcomes than those without. However it remains unclear whether there are differences in outcomes after CABG between patients with anterior PMI versus those with inferior PMI.

Fukui et al. retrospectively reviewed the medical records of 310 patients with a history of PMI whom underwent CABG without valve replacement. PMI was defined as myocardial infarction occurring more than 30 days before surgery. PMI was confirmed most commonly by scintigraphy, although ECG, echocardiography, and MRI were also used. Patients with lateral MI or a combination of anterior and inferior MI were excluded. 151 patients with anterior PMI and 159 patients with inferior PMI were included in the study.

Investigators found that patients with inferior PMI were older (68.3 ± 9.2 vs 65.5 ± 11.0, p = 0.015), had a greater number of diseased vessels per patient (2.9 ± 0.3 vs 2.8 ± 0.5, p = 0.009), had a lower incidence of diabetes (44.0% vs 58.3%, p = 0.02) and a higher rate of mitral regurgitation (18.2% vs 8.6%, p = 0.02) as compared to patients with anterior PMI. There were no differences between groups with respect to operative technique, number of grafts and completeness of revascularisation.

Patients with a history of inferior PMI were observed to have a higher incidence of respiratory failure, requirement for haemodialysis, increased operative mortality and a combined clinical endpoint of operative death and major complications (table).

Multivariate analysis revealed inferior PMI to be the only independent predictor of major postoperative complications including death (p = 0.007). The mechanistic explanation for this remains unclear, however potential right ventricular dysfunction following prior inferior MI may adversely affect respiratory function and renal perfusion. Further large scale randomised control trials may help to explain this observation which, if reproduced, may assist pre-operative risk stratification algorithms.

Fukui T, Shimokawa T, Manabe S et al. Prior Inferior Myocardila Infarction Has Worse Early Outcomes in Patients Undergoing Coronary Artery Bypass Grafting Than Prior Anterior Myocardial Infarction. Ann Thorac Surg 2009;87:475-80

Elevated blood glucose at hospital admission, and elevated fasting blood glucose levels during admission, have been shown to predict worse outcome among patients with STEMI, however, the contribution of glucose levels to risk predictive algorithms involving patients with acute coronary syndromes (ACS) remains unclear.

Admission and fasting glucose levels were available for 13 526 patients enrolled in the Global Registry of Acute Coronary Events (GRACE). This included patients with STEMI, NSTEMI and unstable angina admitted to hospital between April 1999 to December 2005 from 106 hospitals in 14 countries.

In-hospital and 6 month mortality was calculated and correlated against the presence and degree of glucose elevation on admission and in a fasting sample during admission. Researchers found that patients who had higher fasting glucose levels were more often female, had a higher Killip class, and had a history of hypertension, previous stroke / TIA or peripheral vascular disease. 39.7% of patients were newly diagnosed as diabetic.

Elevated admission and fasting glucose levels independently predicted higher in-hospital mortality, however 6 month mortality only appeared to correlate with certain levels of fasting glucose elevation (see table) and did not correlate with glucose levels on admission. Congestive cardiac failure, cardiogenic shock and major bleeding complications also appeared to occur more frequently among patients with elevated glucose levels.

These data extend the relationship between elevated fasting glucose level and adverse outcome to the wider spectrum of ACS. Fasting glucose appeared to be a more robust independent marker of adverse outcome than admission glucose, which may represent a severe stress response rather than disturbed glucometabolism. Overall, these data reinforce the importance of categorising diabetic patients with ACS as high risk.

· Sinnaeve P, Steg G, Fox K et al. Association of elevated fasting glucose with increased short-term and 6-month mortality in ST-segment elevation and non-ST segment elevation acute coronary syndromes. The Global Registry of Acute Coronary Events. Arch Intern Med. 2009;169(4):402-9

The outcomes of coronary artery bypass grafting (CABG), when compared with percutaneous coronary intervention (PCI) might vary according to the patient characteristics, such as the presence of diabetes or the number of diseased vessels. However, no randomized trial to date has been large enough to provide adequate statistical power for sub-group analysis, and meta-analyses have been hampered by inconsistent reporting in published trials.

Hlatky et al. pooled individual patient data from ten randomized trials providing data on 7812 patients. PCI was performed with balloon angioplasty in six trials and bare-metal stents in four trials. 575 of 3889 patients (15%) assigned to CABG died compared with 628 of 3923 (16%) patients assigned to PCI over a median follow-up of 5.9 years. In patients with diabetes, mortality was substantially lower in the CABG group than in the PCI group (hazard ratio 0.70), but mortality was similar in groups without diabetes (hazard ratio, 0.98). 20% of patients aged over 65 died following CABG, compared to a death rate of 24% in the same population following PCI. This interaction remained after adjustment for sex, diabetes, smoking, hypertension, history of myocardial infarction, heart failure and three-vessel disease (p=0.002). No other baseline characteristics were found to significantly alter outcomes.

