Coronary Vasospasm

Transient focal or diffuse constriction of an epicardial coronary artery (typically more than 90% narrowing) that causes myocardial ischaemia, usually at rest (variant or vasospastic angina). It is distinct from microvascular spasm.

• It is more frequent in East Asian populations (up to about 40% of angina patients with non-obstructed arteries) than in Western populations (about 2%). Age 50 to 60 years; male predominance in Japan and a female predominance among Western patients with non-obstructed arteries.
• Risk factors: cigarette smoking (strongest), cocaine, amphetamines, cannabis, fluorouracil and capecitabine, triptans, ergot derivatives, alcohol withdrawal, hyperventilation, magnesium deficiency, hyperthyroidism, emotional stress, cold exposure, migraine and Raynaud phenomenon.
• Mechanism: smooth muscle hyperreactivity (Rho kinase activation), endothelial dysfunction and autonomic imbalance. Attacks cluster at night and in the early morning (midnight to 8 am).
• Consequences: unstable angina, infarction, ventricular tachycardia or fibrillation, atrioventricular block, syncope and sudden death. With treatment the long term outlook is good (5-year survival about 95%), though about 5 to 10% have a cardiac event within 5 years. Poor prognostic features: continued smoking, multivessel spasm, prior cardiac arrest, and coexisting fixed stenosis.

• Chest pain at rest lasting 5 to 15 minutes, often nocturnal or early morning, relieved by nitrates, with transient ST elevation. Palpitations, presyncope or syncope when arrhythmia develops. Normal examination between attacks.
• Differential diagnosis: stable angina, acute coronary syndrome from plaque rupture, Takotsubo syndrome, spontaneous coronary artery dissection, pericarditis, oesophageal reflux, panic attack, Brugada syndrome (ST elevation with nocturnal ventricular arrhythmia), early repolarisation, and aortic dissection.
• Complications: myocardial infarction, ventricular arrhythmia and sudden death, high grade heart block, and recurrent symptoms after drug withdrawal.

• ECG during pain: transient ST elevation (or depression) that resolves with nitrate; ambulatory 24 to 48 hour ST monitoring captures nocturnal episodes. Troponin if the episode is prolonged.
• Echocardiography: normal or transient wall motion abnormality.
• CT coronary angiography or invasive angiography to define fixed stenosis; angiography often shows non-obstructive disease, and spasm may be seen spontaneously.
• Provocation testing in a catheter laboratory when the diagnosis is uncertain and symptoms persist: intracoronary acetylcholine in incremental doses (20, 50 then 100 micrograms in the left coronary artery, each over about 20 seconds with 3 minute intervals; 20 and 50 micrograms in the right), or ergonovine. A positive test is focal or diffuse narrowing of 90% or more with chest pain and ischaemic ECG change, reversed by intracoronary glyceryl trinitrate 100 to 200 micrograms. Stop calcium channel blockers and nitrates 48 to 72 hours beforehand. Do not perform in the presence of significant left main disease, severe left ventricular dysfunction, advanced renal failure, severe uncontrolled hypertension or pregnancy; arrhythmia is the main risk.
• Other tests: potassium, magnesium, calcium, thyroid function, toxicology and a medication review for triggers.

• Remove triggers: stop smoking (the most effective single measure), avoid cocaine, amphetamines, triptans and ergot derivatives, and stop or substitute fluorouracil or capecitabine where possible.
• First line, calcium channel blockers (titrate to symptoms and heart rate):
  • Diltiazem modified release 90 to 360 mg daily, or amlodipine 5 to 10 mg daily, or nifedipine retard 20 to 60 mg daily, or verapamil modified release 120 to 480 mg daily. Combine a dihydropyridine with a non-dihydropyridine agent for refractory symptoms.
  • Check blood pressure, heart rate and PR interval; avoid verapamil and diltiazem together with beta blockers in conduction disease.
• Add long acting nitrates for residual symptoms:
  • Isosorbide mononitrate modified release 30 to 120 mg each morning (tolerance can develop; allow a nitrate free interval where attacks are only nocturnal and use the evening dose of a calcium channel blocker instead).
  • Glyceryl trinitrate 0.4 mg sublingual for attacks, repeated every 5 minutes up to 3 doses.
  • Nicorandil 10 to 20 mg twice daily as an add on (avoid with phosphodiesterase-5 inhibitors; ulceration risk).
• Further options for refractory disease:
  • Atorvastatin 20 to 40 mg daily (may improve endothelial function; evidence limited).
  • Prazosin 1 to 5 mg two to three times daily or clonidine 0.1 mg twice daily (evidence limited).
  • Magnesium sulfate IV for refractory attacks with hypomagnesaemia.
  • Rho kinase inhibition with fasudil is available in some countries (evidence limited).
  • Percutaneous stenting only for a fixed obstructive lesion; spasm can recur beside a stent.
• Drugs to avoid or use with caution: non-selective beta blockers (propranolol) because of unopposed alpha mediated constriction; high dose aspirin; sumatriptan and ergot derivatives. Low dose aspirin 75 to 100 mg daily is acceptable when atherosclerosis coexists.
• Acute attack or acute coronary syndrome from spasm:
  • Glyceryl trinitrate 0.4 mg sublingual, then IV 5 to 200 micrograms/min, and diltiazem 0.25 mg/kg IV over 2 minutes then 5 to 15 mg/h. Avoid IV beta blockers.
  • Cocaine associated spasm: lorazepam 2 mg IV, glyceryl trinitrate, and a calcium channel blocker; avoid beta blockers.
  • Fluorouracil induced spasm: stop the infusion, give glyceryl trinitrate and a calcium channel blocker.
• Arrhythmia: control spasm first; amiodarone 150 mg IV over 10 minutes for sustained ventricular arrhythmia; temporary pacing for high grade block; an implantable defibrillator after cardiac arrest despite optimal medical therapy.
• Continue treatment for at least 6 to 12 months after symptoms settle, then withdraw slowly under review, because abrupt stopping causes rebound spasm and about a third relapse.
• Special groups:
  • Pregnancy: nifedipine and nitrates are acceptable; avoid ACE inhibitors, ARBs and statins.
  • Cancer patients on fluoropyrimidines: prophylactic calcium channel blocker, and avoid rechallenge unless essential.
  • Elderly: monitor blood pressure and heart rate when titrating.
• Red flags: syncope, sustained ventricular arrhythmia, ST elevation not settling within 10 minutes of nitrate (infarction), cardiogenic shock.
• Follow up: review at 2 to 4 weeks, 3 months, then every 6 to 12 months; repeat ambulatory monitoring after dose changes; reinforce smoking cessation at every visit.