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Lessons learnt from negative trials

Session presentations
Cardiovascular Pharmacology and Pharmacotherapy


The session gave important information arisen from the analysis of negative trials conducted in the areas of blood pressure, glucose metabolism and lipid management and in the treatment of arrhythmia.

The first talk was delivered by S.E. Kjeldsen on behalf of Dr Dahlof.  Dr Kjeldsen analysed the negative effect of intense blood pressure lowering in large intervention trials and showed that studies conducted in patients with arterial hypertension have consistently shown that a reduction in systolic blood pressure is associated with a significant reduction in cardiovascular mortality and morbidity and in the occurrence of stroke. Dr Kjeldsen also showed that in population studies, achievement of controlled diastolic blood pressure values is associated with a significant reduction in events and that intervention studies have also shown a significant reduction in cardiovascular and cerebrovascular events with lower diastolic blood pressure values. However, the analysis of blood pressure values achieved in clinical trials showed a J curve with an increased risk of events with lower systolic and diastolic blood pressure values.

Dr. Cicero gave a presentation on the effect of intense glycaemic control in patients with diabetes mellitus. He started showing that intensive glucose control in UKPDS was better than diet alone and that the results were sustained over the long term (10 year follow up). However, more recent trials like ACCORD, ADVANCE and VADT that looked at the effect of intensive glycaemic control using different HbA1c targets showed that aggressive glycaemic control is not associated with any improvement in cardiovascular outcomes, while it is associated with an increased risk of hypoglycaemic-related events. The ACCORD study, where the target of intensive glucose control was HbA1c levels <6%, was stopped early because of an increase in total and cardiovascular mortality. In the ADVANCE trial, the effect on the primary composite end point was driven by the reduction of microvascular events, while the intervention had no effect on macrovascular endpoints. The VADT trial showed neutral results but a high incidence of hypoglycemia-induced events. Furthermore, meta-analysis of intervention studies has shown a neutral effect of intensive glycaemic control on cardiovascular events and mortality and an increased incidence of side effects.

P. Barter presented the effect of selective high-density lipoprotein targeting and started by showing that low HDL is associated with increased risk of cardiovascular events. Furthermore, he said that experimental studies suggest that an increase in HDL is effective in reducing the progression of atherosclerosis. Dr Barter discussed the results of 3 main studies related to HDL increase. The AIM-HIGH study, where niacin was used to increase HDL in patients receiving simvastatin, was terminated early because of futility, despite an increase of 25% in HDL cholesterol.

The ILLUMINATE study was designed to assess the effect of CETP inhibition with torcetrapib on top of atorvastatin. In this study, despite a noticeable increase in HDL-cholesterol levels with torcetrapib, an increased incidence of cardiovascular and non-cardiovascular events led the investigators to stop the study. The study was stopped because of increased risk of death probably because of off target effects of the drug.  The DAL-Outcome trial with the CETP inhibitor dalcetrapib, without any negative off target effects, was stopped early because of futility and not because of safety issues. 

S.H. Hohnloser summarised the effect of anti-arrhythmic drugs and he started by showing the basis of the initial hypothesis of the CAST study, which hypothesised that the suppression of VPB would be associated with improved mortality. The CAST study was also stopped early because of an increase in mortality and cardiac arrest in patients receiving encainide or flecainide. The SWORD trial, which randomised patients with recent MI and left ventricular dysfunction to d-sotalol or placebo was also stopped early because of increased mortality. The meta-analysis of small amiodarone trials in the same time period showed that amiodarone was safe and may have an effect in reducing mortality.

However, after the advent of implantable defibrillators, the SCD-HEFT study showed that there was no effect of amiodarone over placebo to reduce events while ICD significantly reduced mortality by 22%. In the study, patients with NYHA III treated with amiodarone showed a 44% increase in the risk of death. Therefore, as far as ventricular arrhythmia is concerned, the lesson to be learned is that suppression of VPB does not reduce events.

Regarding atrial fibrillation, the AFFIRM trial showed that there is no difference between rate or rhythm control in reducing mortality. In the study, the use of rhythm control drugs was associated with a 41% increased risk in mortality. Although the ATHENA study suggested that cardiovascular mortality was reduced by rhythm control with dronedarone in patients with AF and persistent AF, the PALLAS study in patients with permanent AF was stopped early because of excess mortality in patients treated with dronedarone. Therefore the lesson learned from studies conducted in patients with permanent AF is that they should not be treated with rhythm control drugs

References


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Lessons learnt from negative trials

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.