agent does not greatly relieve angina, use a combination of 2 to 4 agents (β-blocker + DHP +/- nitrate +/- ranolazine).
In HF patients with angina, β-blockers are started slowly. Nitrates may be added for angina or the combination of nitrates + hydralazine may be used for HF. DHP or ranolazine may be added if needed (amlodipine or felodipine may be slowly added, only if HF is compensated).
E. Ranolazine
Ranolazine blocks the late current of the inward sodium channel (INa, phase 0), a channel that is particularly active in ischemia or HF. This reduces intracellular sodium and, subsequently, intracellular calcium through the sodium–calcium sarcoplasmic exchange (opposite to digoxin effect). The main effect of ranolazine is the reduction of diastolic calcium overload, which reduces O2 consumption and improves
LV relaxation. Moreover, the improvement of LV relaxation reduces LVEDP and the coronary compression, which improves microvascular
function and coronary flow.
Ranolazine has been shown to reduce angina burden, increase exercise duration, and reduce ischemic burden on nuclear imaging, particularly in patients with the most severe or frequent angina, whether used in monotherapy or in combination with other antianginal drugs.51,52
In the MERLIN-TIMI 36 trial of NSTE-ACS patients, ranolazine added to standard therapy reduced the endpoint of recurrent ischemia or worsening angina. The benefit was most striking in women and in patients with elevated BNP.53-55 Ranolazine has not shown any effect on mortality.
Ranolazine only slightly prolongs QT from I K blockade (by 2–6 ms) and does not increase the risk of arrhythmia. The blockade of INa serves to shorten the action potential, similarly to the effect of lidocaine, and counteracts the IK blockade. In fact, in the MERLIN trial, ranolazine significantly reduced the risk of VT, SVT, and AF. In addition, ranolazine appeared to reduce the risk of sudden death in patients with VT lasting over 8 beats in the setting of NSTE-ACS.56 However, ranolazine should only be used cautiously in patients with prolonged QT or patients receiving QT-prolonging drugs.
Thus, ranolazine has the advantages of:
Reduction of ischemia without affecting the systemic pressure or heart rate. It is particularly valuable when systemic pressure or heart rate limits the use of other antianginal agents.
Improvement of LV diastolic function.
Reduction of arrhythmias.
Reduction of HbA1c of ~1% in patients with HbA1c ≥8% (MERLIN analysis).
Ranolazine may be used as initial therapy in patients who do not tolerate β-blockers (alternative to CCB and nitrates), or as additional therapy in patients with persistent angina despite standard therapy.
F. Control of risk factors
1 Statin, regardless of LDL. If needed, ezetimibe or PCSK-9 inhibitor may be added to achieve LDL <70 mg/dl.
2 HTN is controlled to <130/80 mmHg (ACC and SPRINT trial).57
3 ACE-I is beneficial in CAD patients (HOPE and EUROPA trials),58 more so in cases of EF <50%, HTN, diabetes, or CKD. In CAD patients with SBP 130–140 mmHg and normal EF, ACE-I did not show any benefit (PEACE trial).59 In the early post-CABG setting (≤7 days) with normal EF and BP, ACE-I initiation did not improve outcomes and was associated with more adverse events in the first 3 months (IMAGINE trial).60
4 Control of diabetes to a Hb A1c ≤7%.
5 Smoking cessation leads to a 50% reduction of the excessive risk of MI and stroke within 1 year (mostly within 2 months). At 3–5 years, the risk approaches that of never-smokers.
VI. Indications for revascularization
The first step is to determine if the patient requires coronary angiography (Figure 3.2). The second step is to determine if the patient requires revascularization. The third step is to determine whether CABG or PCI is appropriate. The need for coronary angiography does not imply a need for revascularization once CAD is found. In fact, medical therapy is frequently appropriate in a patient with significant, even multivessel CAD (with no left main disease). Coronary angiography serves as a risk stratification tool that helps determine whether medical therapy alone is appropriate. Based on ISCHEMIA trial, coronary CTA may replace coronary angiography and may be used to exclude left main disease and proceed with conservative management even in patients with multivessel disease.
In order to benefit from revascularization, one of the following 2 features excluded from ISCHEMIA trial must be present: (1) severe refractory angina, or (2) severe left main disease, regardless of angina.19,20 Extensive 3-vessel CAD or 2-vessel CAD with proximal LAD may also benefit from CABG, but less strongly. Refractory angina is defined as frequent angina (multiple times weekly) that persists despite the use of at least two antianginal medications (or less in case of intolerance or a baseline low BP and heart rate).
Old retrospective analyses suggested that revascularization in the setting of extensive ischemia involving ≥10% of the LV was associated with a reduction of mortality; this suggested a role for ischemia assessment in guiding revascularization.61 However, the large randomized trial ISCHEMIA disproved this hypothesis. Analyses from both ISCHEMIA and COURAGE suggest that the anatomic burden of disease is a far superior predictor of death and cardiac outcomes than ischemia, even though neither one predicts a benefit from revascularization. 62,63 Ruling out left main disease via CTA or angiography appears more important than functional ischemia evaluation.
In chronic stable CAD, revascularization of single or even multivessel CAD mainly has a symptomatic value, particularly in patients with refractory angina, with no effect on survival or MI prevention.
While a significant stenosis has a higher individual risk of plaque rupture and MI (~3% per year) than a non-significant plaque (<0.5%) (COURAGE, ISCHEMIA, FAME trials),19,64–66 non-significant plaques are much more common throughout the coronary vasculature than significant plaques; therefore, MI or ACS often occurs over a lesion that is <50% stenotic: these lesions were responsible for 2/3 of ACS events upon long-term follow-up in PROSPECT trial and coronary CT studies. 32,33,67 In FAME-2 trial, patients with insignificant FFR had a very low risk of MI from individual plaques, but the summation MI risk was still ~2% at 8 months and 8% at 5 years.28,66 While stenting reduces the risk of spontaneous events arising from a significant plaque, the benefit is negated by periprocedural myocardial infarction (~2.5%), stent thrombosis and severe restenosis, which explains why stenting stable CAD does not reduce the overall MI risk.66 Moreover, a larger number of events continues to arise from non-significant plaques.
VII. CABG and CABG vs. medical therapy
CABG is the only revascularization modality shown to improve survival in the high-risk subsets of stable CAD. In a meta-analysis that included the three classic trials of CABG vs. medical therapy, the Coronary Artery Surgery Study (CASS), the European Coronary Surgery Study (ECSS), and the VA study, CABG reduced mortality by 40–50% in the following groups:68
Left main disease (mortality reduction of ~75%).
Three-vessel CAD, or one- or two-vessel CAD involving the proximal LAD. CABG is beneficial in these patients irrespective of LV function, but more so in the case of mild LV dysfunction with EF 35–50% or evidence of moderate/severe ischemia on stress testing (i.e., make sure CAD is functionally significant).
CABG was beneficial in the classic trials despite a 25% crossover to CABG in the medical therapy arm at