Evaluation of subacute change in RAAS activity (as indicated by urinary aldosterone:creatinine, after pharmacologic provocation) and the response to ACE inhibition

Q: What is the clinical evidence from this study?

Population: Experimental renin-angiotensin-aldosterone system (RAAS) activation (n=31). Intervention: Angiotensin-converting enzyme inhibitor (enalapril or benazepril) vs. Baseline (pre-treatment or activated baseline prior to ACEI initiation). Primary outcome: Incidence of incomplete RAAS blockade (IRB), defined by elevated urine aldosterone:creatinine ratio (UAldo:C) above baseline or >1.0 μg/g cut-off (p=<0.0001).

Q: What does this research mean for the field?

Angiotensin-converting enzyme inhibitors frequently fail to fully suppress aldosterone excretion, resulting in incomplete renin-angiotensin-aldosterone system blockade in dogs with experimental RAAS activation. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Marisa K. Ames; Clarke E. Atkins; Andrea C. Lantis; James zum Brunnen

doi:10.1177/1470320316633897

January 1, 2016Journal of the Renin-Angiotensin-Aldosterone SystemOpen Access

Evaluation of subacute change in RAAS activity (as indicated by urinary aldosterone:creatinine, after pharmacologic provocation) and the response to ACE inhibition

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Why the study?

Does subacute angiotensin-converting enzyme inhibitor (enalapril or benazepril) therapy completely suppress renin-angiotensin-aldosterone system activity (as measured by urine aldosterone:creatinine ratio) in healthy dogs with furosemide- or amlodipine-induced RAAS activation?

Key Points

To evaluate subacute changes in renin-angiotensin-aldosterone system activity and the frequency of incomplete blockade during ACE inhibitor therapy in dogs with experimentally provoked activation.
Analyzed urine aldosterone:creatinine ratio and serum ACE activity in 31 healthy dogs receiving furosemide or amlodipine along with an ACE inhibitor (enalapril or benazepril) followed for 7 to 17 days.
Assessed incomplete RAAS blockade using individual pre-activation baseline comparisons and a population-derived cut-off value (>1.0 μg/g).
Serum ACE activity measured in 19 dogs was significantly reduced after ACE inhibitor administration (mean suppression 77% ± 15%, P<0.0001).
When RAAS activation preceded ACE inhibitor therapy, the incidence of incomplete RAAS blockade was 33% using dog baseline values and 8% using the cut-off value.
When ACE inhibitors were given concurrently with RAAS activation, the incidence of incomplete blockade reached 65% using baseline criteria and 61% using the cut-off value.

Structured PICO

Does subacute angiotensin-converting enzyme inhibitor (enalapril or benazepril) therapy completely suppress renin-angiotensin-aldosterone system activity (as measured by urine aldosterone:creatinine ratio) in healthy dogs with furosemide- or amlodipine-induced RAAS activation?

P

Population

31 healthy mature laboratory dogs (mean age 30.9 months, 19.4% female) with furosemide- or amlodipine-induced RAAS activation treated with an ACE inhibitor and followed for 7-17 days across two veterinary centers.

I

Intervention

Oral angiotensin-converting enzyme inhibitor (ACEI) therapy with enalapril (0.5 mg/kg or 1.0 mg/kg po q12h) or benazepril (1 mg/kg po q24h or 1.0 mg/kg po q12h) for 4 to 7 days, administered either after or concurrently with pharmacologic RAAS activation (furosemide 2 mg/kg po q12h or amlodipine 0.5 mg/kg po q12h).

C

Comparator

Baseline values prior to ACEI initiation (either pre-stimulation baseline on days -2 and -1, 'activated' baseline after furosemide/amlodipine run-in, or a population-derived cut-off value of >1.0 μg/g); subgroup comparisons between standard vs high-dose ACEI, enalapril vs benazepril, and furosemide vs amlodipine.

