People on monotherapy

• Ensure that the person is taking the maximum licensed or highest tolerated dose.
• If the person is taking a beta-blocker:
• Add a long-acting dihydropyridine calcium-channel blocker (CCB), such as amlodipine, modified-release nifedipine, or modified-release felodipine.
• If a dihydropyridine CCB is contraindicated or not tolerated, add a nitrate; nicorandil; or ivabradine (if their heart rate is > 60 bpm).
• If the person is taking an anti-anginal drug other than a beta-blocker, and is not known to be intolerant of a beta-blocker and has no contraindications:
• Consider adding a beta-blocker.
• Do not combine a beta-blocker with a rate-limiting CCB (diltiazem or verapamil), as severe bradycardia and heart failure can occur.
• If the person is taking an anti-anginal drug other than a beta-blocker, and a beta-blocker is contraindicated or not tolerated:
• If taking a CCB, add a nitrate or nicorandil.
• If taking a nitrate, add a CCB or nicorandil.
• If taking nicorandil, add a CCB or a nitrate.
• If taking ivabradine, add a dihydropyridine CCB, a nitrate, or nicorandil (consider seeking specialist advice).

People on dual therapy

• Ensure that the person is taking the maximum licensed or highest tolerated dose of each drug.
• If symptom control is poor on the maximum licensed or tolerated doses of two drugs, refer to a cardiologist (for advice on further drug management and assessment for revascularization).
• Consider starting a third anti-anginal drug while awaiting referral.
• Do not combine a beta-blocker with a rate-limiting CCB (diltiazem or verapamil) as severe bradycardia and heart failure may occur.
• Do not combine a rate-limiting CCB with ivabradine, as severe bradycardia and heart failure may occur.

These recommendations are based on guidelines from the Scottish Intercollegiate Guidelines Network [SIGN, 2007] and the European Society of Cardiology [Fox et al, 2006a].

Combining two drugs

• Evidence on combining two drugs for symptomatic relief of angina is limited.
• An industry-sponsored meta-analysis found that a beta-blocker combined with a calcium-channel blocker (CCB) is more effective at improving exercise tolerance than monotherapy [Klein et al, 2002], but other randomized controlled trials (RCT) found that the combination of CCBs and beta-blockers only provided small, if any, benefit in relief of anginal symptoms.
• There is weak evidence that isosorbide mononitrate combined with a beta-blocker improves symptoms of angina.
• Evidence from one large RCT supports the effectiveness of nicorandil plus either a beta-blocker or a CCB in reducing cardiovascular endpoints.
• Evidence from one randomized controlled trial suggests that, in people already taking a beta-blocker, the addition of ivabradine appears to provide increased control of angina symptoms. This combination has recently been licensed for use in the UK.
• CKS found no further RCTs of ivabradine in combination with other treatments for the symptomatic control of angina; however, several expert reviewers recommend their combination with a dihydropyridine CCB or a nitrate.
• Because of the limited evidence and experience of using ivabradine in combination with other anti-anginal drugs, CKS recommends that primary care prescribers consider seeking specialist advice before adding a second anti-anginal drug (other than a beta-blocker) to ivabradine.

Combining three drugs

• Evidence from an RCT found that a nitrate plus amlodipine or atenolol was as effective as the combination of all three in terms of symptomatic outcome measures [Pehrsson et al, 2000].
• Despite the lack of evidence, European guidelines suggest triple therapy as an option if optimal two-drug regimens are not effective, although careful evaluation of the effects and assessment for revascularization is advised [Fox et al, 2006a]. Triple therapy is used in clinical practice, although it increases the risk of adverse effects [Thadani, 2006].
• CKS expert reviewers suggest starting a third drug while awaiting referral.