ACE Inhibitors or ARBs in Hypertension? In Chronic Kidney Disease?

Steve Stiles
January 17, 2008 — A pair of articles in the January 1, 2008 Annals of Internal Medicine brings together the existing literature to address issues that have persisted since the introduction of angiotensin-receptor blockers (ARBs): namely, when and how these drugs might be advantageous in conditions long served by angiotensin-converting enzyme (ACE) inhibitors.
A meticulous survey of studies found that the two drug classes are about equally safe and effective at managing high blood pressure and have similar effects on other risk factors and clinical outcomes in patients with essential hypertension [1]. It also confirmed that ARBs are less likely to cause coughing, but suggested that the side effect might be less common with ACE inhibitors than randomized trials indicate.
In the setting of chronic kidney disease (CKD), concludes the other study, which is a meta-analysis, ACE inhibitor and ARB monotherapy are similarly effective at reducing proteinuria, but a combination of the two angiotensin-2-suppressing drugs works better than either agent individually [2]. But a blanket recommendation to combine them would be premature, according to the authors, because there is little evidence that the combination would improve clinical outcomes over monotherapy, and the safety of such combination therapy is largely undefined.
The authors of both analyses acknowledge that they have major limitations, particularly the heterogeneity of the combined studies, their limited follow-up times, and spotty data on adverse effects.
"The most important contribution of these systematic reviews is that they tell us what we do not know," notes an accompanying editorial [3]. They suggest that the two drug classes are comparably effective as antihypertensive and antiproteinuric agents, writes Dr Patrick S Parfrey (Memorial University of Newfoundland, St John's), but "we know far too little about their long-term safety, especially with combination therapy of ACE inhibitors plus ARBs in stage 3 or 4 chronic kidney disease."
No "clinically meaningful difference" in hypertension
"With the exception of rates of cough, the available evidence does not strongly support the hypothesis that ACE inhibitors and ARBs have clinically meaningful differences in benefits or harms for individuals with essential hypertension," according to the report's authors, led by Dr David B Matchar (Duke Center for Clinical Health Policy Research, Durham, NC).
He and his colleagues analyzed 69 reports based on 61 randomized and observational studies that lasted at least three months and directly compared an ACE inhibitor and an ARB in adults with essential hypertension and evaluated meaningful end points like blood pressure control, treatment compliance, and adverse events.
The strength of evidence was considered high for the observation that the two drug classes are similarly effective at controlling blood pressure. They were comparable in 37 of the 50 studies evaluated for that outcome; 47 of those 50 studies were randomized controlled trials (RCTs).
Also similar were the associated rates of death and cardiovascular (CV) events, quality-of-life measures, successful use of the ACE inhibitor or ARB as the only antihypertensive agent, effects on lipid levels and left ventricular (LV) mass, and risk of dysglycemia or renal dysfunction.
Mortality and CV-event outcomes were available for only nine studies, most of which excluded patients with clinically significant CV disease or comorbidities, the group reported. Few of the studies followed patients for even as long as a year, and "there were really very limited data about major events, such as heart attack and stroke," Matchar told heartwire.
The two drug classes showed similar risks of headache and dizziness, but ACE inhibitors were about three times more likely to have cough as a side effect, regardless of whether the study was cohort-based or an RCT. But the rates of cough were "dramatically higher" in the RCTs, probably because in RCTs, in contrast to cohort-based studies, patients are more likely to be queried specifically for that side effect, Matchar said.
Other evidence suggested that patients are more likely to stick with ARBs than with ACE inhibitors when each were given as initial therapy, but "the magnitude of this difference is difficult to quantify," according to the report.
Although any differences in efficacy between the two drug classes are likely to be small, according to Matchar et al, pinning down such small differences might be worth the challenge of mounting a large long-term randomized study, given that small changes in blood pressure are known to have a substantial outcomes effect.
To heartwire Matchar said, "if there really is a marginal benefit to be had from, say, greater tolerability of ARBs compared with ACE inhibitors, then we really do need some [more definitive] head-to-head studies to show it."
