Treating Stable Angina -- A NICE Way Towards Consensus
Treating Stable Angina -- A NICE Way Towards Consensus
The antianginal properties of organic nitrates have been recognised for over a century, although nitrates do not confer any prognostic benefit.
As outlined by NICE continuous use of nitrates induces tolerance, with reduced therapeutic effect. Tolerance can be avoided by nitrate free intervals, but this may lower the threshold for anginal episodes. The mechanisms of tolerance are incompletely understood but continuous treatment with nitrates causes sympathetic activation, increases oxidative stress, and induces endothelial dysfunction. The NICE Guideline Development Group (GDG) found no evidence to confirm the safety or efficacy of long-term use of nitrates as an additional anti-anginal agent in patients already taking a beta blocker or calcium antagonist.
Evidence to support the use of long-acting nitrates (LAN) in combination with beta blockade in people with stable angina was deemed as being of 'poor quality' and available trials are limited by small sample size and short duration of follow-up.
No trials of nitrates in combination with calcium antagonists were identified, and no economic evidence was available. The GDG concluded that evidence to support the addition of long-acting nitrate to monotherapy with beta blocker or calcium antagonist in people with stable angina is very weak. In addition there is consensus that monotherapy with LAN is effective in the treatment of stable angina in the short-term, but that the efficacy of LAN may be limited, again, by the development of tolerance.
The specific bradycardiac agent, ivabradine by selectively inhibiting the pacemaker If current in a dose dependent manner reduces heart rate and myocardial oxygen demand during rest and exercise, and is an effective antianginal. It has no effect on cardiac contractility, conduction and blood pressure and it can be used in combination with beta blockade. The BEAUTIFUL trial provided evidence that ivabradine reduces hospital admissions for fatal- and non-fatal MI in patients with left-ventricular dysfunction and heart rates ≥70 beats/min. In the more recent, SHIFT trial ivabradine significantly reduced hospitalisations for worsening heart failure and heart failure deaths. Ivabradine can now be used in the treatment of chronic heart failure (New York Heart Association (NYHA) classes II–IV with systolic dysfunction, in patients in sinus rhythm whose heart rate is ≥75 bpm, in combination with standard therapy including beta blocker, or when beta blockers are contraindicated or poorly tolerated. Ivabradine is not currently available in the USA.
Nicorandil, has been in clinical use for nearly 20 years, but it is not widely available throughout Europe It is described as a hybrid drug, acting as a potassium channel opener with a nitrate moiety. Data from the IONA study showed a reduction in hospital admissions for cardiac chest pain in patients with stable angina. Nicorandil appears to mimic ischaemic preconditioning, a cardioprotective mechanism which may reduce myocardial damage during acute ischaemia and in PCI. Further effects have been reported, including nicorandil-mediated vascular growth (angiogenesis) which might be potentially beneficial in heart failure patients but it is presently not advised in this indication. Similarly it is not licensed to be used in combination with other antianginals, although in practice it is widely used as combination therapy.
Ranolazine is a piperazine derivative that specifically blocks the late component of the inward sodium current, which is increased during myocardial ischaemia.
It is an effective antianginal and anti-ischaemic agent and it appears to work ostensibly by reducing sodium-induced calcium overload through inhibition of the late sodium current. In this way by inhibiting reverse mode sodium-calcium exchange and thus diastolic calcium accumulation, it may improve diastolic function. A reduced diastolic wall tension causes an improvement of microvascular blood perfusion in the heart and this may account for the anti-ischaemic properties of ranolazine. Importantly, the cardioprotective effects of ranolazine occur at a concentration that has minimal effects on heart rate and systemic arterial blood pressure, making ranolazine unique among other antianginal agents currently in use.
Indeed, patients with coronary artery disease subjected to quantitative analysis of serial myocardial perfusion images showed significantly reduced perfusion defect sizes during exercise when treated with ranolazine.
Randomised trials of the sustained release formulation [see overview, Nash and Nash] have demonstrated safety and efficacy in stable angina. In the non-ST-elevation acute coronary syndromes, MERLIN-TIMI 36 trial ranolazine had no effect on cardiovascular death, MI or recurrent ischaemia (combined primary end point) but it did significantly reduce recurrent ischaemia and arrhythmias detected on Holter recording during the first 7 days of randomisation. In a sub-group of patients with prior chronic angina, (54% of overall trial patients) ranolazine significantly reduced recurrent ischaemia (−22%) and the incidence of worsening angina (−24%) and was associated with improvement on exercise treadmill testing. Further data from MERLIN-TIMI 36 show that ranolazine significantly improved HbA1c and ischaemia in patients with diabetes mellitus, and reduced its increase in those without evidence of previous hyperglycaemia. Ranolazine does not currently have a licence for treatment of unstable CAD.
NICE has approved the (above) novel compounds, with differing modes of action and tolerability profiles. Some of these not only show anti-ischaemic activity but they may possibly have adjunctive properties, including antiarrhythmic effects, to offer the patient additional cardioprotection. The choice of which drug to use will of course be largely dependent on the presence of comorbidities and relative contraindications. Whether or not this heralds a new era in optimal medical treatment of angina only time, trials and experience will tell.
NICE advises that patients who remain symptomatic despite optimal medical therapy (OMT) should be considered for revascularisation. Similarly, some patients whose symptoms appear to be controlled with medical therapy may still have prognostically significant coronary lesions. PCI does not appear to provide survival benefit. Coronary artery bypass graft surgery, (CABG) has been shown to improve prognosis in a subset of patients including those who have complex three-vessel disease, with or without left main stem involvement, who have diabetes or who are aged over 65 years. If the patient's coronary anatomy is considered suitable for either procedure, then it is recommended that PCI should be offered in preference.
