It has become apparent that coronary microvascular dysfunction (CMD), alone or in combination with coronary artery disease (CAD), is an adjunctive mechanism of myocardial ischemia and angina. However, this condition is rarely correctly diagnosed and, therefore, no tailored therapy is prescribed for these patients who are often dismissed as ¿false positive¿. These patients will continue to experience recurrent angina with poor quality of life, leading to repeated hospitalizations and unnecessary coronary angiography.
The objectives of this study are: 1) to investigate the prevalence of non-obstructive CAD in women vs men in an Italian population referred for ¿clinically indicated¿ coronary angiography; 2) to implement an ¿evidence based¿ therapy in these patients considering the underlying pathophysiological mechanism and evaluate the impact of a tailored therapy on angina.
Patients with angina but without obstructive CAD at angiography will be enrolled in 10 Italian centers. After completion of diagnostic coronary angiography, presence of coronary spasm (both epicardial and microvascular) will be investigated following intracoronary administration of acetylcholine. In case the latter test is negative,the index of microvascular resistance (IMR) and CFR will be assessed using a dedicated wire. According to the cath lab findings patients will be stratified into 2 groups :those with vs. without identified pathophysiological mechanism for their symptoms. A tailored medical therapy will be prescribed for the first group of patients according to the pathophysiologic mechanism involved. The patients will be then evaluated at one year clinical follow up in order to evaluate angina class, quality of life and occurrence of any coronary revascularization and cardiac hospitalization.
While in selected patients (e.g. stenosis of the left main coronary artery) revascularization offers additional opportunities for improving symptomsand in some clinical and lesion subset to improve also prognosis, the first and most established pillar in the management of stable CAD is pharmacological therapy.
Rapidly acting formulations of nitroglycerin are able to provide immediate relief of angina once the episode has started or when the symptom is likely to occur (immediate treatment or prevention of angina). Anti-ischemic drugs, lifestyle changes, regular exercise training, patient education and revascularization instead all minimize or eradicate symptoms over the long term (long-term prevention).
Pharmacological and lifestyle interventions prevent the occurrence of cardiovascular events primarily by reducing the incidence of acute thrombotic events and the development of ventricular dysfunction via reduction of plaque progression, plaque stabilization (by reducing inflammation) and thrombosis prevention, should plaque rupture or erosion occur.
The most adopted strategy is shown in Figure 4, and might be adjusted according to patient comorbidities, contra-indications, personal preference and drug costs. Table 1 indicates the main side-effects, contra-indications and major drug¿drug interactions for each drug class. The medical management consists of a combination of at least a drug for angina relief plus drugs to improve prognosis, as well as use of sublingual nitroglycerin for chest pain management. Double or triple therapy is often needed to control angina.
Table 1. Major side-effects, contra-indications, drug¿drug interactions (DDI) and precautions of anti-ischemic drugs.
ß-blockers
¿ Fatigue, depression
¿ Bradycardia
¿ Heart block
¿ Bronchospasm
¿ Peripheral vasoconstriction
¿ Postural hypotension
¿ Impotence
¿ Hypoglycemia/mask
¿ Low heart rate or heart conduction disorder
¿ Cardiogenic shock
¿ Asthma
¿ COPD caution
¿ Severe peripheral vascular disease
¿ Decompensated heart failure
¿ Vasospastic angina
¿ Heart-rate lowering
CCB
¿ Sinus-node or AV conduction depressors
¿ Diabetics
¿ COPD
CCBs:heart-rate lowering
¿ Bradycardia
¿ Heart conduction defect
¿ Low ejection fraction
¿ Constipation
¿ Gingival hyperplasia
¿ Low heart rate or heart rhythm disorder
¿ Sick sinus syndrome
¿ Congestive heart failure
¿ Low BP ¿Cardiodepressant (ß-blocker, flecainide)
¿ CYP3A4 substrates, e.g. ivabradine -
CCBs:Dihydropyridines
¿ Headache
¿ Ankle swelling
¿ Fatigue
¿ Flushing
¿ Reflex tachycardia ¿ Cardiogenic shock
¿ Severe aortic stenosis
¿ Obstructive cardiomyopathy
¿ CYP3A4 substrates, e.g. ivabradine -
Ivabradine
¿ Visual disturbances
¿ Headache, dizziness
¿ Bradycardia
¿ Atrial fibrillation
¿ Heart block
¿ Low heart rate or heart rhythm disorder
¿ Allergy
¿ Severe hepatic disease
¿ QTc prolonging drugs
¿ Macrolides
¿ Anti-HIV
¿ Anti-fungal
¿ Age >75 years
¿ Severe renal failure
Nicorandil
¿ Headache
¿ Flushing
¿ Dizziness, weakness
¿ Nausea
¿ Hypotension
¿ Gastrointestinal ulceration
¿ Cardiogenic shock
¿ Heart failure
¿ Low blood pressure
¿ PDE5 inhibitors -
Trimetazidine
¿ Gastric discomfort
¿ Nausea
¿ Headache
¿ Movement disorders
¿ Allergy
¿ Parkinson disease
¿ Tremors and movement disorders
¿ Renal impairment
¿ None reported
¿ Moderate renal impairment
¿ Elderly
Ranolazine
¿ Dizziness
¿ Constipation
¿ Nausea
¿ QT prolongation
¿ Liver cirrhosis
¿ CYP450 substrates
¿ QTc prolonging drugs -
Drugs for symptomatic angina are classified as being first choice (ß-blockers, calcium-channel blockers, short-acting nitrates) or second choice (ivabradine, nicorandil, ranolazine, trimetazidine), with the recommendation to reserve second-choice medications for patients who have contraindications to first-choice agents, do not tolerate them, or remain symptomatic.
On the other hand, a recent consensus statement (15)proposed an individualized approach to angina treatment, which takes into consideration the patient, comorbidities, and underlying mechanism of disease. This so-called `diamond¿ approach emphasizes the importance of a tailored patient-specific treatment when dealing with patients affected by CAD.