O

Outcome

Incidence of incomplete RAAS blockade (IRB) at the final study day (days 7-17), defined via spot/pooled urine aldosterone:creatinine ratio (UAldo:C) as either (a) > activated baseline (when RAAS activation preceded ACEI) or > twofold pre-stimulation baseline (when concurrent), or (b) > population-derived cut-off value of 1.0 μg/g.surrogate

Main Result

p-value: p=<0.0001

In a canine subacute model of experimental RAAS activation, incomplete RAAS blockade (elevated urinary aldosterone:creatinine ratio) occurred in approximately half of dogs receiving enalapril or benazepril despite significant suppression of serum ACE activity, suggesting that aldosterone breakthrough can occur early during ACE inhibitor therapy.

Limitations

Studies were carried out in healthy dogs rather than clinical patients with chronic heart failure.
Subacute duration (7-17 days) leaves it unknown whether incomplete RAAS blockade is temporary or persists chronically.
Only circulating RAAS was evaluated (via urinary aldosterone concentration and serum ACE activity), not tissue RAAS.
Diagnostic criteria do not differentiate between failure of RAAS blockade and disease progression.
Small number of dogs in subgroup analyses makes it difficult to draw firm conclusions.
Studies were carried out in healthy laboratory dogs and were subacute in nature (<4 weeks), differing from clinical chronic heart failure.
Subacute duration allows the possibility that incomplete RAAS blockade is temporary and might diminish with longer therapy.
Only circulating RAAS was evaluated using urinary aldosterone concentration and serum ACE activity, without measuring tissue RAAS.
Small number of dogs in subgroup analyses limits firm conclusions regarding drug or dosage differences.
Diagnostic criteria do not allow differentiation between failure of RAAS blockade and progression of heart disease.

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Implication

ACEI may permit early aldosterone breakthrough in experimental canine RAAS activation; leaves open clinical relevance and need for prospective trials.

Abstract

OBJECTIVE: The objective of this study was to evaluate subacute changes in renin-angiotensin-aldosterone system (RAAS) activity during angiotensin-converting enzyme inhibitor (ACEI) therapy in dogs with experimental RAAS activation. METHODS: Analysis of data (urine aldosterone:creatinine ratio (UAldo:C) and serum angiotensin-converting enzyme activity), in 31 healthy dogs with furosemide or amlodipine-activated RAAS that received an ACEI. When furosemide or amlodipine activation of RAAS preceded ACEI administration, incomplete RAAS blockade (IRB) was defined as a UAldo:C greater than (a) the dog's 'activated' baseline value or (b) a population-derived cut-off value (mean + 2 SD (>1.0 μg/g) of pretreatment UAldo:C from our population of research dogs). In studies where RAAS activation occurred concurrently with ACEIs, IRB was defined as (a) a UAldo:C greater than either twofold the dog's prestimulation baseline value or (b) 1.0 µg/g. Dogs were followed for 7-17 days. RESULTS: Serum angiotensin-converting enzyme activity was measured in 19 dogs and was significantly reduced (P<0.0001) after ACEI administration. The overall incidence of IRB, when RAAS activation preceded ACEI administration, was 33% and 8% for definitions (a) and (b), respectively. The overall incidence of IRB, when ACEIs were concurrent with RAAS activation, was 65% and 61% for definitions (a) and (b), respectively. CONCLUSION: Increases in UAldo:C, despite ACEI administration, is evidence of IRB in this subacute model of experimental RAAS activation and suppression.

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Cite This Study

Ames et al. (2016) studied Experimental renin-angiotensin-aldosterone system (RAAS) activation (n=31). Angiotensin-converting enzyme inhibitor (enalapril or benazepril) vs. Baseline (pre-treatment or activated baseline prior to ACEI initiation) was evaluated on Incidence of incomplete RAAS blockade (IRB), defined by elevated urine aldosterone:creatinine ratio (UAldo:C) above baseline or >1.0 μg/g cut-off (p=<0.0001).

synapsesocial.com/papers/6a81ad5975f53d2468f1fc7c https://doi.org/10.1177/1470320316633897

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Evaluation of subacute change in RAAS activity (as indicated by urinary aldosterone:creatinine, after pharmacologic provocation) and the response to ACE inhibition

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Evaluation of subacute change in RAAS activity (as indicated by urinary aldosterone:creatinine, after pharmacologic provocation) and the response to ACE inhibition

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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