12 November 2009
This systematic review found that adding an ACE inhibitor to standard medical therapy reduces the risk of certain serious CV outcomes in patients with stable ischaemic heart disease and preserved ventricular function. Evidence about the effects of angiotensin II receptor antagonists (A2RAs) in these patients is limited – adding an A2RA to an ACE inhibitor in such cases is of no benefit and increases harms.
Level of evidence:
Level 1 (good quality patient-oriented evidence) according to the Sort criteria.
Healthcare professionals should continue to follow the various NICE guidance on the use of ACE inhibitors in patients with or at risk of cardiovascular disease – NICE clinical guidelines on hypertension, chronic heart failure, secondary prevention post-myocardial infarction (MI), type 2 diabetes and chronic kidney disease (CKD). ACE inhibitors are the evidence-based first-line choice over A2RAs in all situations where a renin-angiotensin system (RAS) drug is indicated. A2RAs should be reserved for the small number of patients in whom an ACE inhibitor has to be discontinued because of cough. Combination therapy with an A2RA plus an ACE inhibitor would appear to have a very limited role. It may be a specialist option in patients with heart failure who are still symptomatic despite optimised ACE inhibitor and beta-blocker therapy. However, this requires very careful monitoring for adverse effects, including worsening renal function.
What is the background to this?
There is still debate as to whether patients with stable ischaemic heart disease but no left ventricular systolic dysfunction benefit from treatment with an ACE inhibitor (or an A2RA) in addition to standard medical therapy including aspirin, beta-blockers and statins. This systematic review investigated the clinical effects and harms of using ACE inhibitors, A2RAs or a combination of these drugs in this group of patients. It included seven long-term randomised controlled trials (RCTs) comparing ACE inhibitors with placebo (most data coming from HOPE with ramipril, EUROPA with perindopril and PEACE with trandolapril), one RCT comparing the A2RA, telmisartan, with placebo in patients intolerant of ACE inhibitors (TRANSCEND), and one RCT comparing combination treatment with telmisartan plus ramipril with either drug alone (ONTARGET). See our earlier blog on TRANSCEND and blog on ONTARGET for further details on these studies.
What does this study claim?
This systematic review found that ACE inhibitors reduced the risk of total mortality, MI and stroke in patients with stable ischaemic heart disease and preserved left ventricular function already receiving standard treatments. Moderate to high strength evidence from six RCTs (n=32,210) comparing ACE inhibitors with placebo found relative risks [RR] of 0.87 (95% confidence interval [CI] 0.81 to 0.94) for total mortality, 0.83 (95%CI 0.73 to 0.94) for non-fatal MI and 0.78 (95%CI 0.63 to 0.97) for stroke.
Data were insufficient to adequately assess the benefits of A2RAs, as there was only one trial and the population was limited to patients who could not tolerate ACE inhibitors. Low-strength evidence from this one RCT (TRANSCEND; n=5,926) suggested that A2RAs reduced the composite endpoint of cardiovascular mortality, non-fatal MI or stroke (RR 0.88; 95%CI 0.77 to 1.00) but not the individual components of this endpoint.
Based on one very large RCT, ONTARGET (n=25,620), combination therapy with an A2RA plus an ACE inhibitor was no better than an ACE inhibitor alone and increased harms. There was no significant difference in total mortality (RR 1.07; 95%CI 0.98 to 1.16), MI (RR 1.08; 95%CI 0.94 to 1.23), stroke (RR 0.93; 95%CI 0.81 to 1.07) or a composite of cardiovascular mortality, MI or stroke (RR 1.00; 95%CI 0.93 to 1.09) with telmisartan plus ramipril compared with ramipril alone. Combination therapy was, however, associated with more study discontinuations due to hypotension (P<0.001) and syncope (P=0.03).
This systematic review adds to the weight of evidence supporting the use of ACE inhibitors in addition to standard medical treatments in patients with stable ischaemic heart disease and preserved ventricular function. This could include patients with a history of coronary artery, peripheral vascular, or cerebrovascular disease, as well as those with diabetes and evidence of end-organ damage (as these were the diverse range of patients recruited in the included trials). The mean age of the trial participants ranged from 57 to 67 years, 57% to 89% of whom were men. In all, 8% to 39% of participants had diabetes, 27% to 100% had hypertension, 7% to 45% had peripheral vascular disease, and 3% to 22% had a previous stroke or transient ischaemic attack. Most patients in the included trials were already receiving aspirin and statins, and about half were being treated with beta-blockers.
