Editorial comments [7]

The effect of combination treatment with aliskiren and blockers of the renin-angiotensin system on hyperkalaemia and acute kidney injury: systematic review and meta-analysis.

Harel Z, Gilbert C, Wald R, Bell C, Perl J, Juurlink D, Beyene J, Shah PS.

BMJ. 2012 Jan 9;344:e42. doi: 10.1136/bmj.e42.

Background

Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers can be used to block the renin-angiotensin system in congestive heart failure, hypertension, and proteinuria [1,2]. The renin-angiotensin system might be blocked at multiple foci, but this may be associated with significant toxicity, such as hyperkalaemia and acute kidney injury [3-6].
As aliskiren also blocks the renin-angiotensin system, it may cause similar adverse effects when used in combination with ACE inhibitors and angiotensin receptor blockers. In this meta-analysis the risk of acute kidney injury and hyperkalaemia is analysed when various blockers of the renin-angiotensin system are combined.

Main results

10 studies reported on the outcome of hyperkalaemia. The risk of hyperkalaemia was significantly higher among participants given aliskiren in combination with an ACE inhibitor or angiotensin receptor blocker than among those given ACE inhibitor or angiotensin receptor blocker monotherapy (relative risk 1.58, 95% confidence interval 1.24 to 2.02; risk difference 0.02, 95% confidence interval 0.01 to 0.04). Similarly, the risk of hyperkalaemia from combined use of aliskiren and an ACE inhibitor or angiotensin receptor blocker compared with aliskiren monotherapy was significantly increased (relative risk 1.67, 1.01 to 2.79; risk difference 0.02, 0.03 to 0.01).

Acute kidney injury was reported as an outcome measure in 8 studies. The risk of acute kidney injury was not significantly increased among participants given aliskiren in combination with an ACE inhibitor or angiotensin receptor blocker than among those given ACE inhibitor or angiotensin receptor blocker monotherapy (relative risk 1.14, 95% confidence interval 0.68 to 1.89) or aliskiren monotherapy (0.80, 0.31 to 2.04).

Conclusion

The use of aliskiren in combination with ACE inhibitors or angiotensin receptor blockers is associated with a significantly increased risk of hyperkalaemia compared with monotherapy using ACE inhibitors or angiotensin receptor blockers. No effect was found of combination therapy on the risk of acute kidney injury.

An important message from this study is that use of a combination of aliskiren and an ACE inhibitor or ARB increases the risk of hyperkalaemia. This study did not show a clear association between the risk of hyperkalaemia and the patient’s clinical state. It is therefore not clear whether or not clinicians should exercise caution in prescribing dual treatment in the subgroup of patients with hypertension but no other risk factors for hyperkalaemia. Another drawback is that ACE inhibitors and ARBs were considered together as a single class, which reduces the usefulness of the study’s findings from a pharmacological perspective, as the two drug classes have divergent effects on angiotensin II concentrations and receptor occupancy, and their effects may also differ when combined with aliskiren. Finally, it is not clear whether the patients who were included in the various studies were representative of the general population of patients with hypertension. The risk estimates from the current meta-analysis may not accurately reflect risk in “real life”—the risk of developing severe hyperkalaemia may be greater still.

The ALTITUDE trial, which was designed to explore whether dual blockade with aliskiren combined with an ACE inhibitor or ARB would reduce morbidity and mortality in a broad range of high risk patients with type 2 diabetes [8], was stopped prematurely in December 2011. The trial’s data safety monitoring board advised against continuing the study because the active treatment group experienced an increased incidence of non-fatal stroke, renal complications, hyperkalaemia, and hypotension over 18 to 24 months of follow-up. The committee concluded that patients were unlikely to benefit from aliskiren on top of standard antihypertensive treatment.

Summarizing, clinicians should avoid using a combination of renin-angiotensin system blockers in high risk patients and be extremely cautious when using combination treatment in low risk patients. Future work should concentrate on how different renin-angiotensin system blockers interact and in which types of patients the combination can be used safely.

References

1. Navaneethan SD, Nigwekar SU, Sehgal AR, Strippoli GF. Aldosterone antagonists for preventing the progression of chronic kidney disease: a systematic review and meta-analysis. Clin J Am Soc Nephrol 2009;4:542-51.
2. Alfie J, Aparicio LS, Waisman GD. Current strategies to achieve further cardiac and renal protection through enhanced renin-angiotensin-aldosterone system inhibition. Rev Recent Clin Trials 2011;6:134-46.
3. MacKinnon M, Shurraw S, Akbari A, Knoll GA, Jaffey J, Clark HD. Combination therapy with an angiotensin receptor blocker and an ACE inhibitor in proteinuric renal disease: a systematic review of the efficacy and safety data. Am J Kidney Dis 2006;48:8-20.
4. Phillips CO, Kashani A, Ko DK, Francis G, Krumholz HM. Adverse effects of combination angiotensin II receptor blockers plus angiotensin-converting enzyme inhibitors for left ventricular dysfunction: a quantitative review of data from randomized clinical trials. Arch Intern Med 2007;167:1930-6.
5. Mann JF, Schmieder RE, McQueen M, Dyal L, Schumacher H, Pogue J, et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet 2008;372:547-53.
6. Berl T. Review: renal protection by inhibition of the renin-angiotensin-aldosterone system. J Renin Angiotensin Aldosterone Syst 2009;10:1-8.
7. De Leeuw PW. Dual renin-angiotensin system blockade. BMJ. 2012 Feb 1;344:e656. doi: 10.1136/bmj.e656.
8. Parving HH, Brenner BM, McMurray JJ, de Zeeuw D, Haffner SM, Solomon SD, et al. Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE): rationale and study design. Nephrol Dial Transplant 2009;24:1663-71.


AbstractOBJECTIVE: To examine the safety of using aliskiren combined with agents used to block the renin-angiotensin system.
DESIGN: Systematic review and meta-analysis of randomised controlled trials.
DATA SOURCES: Medline, Embase, the Cochrane Library, and two trial registries, published up to 7 May 2011.
STUDY SELECTION: Published and unpublished randomised controlled trials that compared combined treatment using aliskiren and angiotensin converting enzyme inhibitors or angiotensin receptor blockers with monotherapy using these agents for at least four weeks and that provided numerical data on the adverse event outcomes of hyperkalaemia and acute kidney injury. A random effects model was used to calculate pooled risk ratios and 95% confidence intervals for these outcomes.
RESULTS: 10 randomised controlled studies (4814 participants) were included in the analysis. Combination therapy with aliskiren and angiotensin converting enzyme inhibitors or angiotensin receptor blockers significantly increased the risk of hyperkalaemia compared with monotherapy using angiotensin converting enzymes or angiotensin receptor blockers (relative risk 1.58, 95% confidence interval 1.24 to 2.02) or aliskiren alone (1.67, 1.01 to 2.79). The risk of acute kidney injury did not differ significantly between the combined therapy and monotherapy groups (1.14, 0.68 to 1.89).

CONCLUSION: Use of aliskiren in combination with angiotensin converting enzyme inhibitors or angiotensin receptor blockers is associated with an increased risk for hyperkalaemia. The combined use of these agents warrants careful monitoring of serum potassium levels.