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OUR MISSION: TO REDUCE THE BURDEN OF CARDIOVASCULAR DISEASE
Dr. Guy De Backer,
Dr. Peter S Sever ,
Presenter | see Discussant report
Peter S Sever(United Kingdom)Presentation webcastPresentation slides
List of Authors: Peter Sever, Choon L Lang, Ajay Gupta, Andrew Whitehouse and Neil R Poulter, on the behalf of ASCOT investigators
Background: The Anglo-Scandinavian Cardiac Outcomes Trial Lipid-lowering Arm ( ASCOT-LLA) was terminated prematurely in 2003 owing to highly significant benefits of atorvastatin compared with placebo, on several cardiovascular outcomes including coronary heart disease (HR 0.64,CI 0.50-0.83, p=0.0005) and stroke (HR 0.73,CI 0.56-0.96, p=0.02). Cardiovascular and all cause mortality were reduced but not significantly ( HR 0.90, CI 0.66-1.23, p=0.50 and HR 0.87,CI 0.71-1.06, p=0.16 respectively). We have now obtained mortality data from subjects who participated in the trial in the UK, 7 years after its termination. Methods: In the UK, ASCOT originally randomised 4605 hypertensive patients to either atorvastatin, 10mg, or placebo and average follow-up was 3.3 years. Results: Atorvastatin lowered LDL-cholesterol by, 1.1mmol/L. At the end of the trial all patients were offered statins and at follow-up 2 years after the end of LLA, approximately 60% of patients were receiving statins and lipid levels were identical in those formerly assigned atorvastatin or placebo. By 2010, 8 years after completion of LLA, there were 980 all cause deaths, 460 in those originally assigned atorvastatin and 520 in those formerly assigned placebo (HR 0.86, CI 0.76-0.98, p=0.02). Cardiovascular deaths were 154 and 168 in those formerly assigned atorvastatin and placebo, respectively ( HR 0.89, CI 0.72-1.11, p= 0.32). There was, however, a significant reduction in non- CV deaths in those formerly assigned atorvastatin (HR 0.85, CI 0.73-0.99, p=0.03) explained by a significant reduction in deaths due to infection and/or respiratory illness. There were no differences in deaths from cancer. Conclusion: In these hypertensive patients, the findings establish a legacy of the long term benefits of treatment with atorvastatin on all cause mortality, 8 years after completion of the trial. Conclusion: In these hypertensive patients, the findings establish a legacy of the long term benefits of treatment with atorvastatin on all cause mortality, 8 years after completion of the trial. Discussant | see Presenter abstract
Guy De Backer(Belgium)Presentation webcastPresentation slides
If drugs are introduced in the primary prevention of cardiovascular diseases (CVD) for the management of dyslipidaemias it implicates that people free of CVD are advised to take lipid lowering drugs, every day for the rest of their life. Results from randomized clinical trials have demonstrated that statins are effective and safe in preventing CVD over a short time period. The challenge remains as to the long term safety particularly with drugs that may interact with other drugs and that may have side effects especially in elderly persons with co-morbidity. Since most clinical trials in CVD prevention rarely continue for longer than about 5 years this leaves us in the dark concerning lifetime effects and safety. In the 10 placebo-controlled primary prevention trials with statins that have been carried out the median follow-up was 4.8 years, the longest 5.5 yrs. The mean age range of the study populations varied between 55 and 66 yrs ; some participants were as young as 40 years; if the effective treatment is applied to them they have to take these pills for 30-40 years while the safety guarantee based on trial results is limited to 5yrs . Therefore results from long term follow-up such as in the UK cohort of ASCOT –LLA are very welcome . What finally counts in primary prevention is total mortality and quality of life; and one of the reassuring results from this long term follow-up is that ASCOT- LLA- UK confirms what has been seen in two other statin trials that have published long term follow-up results . In the table the differences in total mortality between the groups originally assigned to statin or placebo during long term follow-up in 4S, WOSCOPS and ASCOT-LLA-UK are shown : the relative risk or hazard ratios (RR, HR) are very similar all in favour of the statin therapy and all statistically significant at p < .03; these results are very reassuring for a time period varying from 10 to 15 yrs. Table: Differences in Total Mortality between the groups originally assigned to statin or placebo during long term follow-up in 4S, WOSCOPS and ASCOT-LLA-UK.CI: confidence interval.
Another safety issue relates to statins and cancer with in the background results from animal models suggesting cancer induction by statins in rodents, unexpected and conflicting results regarding specific cancers in single trials but more important competition between cardiovascular and non-cardiovascular causes of death that could potentially take place during long term follow-up of an ageing population; the original statin group could be expected to be at an increased risk of cancer death during long term follow up because their survival improved during the trial through the reduction of CV deaths. Results from meta-analysis of the statin trials have been reassuring on the short term regarding statins and cancer ; pharmaco-surveillance and large propensity –matched pairs studies have been reassuring on a longer time period and now the results from the UK cohort of ASCOT -LLA go in the same direction: the incidence of cancer deaths in the groups originally assigned to atorvastatin and placebo is very similar: 0.85/100 personyears in the atorvastatin group and 0.92/100 personyears in the placebo group. Short term – on average 2 yrs – post statin trial follow-up in 4S , WOSCOPS and ALERT provided convincing evidence that withdrawal from statin therapy is followed by sustained treatment benefit. This was confirmed in ASCOT -LLA between the premature closure of the trial at 3.3 yrs and the discontinuation at 5.5 yrs. What about carry-over effects on the long run? In the extended follow-up of WOSCOPS there was evidence of an ongoing reduction in the risk of major coronary events among subjects treated with pravastatin during the trial period; the authors consider it as an ongoing carry-over effect related to a slowing of the progression of the disease and/or a stabilization of existing plaques. During the 5 year extension of the 4S study no ongoing benefits were observed; the reduction in the relative risk between the two original treatment groups was ascribed to the open-label treatment with statins of the large majority of the patients in both groups when the trial ended. In the UK cohort of ASCOT-LLA the results regarding CV mortality are comparable with those from 4S. CV mortality was non-significantly reduced by -17% at the end of the LLA trial and this became -11% after 11 years .But more surprising are the results of total mortality. Total mortality was not significantly different between the atorvastatin and the placebo groups of the UK cohort when ASCOT-LLA was prematurely closed but the difference was significant at the end of the 11 yrs follow-up. Since CV mortality went in the opposite direction one expects a trend in favor of the group originally assigned to atorvastatin in non-CV mortality and this was also observed. This was unrelated to cancer deaths but a significant difference was observed in deaths due to infections or respiratory disease. One has to remain very cautious in the interpretation of such unexpected findings; they can occur by chance only but are interesting; they do not stand on their own but are congruent with results from observational studies; they are hypothesis-generating and should be examined in adequate clinical trials ; they re-emphasize however also the continuous need for long term follow-up of clinical trial cohorts and the importance of pharmaco-surveillance.
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Clinical Trial Update I - Drug treatment