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Congress Report: European Society of Cardiology (ESC) 2014

Congress Report: European Society of Cardiology (ESC) 2014
  • Cardiometabolic
  • Hypertension

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Article

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European Society of Cardiology
ESC
SYMPLICITY HTN-3
ADVANCE-ON
PARADIGM-HF
SIGNIFY
UKPDS
Trial Results
Hypertension
heart failure
Renal denervation
BP control in diabetes
coronary artery disease

The ESC Congress 2014 in Barcelona was once again well attended with over 30,000 participants from 140 different countries. There were several presentations providing important new information on hypertension and related conditions.

Professor Brian Tomlinson reports from the European Society of Cardiology (ESC) Congress 2014 (Barcelona, 30 August to 3 September), which was attended by over 30,000 participants from 140 countries. He takes an in-depth look at, and provides updates on, the new data on hypertension and related conditions presented during the Congress.

SYMPLICITY HTN-3

Professor George Bakris (USA) presented the 12 months’ follow-up results from SYMPLICITY HTN-3, which showed that there was no overall benefit from the renal-artery denervation procedure (similar to the 6-month findings published earlier in 20141). SYMPLICITY HTN-3 was the first trial to compare renal denervation to a sham procedure, to examine for any placebo effect. Originally, 535 patients with resistant hypertension were randomised to receive renal denervation or a surgical intervention with no denervation procedure. After 6 months, compared with the sham control group, there was no difference in systolic blood pressure (SBP) reduction in patients receiving renal-artery denervation. At that stage, patients and clinicians were unblinded and 101 of the 171 patients randomised to the sham procedure crossed over and received renal denervation. The group that did not cross over had lower SBP (176.1 mmHg) due to inclusion of subjects with SBP <160 mmHg at 6 months’ follow-up (SBP >160 mmHg was one criterion for crossover) and thus could no longer serve as a comparator group. This group had shown a larger decrease in office SBP at 6 months (-32.9 mmHg) than the other groups, and between 6 and 12 months their office SBP increased by 11.5 mmHg, resulting in a net decrease in office SBP at 12 months of -21.4 mmHg compared to baseline.

Office SBP measurements for 320 patients in the original renal denervation arm showed a decrease from baseline of -18.9 mmHg at the 12-month follow-up, representing an additional 3.6 mmHg decrease in SBP compared to the 6-month data. The group crossing over to renal denervation after 6 months with available data (n=92) had a decrease of -17.7 mmHg from baseline, which was slightly greater than the reduction of -15.3 mmHg in SBP seen at 6 months in the group originally randomised to denervation.

Changes in ambulatory SBP were smaller than changes in office SBP and were not different between treatment groups. There was no difference in major adverse events between the groups originally having the sham procedure and the group originally having renal denervation at 12 months. Reductions in office blood pressure at 12 months were similar in all three groups: those that originally received denervation, those that crossed over to receive denervation at 6 months and those that did not cross over. Professor Bakris concluded that possible confounding factors included the population studied, drug prescription changes, variable adherence to therapy and procedural variability. He said further research on this technique and the issue of medication adherence is still required. The findings have now been published.2

ADVANCE-ON

Professor John Chalmers (Australia) presented findings from the intensive blood pressure control arm of ADVANCE-ON (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation Observational Study). This was a post-trial follow-up for a median of 5.9 years of the ADVANCE (The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) trial, which showed that a fixed combination of perindopril and indapamide compared to placebo was well tolerated and reduced the risks of major vascular events, including death, in patients with type 2 diabetes.3 From 11,140 randomised patients, data were available in 8494. Differences in blood pressure between the two groups had disappeared by the first post-randomisation visit and reductions in all-cause death and cardiovascular death recorded during active treatment were diminished but remained significant to the end of post-trial follow-up (hazard ratios [95% CI] 0.91 [0.84-0.99], p=0.03 and 0.88 [0.77-0.99], p=0.04, respectively). Reductions in major macrovascular events were not significant (0.92 [0.85-1.00], p=0.06). These findings suggest a legacy effect of the intensive blood pressure lowering treatment. The study has now been published.4

The findings from the long-term follow-up of the tight glycaemic control arm of the ADVANCE-ON study were reported 2 weeks later by Sophia Zoungas at the European Association for the Study of Diabetes meeting in Vienna. In the ADVANCE study, the strategy of intensive glucose control involving gliclazide (modified release) and other drugs as required did not reduce major macrovascular events, cardiovascular death or all-cause mortality but did reduce microvascular events, mainly by reduction in nephropathy.5 In the follow-up study there was no difference in cardiovascular outcomes between the groups with or without tight glucose control but there was a significant reduction in the secondary outcome of end-stage renal disease (HR 0.54 [0.34-0.85], p=0.007) although the number of these events was small.5

John Chalmers also noted that the continued reduction in all-cause mortality in the intensive blood pressure treatment arm after completion of the randomised study seen in ADVANCE-ON was similar in the UKPDS (United Kingdom Prospective Diabetes Study), but it was not significant in UKPDS probably because of the much smaller number of participants. In UKPDS tight blood pressure control was achieved with therapy based on atenolol or captopril. Tight blood pressure control reduced macrovascular events and there was no difference between the groups treated with regimens based on atenolol or captopril.6 Interestingly, the long-term follow-up after tight control of blood pressure in UKPDS showed a reduction in all-cause mortality in the group originally assigned to atenolol compared to the captopril group, which did not appear until at least 12 years after the original randomisation.7 The reason for this effect remains uncertain. 

