Download Guidelines for prescribing of Ivabradine for symptomatic treatment of

Worcestershire Area Prescribing Committee
April 2011
Guidelines for prescribing of
Ivabradine for symptomatic treatment of chronic stable angina.
Recommendation:
Ivabradine is appropriate for prescription to patients with chronic stable angina in patients in
sinus rhythm for whom rate control is desirable, if:
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Treatment with a beta-blocker is contra-indicated or not tolerated, and
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Rate-limiting calcium channel blockade, usually a once daily diltiazem preparation, is
contra-indicated or not tolerated.
(Refer to the “Medical treatment of chronic stable angina pathway” for further details).
Background:
• Ivabradine is a selective sinus node inhibitor which decreases heart rate and myocardial oxygen consumption
at rest and during exercise. It is licensed for the treatment of chronic stable angina in patients with normal
sinus rhythm, who have a contraindication to or intolerance of beta-blockers.
• The dose regimen is 5mg twice daily initially, increasing to 7.5mg twice daily after 3 to 4 weeks if necessary. A
dose of 2.5mg twice daily should be used initially in the elderly. If the resting heart rate falls below 50/minute
consider dose reduction and/or use of different anti-anginal therapy.
• There are a number of contra-indications to the use of ivabradine, including:
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Pre-existing bradycardia; ivabradine should not be initiated if resting heart rate is less than 60 beats per minute
Cardiogenic shock
Acute phase of myocardial infarction or stroke
Sinoatrial disease (“sick sinus syndrome”)
Moderate to severe heart failure (NYHA Class III or IV)
Class II or complete AV block
Severe renal or hepatic impairment
Pregnancy or breast feeding
Atrial fibrillation (ineffective)
Ivabradine should only be initiated on expert cardiology advice in the presence of other arrhythmia, prolonged
QT interval and unstable angina or when a pacemaker has been implanted.
Ivabradine should be avoided in the presence of hypotension (< 90/50mmHg).
Ivabradine has a neutral effect on blood pressure.
In general Ivabradine should not be prescribed with other drugs that suppress heart rate, including
amiodarone, beta-blockers, diltiazem and sotalol. However it has been used safely in combination with beta
blockade, so may be considered for use in this way if additional heart rate control is needed.
Ivabradine is metabolised by the liver. Avoid co-prescription with macrolides (e.g. erythromycin), azole
antifungal agents, antimalarial agents, antiviral agents, grapefruit and cranberry juice.
Adverse effects are relatively few but ivabradine may cause visual disturbances including phosphenes and
some blurring of vision, reversible on stopping the drug.
Evidence:
There have been a number of clinical efficacy studies including:
• 1360 patients were randomised to receive ivabradine 2.5mg, 5mg or 10mg twice daily or placebo for 2 weeks.
173 patients were then given ivabradine 10mg twice daily (unlicensed dose) in a 2 to 3 month open label
extension phase. The time to limiting angina was increased across all doses of ivabradine, compared to
placebo, in a similar way, however statistical significance was only shown for the 10mg group. The number of
angina attacks was reduced in both the dose ranging phase and the open label extension phase, although
only statistically significant in the extension phase.
• 2The INITIATIVE study randomised 939 patients to either ivabradine 7.5mg or 10mg twice daily, or atenolol
100mg daily. Total exercise duration (TED) increased by +86.8s and +91.7s for ivabradine 7.5mg and 10mg
compared with +78.8s for the atenolol group. The time to angina onset and time to limiting angina were
reduced in all groups. Ivabradine was shown to be non-inferior to atenolol. There was no difference in the
efficacy results between 7.5mg and 10mg ivabradine doses, however there was a higher incidence of visual
adverse effects in the 10mg group.
• 3In a third study patients were randomised to receive ivabradine 7.5mg daily, 10mg twice daily or amlodipine
10mg daily for 3 months. For the primary efficacy endpoint, TED, the change from baseline was 28 and 31
seconds for ivabradine 7.5mg and amlodipine groups respectively. Non-inferiority of ivabradine compared with
amlodipine was established.
References:
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Borer JS, Fox K, Jaillon P et al. Anti-anginal and anti-ischaemic effects of ivabradine an If inhibitor, in stable angina. Circulation 2003; 107: 817-823.
Tardif JC, Ford I, Tendera M et al. Efficacy of ivabradine, a new selective If inhibitor, compared with atenolol in patients with chronic stable angina. European
Heart Journal 2005; 26: 2529-2536.
Ruzyllo W, Ford I, Tendera MT et al. Antianginal and anti-ischaemic effects of the If current inhibitor ivabradine compared to amlodipine as monotherapies in
patients with chronic stable angina. Randomised controlled double blind trial. European Heart Journal 2004; 25 (suppl): 138 (abstract 878).
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