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Long term effects of blood pressure lowering in type 2 diabetes:ADVANCE-ON, a 6 year post-trial follow-up of the ADVANCE trial

ESC Congress 2014 - Hot Line report




By John P Chalmers, (Sydney, Australia)
View Discussant report by Lars Ryden, FESC

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List of Authors:
John Chalmers 1() on behalf of the ADVANCE-ON Collaborative Group
(1) The George Institute for Global Health, Sydney, Australia


The Action in Diabetes and Vascular Disease:  Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, was a 2x2 factorial trial whose blood pressure lowering arm demonstrated that the combination of perindopril-indapamide reduced all-cause mortality  by 14%,  cardiovascular death by 18% and vascular events by 9% in patients with type 2 diabetes.  We present here the results of post-trial follow-up, conducted to determine whether these benefits were sustained.
Survivors, previously randomly assigned to perindopril-indapamide or placebo were invited to post-trial follow-up.  Primary outcomes were all-cause mortality and major macrovascular events (myocardial infarction, stroke and death from a cardiovascular cause).  Effects on pre-specified endpoints were compared according to previous randomised treatment. (ClinicalTrials.Gov NCT 0094286)
Baseline characteristics of 11140 patients originally randomised, and 8494 who contributed to post-trial follow-up for a median of 5.9 years, were similar.  Differences in blood pressure between the two groups disappeared by the first post-randomisation visit.  The reductions in all-cause death and  cardiovascular death recorded during active treatment were sustained to the end of post-trial follow-up (hazard ratios [95% confidence intervals] 0.91[0.84-0.99], p=0.03 and 0.88[0.77-0.99], p=0.04) respectively, but were diminished. The reductions in major macrovascular events were not significant (0.92[0.85-1.00], p=0.06)
These results emphasise the importance of active blood pressure lowering in patients with type 2  diabetes in both the short term and the long term in order to maximise survival and cardiovascular protection.


By Lars Ryden, FESC (Stockholm, Sweden)
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A majority of patients with Type 2 diabetes have hypertension and the presence of elevated BP is of prognostic importance. The 2013 European Guidelines on management of patients with diabetes, pre-diabetes and cardiovascular disease recommends that BP is lowered to < 140/85 mmHg, a strong recommendation based on many clinical trials among them ADVANCE.

The 6 year post-trial follow up of ADVANCE, ADVANCE-ON, represents a total follow up of almost 10 years of this important study of blood pressure (BP) lowering in patients with type 2 diabetes In this trial a combination of Perindopril-Indapamide was compared to placebo as add on therapy in patients with elevated BP. The actively treated patients had a 14 % reduction in total and 18 % reduction In cardiovascular mortality and a 21 % reduction in renal events. These beneficial results were obtained although patients at study entry had a fairly well controlled BP (average 145/81) as a response to a reduction on systolic blood pressure of 5,6 and diastolic of 2,2 mmHg.
The follow up, ADVANCE-ON, comprised 5.131 of the original 11.140 patients. By the end of the post trial follow up BP was almost equal in the two study groups amounting to 137/74 and 138/75 respectively. The trialists concluded that ADVANCE-ON showed a somewhat attenuated but still persistent long term benefit with a significant reduction of all cause of mortality in the actively treated group (HR 0,91 (95 % CI 0,84-0,99;p=0,03). The greatest part of the benefit was considered to be a carry forward effect of the original trial benefits i.e. BP lowering during the original trial. The trialists supported their data by performing a metaanalysis of other BP lowering trials.
As always there are potential confounders in a post trial follow up of present kind. One may question the representativity considering that only 46%, 5.131 of the 11.140 original patients participated. Patients in continued follow up were survivors and since all centers did not participate and one may therefore suspect that those interested in ADVANCE-ON were from ambitious centers with particularly interested physicians. This is one of potential positive selection bias that may have influenced the outcome. Moreover blood pressure treatment may have differed between the groups during the post trial period.
It is obvious that few of patients, originally on Perindopril-Indapamide remained on that drug (< 10 %) and some patients where at least temporarily without any blood pressure reducing treatment and several without blockers of the Renin-Angiotensin system. This may also be another confounder. Another important question was of course that ADVANCE also contained a glucose lowering part. It is known that glucose lowering treatment has a legacy effect with the implication od improved cardiovascular benefits over a prolonged period of follow up. The authors acknowledged that by performing interaction analyses and did not find any heterogeneity in this and several other tested respects.
Regarding the conclusions one can, with the mentioned reservations, agree that there is a persistent benefit after the end of randomized BP lowering treatment. It is likely, as stated by the authors, that the greatest benefit presumably is a carry forward effect of BP lowering during the ADVANCE trial. This underlines the importance of lowering BP per se and is agreement with previous observations that the choice of BP lowering drug may be less important than BP reduction in it self. To support the statements the authors made a metaanalysis of other trials and claimed that the result indicates a small but definite reduction during the post trial period lowering. This is, however, doubtful since the discrepancies between these trials, the follow up times the used drugs and the blood pressure reduction, is considerable. The authors also discussed possible reasons between the benefits and argued that structural changes in the vascular bed and/or the heart due to the Perindopril-Indapamide treatment with a long lasting beneficial effect on the endothelium may be the reason. This is rather speculative and not studied in any detail neither in ADVANCE nor in ADVANCE-ON.
An key question is if the results from ADVANCE-ON are important? In my opinion they are. We need convincing long-term data on the benefit of BP control. This has lately been underscored by results from the EUROASPIRE-IV observations during 2012-13 in 24 European countries. Around 3.200 patients with known or newly detected diabetes where investigated. A substantial proportion of them never reached the systolic target of <140 mmHg and 10 % were indeed above 160 and 5 % above 170. Realizing that a small BP reduction during the ADVANCE trial resulted in a significant and long lasting mortality reduction in patients with type 2 diabetes can be hoped that more attention will be put on a proper BP reduction.




Clinical Trial Update Hot Line: Interventions and drug therapy

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.