Taken together, these findings confirm the importance of effective blood-pressure control in diabetic patients in both the short and long term. ADVANCE and ADVANCE-ON support lowering blood pressure to levels <140/80 mmHg in diabetic patients; looking at ADVANCE and UKPDS together, however, it is not clear that there is a single optimal first-line antihypertensive treatment for diabetic patients.

PARADIGM-HF

The findings from the PARADIGM-HF trial were presented by Milton Packer (USA), and published simultaneously in N Engl J Med.8 Although this was a trial in heart failure, it is relevant to hypertension because the angiotensin receptor-neprilysin inhibitor LCZ696 can be used in both conditions. In PARADIGM-HF 8442 patients with class II to IV heart failure and an ejection fraction of ≥40% were randomised to receive either LCZ696 or enalapril in addition to recommended therapy. The trial was stopped early after a median follow-up of 27 months because of an overwhelming benefit with LCZ696. Death from cardiovascular causes or hospitalisation for heart failure (the primary composite outcome) occurred in 21.8% of the LCZ696 group and 26.5% of the enalapril group (HR 0.80; 95% CI 0.73-0.87; p<0.001). Compared to enalapril, LCZ696 reduced the risk of death from cardiovascular causes by 20% (13.3% vs. 16.5%; HR 0.80; 95% CI 0.71-0.89; p<0.001). The superiority of LCZ696 over enalapril was not accompanied by any important safety concerns: the LCZ696 group had more patients with hypotension and nonserious angioedema but fewer with renal impairment, hyperkalemia and cough than the enalapril group. These striking benefits with LCZ696 (now called sacubitril/valsartan) led to approval (priority review) by the United States Food and Drug Administration for heart failure in July 2015.

SIGNIFY

SIGNIFY was a trial in 19,102 patients with stable coronary artery disease without clinical heart failure with a heart rate of ≥70 beats/minute randomised to ivabradine or placebo. The dose of ivabradine was adjusted up to a maximum of 10 mg twice daily to achieve a target heart rate of 55–60 beats/minute. Median follow-up was 27.8 months and results showed no significant difference in the primary end point – cardiovascular death or non-fatal myocardial infarction – between the ivabradine and placebo groups (6.8% vs. 6.4%, HR=1.08, p=0.20).9 In the 12,000 patients with more severe angina, the ivabradine group actually showed a significant increase vs. placebo in the primary outcome but ivabradine did significantly reduce the occurrence of angina in the more severe angina cohort. This disappointing outcome does not support the role of heart rate reduction with ivabradine in angina and the SIGNIFY authors concluded that an elevated heart rate may be only a marker of risk rather than a modifiable determinant of outcomes in patients who have stable coronary artery disease without clinical heart failure. Some discussants suggested that ivabradine may have lowered heart rate too much in some patients and the dose of ivabradine used in SIGNIFY was higher than the approved dose.

 References

1.            Bhatt DL, Kandzari DE, O'Neill WW, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014;370:1393-1401. http://www.ncbi.nlm.nih.gov/pubmed/24678939

2.            Bakris GL, Townsend RR, Flack JM, et al. 12-month blood pressure results of catheter-based renal artery denervation for resistant hypertension: the SYMPLICITY HTN-3 trial. J Am Coll Cardiol. 2015;65:1314-1321. http://www.ncbi.nlm.nih.gov/pubmed/25835443

3.            Patel A, MacMahon S, Chalmers J, et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet. 2007;370:829-840. http://www.ncbi.nlm.nih.gov/pubmed/17765963

4.            Zoungas S, Chalmers J, Neal B, et al. Follow-up of blood-pressure lowering and glucose control in type 2 diabetes. N Engl J Med. 2014;371:1392-1406. http://www.ncbi.nlm.nih.gov/pubmed/25234206

5.            Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560-2572. http://www.ncbi.nlm.nih.gov/pubmed/18539916

6.            UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ. 1998;317:713-720. http://www.ncbi.nlm.nih.gov/pubmed/9732338

7.            Holman RR, Paul SK, Bethel MA, et al. Long-term follow-up after tight control of blood pressure in type 2 diabetes. N Engl J Med. 2008;359:1565-1576. http://www.ncbi.nlm.nih.gov/pubmed/18784091

8.            McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993-1004. http://www.ncbi.nlm.nih.gov/pubmed/25176015

9.            Fox K, Ford I, Steg PG, et al. Ivabradine in stable coronary artery disease without clinical heart failure. N Engl J Med. 2014;371:1091-1099. http://www.ncbi.nlm.nih.gov/pubmed/25176136

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