The results must be interpreted with caution; patients included in the analysis had only single- or double-vessel disease (the recently published SYNTAX trial was not included), a group in which CABG is already known to have no prognostic benefit. Furthermore, internal mammary grafts were underused in the surgical group, and drug-eluting stents were not used in the PCI studies included. Nonetheless, the finding that CABG is the preferred treatment method in diabetics agrees with the findings of the BARI trial. Furthermore, the study suggests that CABG is also preferred for those aged greater than 65 – but it should be noted that only 5% of the patients in this study were aged greater that 75.

• Hlatky MA, Boothroyd DB, Bravata DM, et al. Coronary artery bypass surgery compared with percutaneous coronary interventions for multivessel disease: A collaborative analysis of individual patient data from ten randomised trials. Lancet 2009; DOI:10.1016/S0140-6736(09)60552.
• Taggart DP. PCI or CABG in coronary artery disease? Lancet 2009; DOI:10.1016/S0140-6736(09)60574-2.

Previous studies, such as the World Health Organisation MONICA (monitoring trends and determinants in cardiovascular disease) project, have demonstrated the rapid and progressive uptake of medical care that has been shown in randomised clinical trials to reduce cardiovascular mortality [Lancet 2000;355:688-700]. However, there are relatively few population based studies available that describe how this apparent uptake of evidence-based therapy translates to actual long-term survival following myocardial infarction (MI) or death rates from coronary heart disease in the real world.

In order to address this question Briffa and co-workers examined the impact of evidence based medical treatment and coronary revascularisation on the long term survival of 4,451 patients registered by the MONICA project who were admitted to hospital with acute MI between 1984 to 1993 in Perth, Western Australia. Patients who died in the first 28 days were excluded. The cohort was divided into 3 subgroups according to date of admission (1984-7, 1988-90, and 1991-3), which allowed for temporal changes in the use medical therapy to be identified (table 1).

Over 12 year follow up, patients from the most recent subgroup (1991-3) had a 7.6% (95% CI, 4% to 11%) reduction in absolute events or a 28% lower relative risk reduction (RRR) (16 to 38%) when compared with the cohorts who presented earlier, either 1984-7 or 1988-90.

This improved survival persisted after adjustment for demographic factors, coronary risk factors, severity of disease, and event complications; adjusted RRR, 26% (14% to 37%), but was absent after further adjustment for medical treatments in hospital and coronary revascularisation procedures within 1 year of index presentation, which may provide support for their favourable influence on mortality.

Although observational data must always be interpreted with caution the observations made in the present study suggest improved survival rates which appear to correspond with the initiation evidence based treatment. Consequently, this data describes how improved cardiovascular survival observed in the setting of clinical trials may translate into a ‘real world’ population based setting.

· Briffa T, Hickling S, Knuiman M et al. Long term survival after evidence based treatment of acute myocardial infarction and revascularisation: follow-up of population based Perth MONICA cohort, 1984-2005. BMJ 2009;338:b36

Renal sympathetic efferent and afferent nerves are crucial for the initiation and maintenance of systemic hypertension, and as such renal sympathetic denervation is a potential therapeutic target for hypertension. Krum et al. describe the development of a novel, percutanoeus, catheter-based approach to renal sympathetic denervation. The lumen of the main renal artery is cannulated and the surrounding sympathetic nerves destroyed by radiofrequency waves, and in a swine model this technique has been shown to reduce noradrenaline content in the kidney by as much as 85%.

Fifty patients received percutaneous radiofrequency catheter-based treatment between June 2007 and November 2008, with subsequent follow-up to 1 year. The primary endpoints were office blood pressure and safety data at 1,3,6,9, and 12 months after the procedure. Both renal and magnetic resonance angiography were performed to ensure no anatomical damage from the procedure, and blood-pressure lowering effectiveness was assessed by repeated measures ANOVA. 5 patients were excluded from treatment for anatomical reasons (such as the presence of dual renal artery systems).

Following the procedure, a significant and progressive reduction in blood pressure was observed over the 12 months since treatment (figure 1); by comparision the 5 patients not treated showed a mean rise in blood pressure. Baseline and six-moth glomerular filtraion rate data were available for 25 patients, and showed a mean increase from 79 to 83mL/min/1.73m2. One intraprocedural renal artery dissection occurred before radiofrequency energy delivery, without further sequelae, and there were no other renovascular complications.

This was a proof-of-concept study, and as such lacks a control group. Furthermore, in an age of advanced pharmacotherapy for hypertension, can an invasive approach ever be completely justifiable? It is most likely that this technique will evolve to have a role in those with truly resistant hypertension.

· Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet 2009; published online March 30. DOI:10.1016/S0140-6736(09)60566-3

· Interventional management of resistant hypertension. Doumas M, Douma S. Lancet 2009; published online March 30. DOI:10.1016/S0140-6736(09)60624-3