Hypertension

How exciting, just in time for Christmas a new class of anti hypertensive. Darusentan is a direct, selective endothelin antagonist which exerts its antihypertensive effect by vasodilation. In a placebo controlled, randomised trial of 3 doses of the drug in patients who had not achieved target blood pressure after three conventional antihypertensives, all three doses of the drug were found to be effective. One side effect was oedema; intriguingly it required 117 sites to recruit 379 patients.

Michael A Weber and others, The Lancet 374; 9699, 1423 - 1431

Many patients are prescribed prognostically significant drugs but often do not achieve the doses demonstrated to be beneficial in the trials. In a direct, randomised, blinded comparison of low (50mg) vs high dose (150mg) Losartan in 3846 patients with moderate heart failure and intolerance of ACE inhibitors the high dose group had significantly less heart failure admissions over 4.7 years follow up. The authors note the value demonstrated in the often difficult process of titrating up medication in heart failure patients.

Marvin A Konstam and others, Lancet 2009; 374: 1840–48

Antiplatelets/Anticoagulants

The new kid on the block in anti platelet therapy is Cangrelor, an intravenous, reversible ADP inhibitor with some theoretical advantages in terms of speed of action and safety compared to oral clopidogrel. A group of investigators managed the quite remarkable feat of having two simultaneous attempts at demonstrating a benefit over clopidogrel/placebo, failing to meet their primary endpoint and still getting both trials published in the NEJM.

Deepak L. Bhatt and others, New Eng J Med 361:2330-2341
Robert A. Harrington and others New Eng J Med 361:2318-2329

Bleeding risk on combinations of antithrombotic and antiplatelet agents are a real concern in the post infarct/PCI population. In an observational study of over 40 000 Danish patients experiencing their first infarct, bleeding risk over a mean of 476 days was found to be 2.6, 4.6 and 4.3% aspirin, clopidogrel and warfarin monotherapies respectively. This risk was not clinically significantly elevated by either dual antiplatelets or aspirin/warfarin combination. Combination of clopidogrel and warfarin (with or without aspirin) however increased major bleeding risk to 12%. This presents a real therapeutic challenge for patients with drug eluting stents, atrial fibrillation and stroke risk factors.

Rikke Sørensen and others, The Lancet 374; 9706, 1967-1974

Cardiac Resynchronisation

Some of the most marked responses to cardiac resynchronisation therapy are seen in right ventricular paced patients. This is not surprising given that right ventricular pacing induces gross dysynchrony and heart failure patients respond so badly to it.

How far can this effect be demonstrated in individuals with structurally normal hearts? In a trial of 177 patients with normal ejection fraction randomised to either biventricular or right ventricular apical pacing there was a significant decrease in ejection fraction and increase in left ventricular dimension in the right ventricular pacing group. This did not translate into any clinical endpoints and a number of criticisms of the pacing implant and programming were raised. The proof of concept remains and we are set to see a creep of CRT into a wider range of pacing patients.

Cheuk-Man Yu and others N Eng J Med 361:2123-2134

The magnitude of the physiological benefits of cardiac resynchronistion therapy, should be independent on the degree of heart failure. The move to apply CRT to less symptomatic individuals is therefore no surprise. In the REVERSE study six hundred and ten NYHA class 1-2 patients were implanted and then randomised to on or off and followed for 12 months. There was significant reverse remodelling in the CRT on group compared with baseline and the CRT off group.
On its own this is probably insufficient evidence to recommend CRT in NYHA 1-2 patients who are not otherwise indicated for device therapy but taken with the MADIT CRT trial a good evidence base for CRT in patients receiving a device for other reasons is emerging.

Martin St. John Sutton Circulation 2009;120;1858-1865

Clinical results in CRT have been mixed in the QRS<120 msec population. There remains a suspicion that certain subgroups of these patients would benefit. Perhaps efforts at selection have been misdirected, as the problem (and hence mechanism of benefit) is as much to with diastolic filling as systolic dysychronous contraction.
In an acute study of 30 patients with heart failure and QRS<120 msec 15 were noted to have evidence of external constraint and CRT abolished this in all. This resulted in an overall increase in stroke volume and ejection fraction as well as improved filling.

Lynne K Williams and others Circ 2009;120:1687-1694

Hypertrophic Cardiomyopathy

A small study of families with identified hypertrophic cardiomyopathy mutations sought to investigate, amongst other things, the penetrance of the disease in carriers. Only 41% of carriers expressed the phenotype in this snapshot with age and male gender increasing risk of expression. Risk factors for sudden cardiac death were noted to be present even in (as yet) unaffected carriers.

Michelle Michels and others, European Heart Journal 2009 30(21):2593-2598

Exercise testing is often used to risk stratify hypertrophic cardiomyopathy patients but its value is not well established. Analysis of the Heart Hospital’s referrals finds exercise induced arrhythmias to be rare (27 out 1380) but a significant predictor of malignant arrhythmias (a 3.73 fold increase in risk of sudden death/ICD discharge). Although the effect ceased to be significant if only NSVT patients were considered in a multivariate analysis it is the raw data that has more relevance to clinical practise as exercise induced arrhythmias are associated with a number of softer risk factors which might not score in their own right.

Perry Elliot and others Eur Heart J 2009 30(21):2599-2605

Implantable Cardioverter Defibrillators

SCD-HeFT (published 2005) continues to be mined for data. To recap this was a study of single lead ICDs in NYHA II-III individuals with ejection fractions under 0.35. Detailed analysis of the 666 deaths in the trial has revealed that ICDs exerted their effect by cutting all cause, cardiac and tachyarrhythmic death but not non cardiac or heart failure death. Interestingly, the mortality reduction was significant only in NYHA II individuals and he benefit was independent of aetiology.

Douglas L Packer and others Circulation. 2009;120:2170-2176

In ICD therapy, inappropriate shocks are well recognised but the concept of unnecessary shocks is gaining currency. The commendably low detection and charge times of modern devices have the potential to deliver shock therapy in patients with non sustained but fast arrhythmias, a profile known to be seen in the primary prevention CRT D population.

The RELEVANT study examined a simple programming change extending the detection interval in these patients which reduced inappropriate shocks and heart failure events compared to normal programming.

Maurizio Gasparini and others Eur Heart J 2009 30, 2758–2767

Electrophysiology

Does every patient undergoing left atrial ablation for atrial fibrillation need a pre procedure transoesophageal echo? In a report of 1058 patients there was not a single incidence of left atrial appendage clot in the 47% of these patients with CHADS2 profile of 0. The authors conclude that TOE should continue to be performed in patients with a CHADS2 profile of 1 or more or in CHADS2 0 patients only if AF is persistent and anticoagulation has not been maintained for 4 weeks.

Sarinya Puwanant and others J Am Coll Cardiol. 2009 Nov 24;54(22):2032-9

Revascularisation

Not so long ago it looked as though off pump surgery was going to be the best thing since free radial grafts..... fortunately it doesn’t look as though it will be as poor as that turned out - merely time consuming, pointless and slightly worse than standard care. In the latest instalment of this story a randomised trial of 2203 patients the off pump group had worse cardiac outcomes than standard on pump operations with no difference in neurological sequelae.

Laurie Shroyer New Eng J Med 361:1827-1837