"Encouraging" support for combination therapy in CKD
The other reported study provided "high-quality evidence" that monotherapy with ACE inhibitors or ARBs reduces proteinuria to comparable degrees in patients with CKD, regardless of the underlying cause of renal dysfunction. And, write the authors, led by Dr Regina Kunz (University Hospital, Basel, Switzerland), "evidence is encouraging that the combination of the two drugs is more effective, at usual doses, than either drug alone."
The group analyzed 49 RCTs that compared ARBs with ACE inhibitors, a combination of the two drug classes, placebo, or calcium-channel blockers and tracked microalbuminuria and proteinuria over at least four weeks in patients with CKD.
ARBs and ACE inhibitors were similarly effective at lowering proteinuria, ARBs were more effective than calcium-channel blockers, and a combination of ARBs and ACE inhibitors was more effective than either agent alone.
Ratio of means (95% CI)* for change in proteinuria, by randomized therapy, over two follow-up intervals
Randomized therapy
Over 1 - 4 mo
Over 5 - 12 mo
ARBs vs placebo
0.57 (0.47 - 0.68)
0.66 (0.63 - 0.69)
ARBs vs ACE-I
0.99 (0.92 - 1.05)
1.08 (0.96 - 1.22)
ARBs vs CCBs
0.69 (0.62 - 0.77)
0.62 (0.55 - 0.70)
ARB+ACE-I vs ARBs
0.76 (0.68 - 0.85)
0.75 (0.61 - 0.92)
ARB+ACE-I vs ACE-I
0.78 (0.72 - 0.84)
0.82 (0.67 - 1.01)
ACE-I = angiotensin-converting-enzyme inhibitor; ARB = angiotensin-receptor blocker; CCB = calcium-channel blocker*Ratio of means = ratio of the average treatment effect in the intervention group (either ARBs alone or in combination with ACE inhibitors) relative to the control group (placebo or single-drug comparator), with 95% CI
Only one-third of the reports included details on how adverse drug effects were assessed in the studies; according to the authors, few "presented adverse drug reactions in a structured manner that allowed us to make causal inferences," and 45 of the 49 studies "lacked quantitative data even on more common but less severe adverse drug reactions, prohibiting a reliable estimate of their incidence."
According to Parfrey, the editorialist, the findings from Kunz et al, along with those of the recent Irbesartan in the Management of PROteinuric patients at high risk for Vascular Events (IMPROVE) trial [4], suggest that "monotherapy with inhibitors of the renin-angiotensin system is sufficient for patients with early-stage renal disease and relatively low albumin excretion and that combination therapy is effective for patients with heavier proteinuria." However, he cautions, "for combination therapy, we have no safety data in chronic kidney disease, and we do not know the rates of progression of chronic kidney disease. . . . We need a large-scale, long-term, head-to-head, three-group RCT comparing monotherapy with ARBs or ACE inhibitors and with combination therapy involving both ARBs and ACE inhibitors."
The report by Matchar et al notes that coauthor Dr Douglas C McCrory (Duke Center for Clinical Health Policy Research) has received honoraria from AstraZeneca and coauthor Dr Gregory P Samsa (Duke Center for Clinical Health Policy Research) holds Pfizer stock or stock options. The article by Kunz et al says that "meetings, literature search, and statistical analysis were supported in part by Novartis" and that coauthor Dr Johannes F E Mann (Munich General Hospital, Germany) has received honoraria from Boehringer-Ingelheim, Novartis, and Aventis and grants from Aventis and Novartis.
Sources
Matchar DB, McCrory DC, Orlando LA, et al. Systematic review: Comparative effectiveness of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers for treating essential hypertension. Ann Intern Med. 2008;148:16-29.
Kunz R, Friedrich C, Wolbers M, Mann JFE. Meta-analysis: Effect of monotherapy and combination therapy with inhibitors of the renin angiotensin system on proteinuria in renal disease. Ann Intern Med. 2008;148:30-48.
Parfrey PS. Inhibitors of the renin angiotensin system: Proven benefits, unproven safety. Ann Intern Med. 2008; 48:76-77.
Bakris GL, Ruilope L, Locatelli F, et al. Treatment of microalbuminuria in hypertensive subjects with elevated cardiovascular risk: results of the IMPROVE trial. Kidney Int. 2007;72:879-885.