What Second Line Drugs Offer
Nitrates
The antianginal properties of organic nitrates have been recognised for over a century, although nitrates do not confer any prognostic benefit.
As outlined by NICE continuous use of nitrates induces tolerance, with reduced therapeutic effect. Tolerance can be avoided by nitrate free intervals, but this may lower the threshold for anginal episodes. The mechanisms of tolerance are incompletely understood but continuous treatment with nitrates causes sympathetic activation, increases oxidative stress, and induces endothelial dysfunction. The NICE Guideline Development Group (GDG) found no evidence to confirm the safety or efficacy of long-term use of nitrates as an additional anti-anginal agent in patients already taking a beta blocker or calcium antagonist.
Evidence to support the use of long-acting nitrates (LAN) in combination with beta blockade in people with stable angina was deemed as being of 'poor quality' and available trials are limited by small sample size and short duration of follow-up.
No trials of nitrates in combination with calcium antagonists were identified, and no economic evidence was available. The GDG concluded that evidence to support the addition of long-acting nitrate to monotherapy with beta blocker or calcium antagonist in people with stable angina is very weak. In addition there is consensus that monotherapy with LAN is effective in the treatment of stable angina in the short-term, but that the efficacy of LAN may be limited, again, by the development of tolerance.
Ivabradine
The specific bradycardiac agent, ivabradine by selectively inhibiting the pacemaker If current in a dose dependent manner reduces heart rate and myocardial oxygen demand during rest and exercise, and is an effective antianginal. It has no effect on cardiac contractility, conduction and blood pressure and it can be used in combination with beta blockade. The BEAUTIFUL trial provided evidence that ivabradine reduces hospital admissions for fatal- and non-fatal MI in patients with left-ventricular dysfunction and heart rates ≥70 beats/min. In the more recent, SHIFT trial ivabradine significantly reduced hospitalisations for worsening heart failure and heart failure deaths. Ivabradine can now be used in the treatment of chronic heart failure (New York Heart Association (NYHA) classes II–IV with systolic dysfunction, in patients in sinus rhythm whose heart rate is ≥75 bpm, in combination with standard therapy including beta blocker, or when beta blockers are contraindicated or poorly tolerated. Ivabradine is not currently available in the USA.
Nicorandil
Nicorandil, has been in clinical use for nearly 20 years, but it is not widely available throughout Europe It is described as a hybrid drug, acting as a potassium channel opener with a nitrate moiety. Data from the IONA study showed a reduction in hospital admissions for cardiac chest pain in patients with stable angina. Nicorandil appears to mimic ischaemic preconditioning, a cardioprotective mechanism which may reduce myocardial damage during acute ischaemia and in PCI. Further effects have been reported, including nicorandil-mediated vascular growth (angiogenesis) which might be potentially beneficial in heart failure patients but it is presently not advised in this indication. Similarly it is not licensed to be used in combination with other antianginals, although in practice it is widely used as combination therapy.
Ranolazine
Ranolazine is a piperazine derivative that specifically blocks the late component of the inward sodium current, which is increased during myocardial ischaemia.
It is an effective antianginal and anti-ischaemic agent and it appears to work ostensibly by reducing sodium-induced calcium overload through inhibition of the late sodium current. In this way by inhibiting reverse mode sodium-calcium exchange and thus diastolic calcium accumulation, it may improve diastolic function. A reduced diastolic wall tension causes an improvement of microvascular blood perfusion in the heart and this may account for the anti-ischaemic properties of ranolazine. Importantly, the cardioprotective effects of ranolazine occur at a concentration that has minimal effects on heart rate and systemic arterial blood pressure, making ranolazine unique among other antianginal agents currently in use.
Indeed, patients with coronary artery disease subjected to quantitative analysis of serial myocardial perfusion images showed significantly reduced perfusion defect sizes during exercise when treated with ranolazine.
Randomised trials of the sustained release formulation [see overview, Nash and Nash] have demonstrated safety and efficacy in stable angina. In the non-ST-elevation acute coronary syndromes, MERLIN-TIMI 36 trial ranolazine had no effect on cardiovascular death, MI or recurrent ischaemia (combined primary end point) but it did significantly reduce recurrent ischaemia and arrhythmias detected on Holter recording during the first 7 days of randomisation. In a sub-group of patients with prior chronic angina, (54% of overall trial patients) ranolazine significantly reduced recurrent ischaemia (−22%) and the incidence of worsening angina (−24%) and was associated with improvement on exercise treadmill testing. Further data from MERLIN-TIMI 36 show that ranolazine significantly improved HbA1c and ischaemia in patients with diabetes mellitus, and reduced its increase in those without evidence of previous hyperglycaemia. Ranolazine does not currently have a licence for treatment of unstable CAD.
NICE has approved the (above) novel compounds, with differing modes of action and tolerability profiles. Some of these not only show anti-ischaemic activity but they may possibly have adjunctive properties, including antiarrhythmic effects, to offer the patient additional cardioprotection. The choice of which drug to use will of course be largely dependent on the presence of comorbidities and relative contraindications. Whether or not this heralds a new era in optimal medical treatment of angina only time, trials and experience will tell.
Revascularisation
NICE advises that patients who remain symptomatic despite optimal medical therapy (OMT) should be considered for revascularisation. Similarly, some patients whose symptoms appear to be controlled with medical therapy may still have prognostically significant coronary lesions. PCI does not appear to provide survival benefit. Coronary artery bypass graft surgery, (CABG) has been shown to improve prognosis in a subset of patients including those who have complex three-vessel disease, with or without left main stem involvement, who have diabetes or who are aged over 65 years. If the patient's coronary anatomy is considered suitable for either procedure, then it is recommended that PCI should be offered in preference.
