Side effects and tolerability of combination blood pressure lowering according to blood pressure levels: an analysis of the PROGRESS and ADVANCE trials.

Abstract

OBJECTIVE:

To measure the placebo-controlled effects of combination therapy on hypotension, treatment discontinuation, and major renal outcomes, according to baseline blood pressure.

METHODS:

We conducted an analysis of the action in diabetes and vascular disease: preterax and diamicron-MR controlled evaluation ADVANCE and perindopril protection against recurrent stroke study PROGRESS trials, including 14 684 participants allocated combination therapy or placebo. The mean age was 65 years, 61% were men, and 64% were receiving background blood pressure lowering (BPL) therapy. Participants were stratified into five subgroups by baseline SBP less than 120, 120-129, 130-139, 140-159, and at least 160 mmHg. Discontinuation of study treatment during the active run-in phase and postrandomization follow-up was assessed for hypotension/dizziness and other causes. Major renal outcomes (sustained doubling in creatinine or renal death) were also assessed.

RESULTS:

Discontinuation during the 4-6-week active run-in phase due to hypotension/dizziness ranged from 3.6% in those with SBP less than 120 mmHg to 1.3% in those with SBP at least 160 mmHg. Median follow-up in the randomized phase was 5.6 years, and discontinuation for hypotension was higher with combination therapy compared with placebo in the less than 120 mmHg group (4.7 vs. 1.2%). However, for each subgroup with baseline SBP 120-129, 130-139, and 140-159 mmHg, the absolute excess of discontinuation due to hypotension with combination therapy was 0.7%. Total discontinuations were only increased in the less than 120 mmHg group (18.4 vs. 12.5%) and the 120-129-mmHg subgroup (17.6 vs. 14.2%). There were no clear differences across the SBP subgroups for the combined renal outcome (overall, 0.8 vs. 0.6%).

CONCLUSION:

Compared with those with baseline SBP 140-159 mmHg, side effects of dual combination BPL are essentially the same for people with SBP 130-139 mmHg and only modestly increased among patients with SBP 120-129 mmHg. During long-term therapy, side effects sufficient to stop treatment that are treatment related (i.e. occur in excess of rates seen with placebo) occur at less than 0.5%/year in patients with baseline SBP 120-139 mmHg. These results have important implications in assessing the likely balance of benefits and side effects of BPL with combination therapy among those with SBP 120-139 mmHg.

• Authors: Emily R Atkins, Yoichiro Hirakawa, Abdul Salam, Mark Woodward, Mark Cooper, Pavel Hamet, Stephen Harrap, Kennedy Lees, Lisheng Liu, Giuseppe Mancia, Michel Marre, Vlado Perkovic, Neil Poulter, Bryan Williams, John Chalmers, Anthony Rodgers
• Journal: Journal of hypertension (J Hypertens) Vol. 35 Issue 6 Pg. 1318-1325 (06 2017) ISSN: 1473-5598 [Electronic] England
• PMID: 28169881 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Antihypertensive Agents
• Drug Combinations
• Placebos
• indapamide, perindopril drug combination
• Indapamide
• Perindopril

Topics

• Aged
• Antihypertensive Agents (adverse effects, therapeutic use)
• Blood Pressure (drug effects)
• Diabetes Mellitus, Type 2 (drug therapy)
• Drug Combinations
• Female
• Humans
• Hypertension (drug therapy)
• Hypotension (chemically induced)
• Indapamide (administration & dosage, adverse effects)
• Male
• Medication Adherence
• Middle Aged
• Multicenter Studies as Topic
• Perindopril (administration & dosage, adverse effects)
• Placebos (adverse effects)
• Proportional Hazards Models
• Randomized Controlled Trials as Topic
• Stroke (prevention & control)