The review is limited in its ability to balance the benefits of ACE inhibitor therapy with possible harms, as data reporting on harms were inconsistent and incomplete. Also, there was very little data on which to base conclusions about any differing effects in different patient subgroups. However, it clearly highlights the wealth of data there are for ACE inhibitors in the treatment of patients with ischaemic heart disease compared with the limited data there are for A2RAs. The review also highlights the very important results from the ONTARGET study (discussed in a previous blog), where combination of an ACE inhibitor with an A2RA did not benefit patients with stable ischaemic heart disease without heart failure, but increased their risk of harms compared with use of an ACE inhibitor alone, .
The results from ONTARGET (median follow-up 56 months), particularly those relating to worse major renal outcomes with combination therapy, are changing peoples’ views on what role, if any, combination therapy has. The primary renal outcome (composite of dialysis, doubling of serum creatinine and death) was statistically significantly increased with telmisartan plus ramipril compared with ramipril alone (number needed to harm [NNH] 91), as was the secondary renal outcome of dialysis or doubling of serum creatinine (NNH 215), and the individual endpoint of acute dialysis (NNH 562). However, these latter results need to be viewed with some caution as the number of actual events was very low.
Combination therapy has also come under the spotlight recently, with the retraction from the Lancet of the Japanese COOPERATE trial, originally published in 2003. An investigation into this trial of combination therapy in patients with non-diabetic renal disease found serious issues with the way the trial had been conducted which left the investigators unable to prove the authenticity of the data. These included issues with ethics committee approval, patient consent, statistician involvement and the fact that it was not a double-blind study as the investigator knew the treatment allocation. The retraction of this paper is concerning as it was a ‘landmark study’ favouring combination therapy in CKD. Issues surrounding this trial and further information on the hazards of dual RAS blockade in CKD are discussed in more detail in an Archives of Internal Medicine commentary from earlier this year.
NICE guidance on the use of ACE inhibitors in patients with or at risk of cardiovascular disease is outlined in clinical guidelines on hypertension (CG34), chronic heart failure (CG5), secondary prevention post-MI (CG48), type 2 diabetes (CG87) and chronic kidney disease (CG73). In all these indications, where a RAS drug is recommended, NICE recommend an ACE inhibitor first-line over an A2RA. A2RAs are reserved for patients where a RAS drug is indicated but an ACE inhibitor has to be discontinued because of an intractable ACE-inhibitor induced cough. ACE inhibitors are the evidence-based first line choice over A2RAs as they have a more robust evidence base across all indications, and are unsurpassed by A2RAs in terms of evidence for their efficacy, safety and cost. This systematic review, with its wealth of data for ACE inhibitors in ischaemic heart disease compared with the lack of such data for A2RAs, reinforces this position.
NICE guidance on stable angina is due to be published in 2011. In 2007, SIGN published guidance on the management of stable angina (SIGN 96) which recommended that all patients with stable angina should be considered for treatment with an ACE inhibitor. This was based on an earlier meta-analysis of the HOPE, EUROPA and PEACE trials.
Combination therapy with an A2RA plus an ACE inhibitor would appear to have a very limited role. SIGN guidance on the management of chronic heart failure (SIGN 95) suggests this may be a specialist option in patients with heart failure who are still symptomatic despite optimised ACE inhibitor and beta-blocker therapy. This is based on results from the CHARM-Added trial were the addition of candesartan to ACE inhibitor treatment reduced hospitalisations for heart failure but not all-cause mortality. However, combination therapy in patients with heart failure increases adverse effects, including hypotension, worsening renal function and hyperkalaemia, and requires very careful monitoring.
Study details –
Baker WL, et al. Systematic review: Comparative effectiveness of angiotensin-converting enzyme inhibitors or angiotensin II-receptor blockers for ischaemic heart disease. Ann Intern Med, published online October 19 2009
Design, patients, intervention and comparison: Systematic review and meta-analysis of trials of at least 6 months duration that compared ACE inhibitors, A2RAs or combination therapy with placebo or active control and reported any of several clinical outcomes. Nine RCTs, 2 non-randomised comparative studies and 6 systematic reviews met eligibility criteria. Included RCTs were HOPE (ramipril vs. placebo), PART-2 (ramipril vs. placebo), SCAT (enalapril vs. placebo), EUROPA (perindopril vs. placebo), CAMELOT (enalapril vs. amlodipine vs. placebo), PEACE (trandolapril vs. placebo), SMILE-ISCHEMIA (zofenopril vs. placebo), TRANSCEND (telmisartan vs. placebo) and ONTARGET (ramipril vs. telmisartan vs. both).
Outcomes and results: see above
Sponsorship: funded from the Agency for Healthcare Research and Quality
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