to the total daily dose of metoprolol tartrate.Atenolol 12.5–25 mg BID (Qday in renal failure), titrated to 50 mg BID. Carvedilol: 3.125–25 mg BID; labetalol 100–400 mg BID.
Notes
Severe PAD was considered a relative contraindication to non-selective β-blockers, because of an initial β2-blocker vasoconstrictive effect. However, this is no longer a contraindication to β-blockers, as they proved safe in PAD.45 Also, PAD patients often die of CAD, and thus, β-blockers are valuable in the PAD setting. Individual responses may vary, so be aware of a potential worsening of severe rest symptoms.
In diabetic patients, metoprolol appears to slightly worsen diabetes control (HbA1c). This is not the case with carvedilol and nebivolol, which should be the preferred β-blockers in diabetic patients (GEMINI trial).46
B. Nitrates
1 Nitrates are venodilators and thus reduce ischemia primarily by reducing preload. They also improve coronary flow by reducing intramyo- cardial diastolic tension, i.e., LVEDP. They are also, to a lesser extent, arterial vasodilators and thus reduce afterload.The dilatation of epicardial coronary arteries is a less important anti-ischemic mechanism than preload reduction, but dilatation of collaterals may be particularly useful. Vasodilators, in general, may worsen myocardial ischemia in critical CAD as they increase flow through the normal coronary arteries at the expense of the abnormal artery that cannot further increase its flow, creating a coronary steal phenomenon through collaterals (e.g., adenosine). This, however, does not usually happen with nitrates as they do not drastically affect the microvascular tone, and thus do not drastically increase coronary flow to the normal myocardium.
2 While sublingual nitroglycerin (NTG) is used as needed (during angina or before exertion) and has a short effect <5 min, long-acting formulations are used as adjunct to background β-blocker or calcium channel blocker therapy:Isosorbide dinitrate (ISDN) 10–40 mg TID, isosorbide mononitrate (ISMN) 30–240 mg Qday, NTG paste 0.5–2 inches TID, NTG patch 0.2–0.6 mg/h Q24h.
3 Tolerance to nitrates develops quickly, within 24 hours of therapy. It is minimized by providing nitrate-free intervals (e.g., administer ISDN at 8 a.m., 2 p.m., and 8 p.m., with 10–14 hours free interval; administer ISMN once daily; or place NTG patch for 12 out of 24 hours every day). However, rebound ischemia may occur during the nitrate-free intervals.
4 Nitrates are metabolized into NO by large arteries. NO promotes the release of cGMP, a smooth muscle relaxant. In contrast to large arteries, arterioles cannot metabolize nitrates into NO.
Nitrate tolerance occurs as the beneficial NO eventually gets metabolized into reactive oxygen species, which reduce NO generation and NO effect and increase the vascular sensitivity to vasoconstrictors; nitrates may, in fact, impair endothelial function.47 Neurohormonal activa- tion may also contribute to nitrate tolerance. The same phenomenon leads to vasoconstriction and rebound ischemia in the first 4 hours after nitrate withdrawal in a tolerant patient. Several studies have shown that statin, ACE-I (and possibly ARB), hydralazine, and carvedilol reduce nitrate tolerance as they reduce the production of reactive oxygen species and counteract the neurohormonal activation.47–50 Thus, with the contemporary drug regimens, nitrate tolerance and rebound are minimized.
C. Calcium channel blockers (CCBs)
1 Non-dihydropyridines (non-DHPs) decrease cardiac inotropism and chronotropism and have a vasodilatory effect (afterload reduction). Also, they dilate the coronary arteries.Examples: diltiazem and verapamil. Verapamil has more negative inotropic effect and slightly more AV and SA nodal depressant effect than diltiazem.Non-DHPs are contraindicated in bradycardia or systolic HF. Avoid non-DHPs, particularly verapamil, in combination with a β-blocker. Diltiazem may be combined with a β-blocker in rate-uncontrolled AF.Doses: diltiazem 30–90 mg TID–QID, diltiazem ER 120–480 mg Qday; verapamil 80–120 mg TID–QID, verapamil ER 180–480 mg/d.
2 Dihydropyridines (DHPs) are more pure and powerful vasodilators than non-DHPs, with minimal ino- and chronotropic effects.Only the long-acting formulations are used. Short-acting DHPs may cause reflex tachycardia, which leads to ischemia.DHPs are not contraindicated in bradycardia or HF, except for nifedipine which has some negative inotropic effect and is preferably avoided in HF; other DHPs have minimal to no negative inotropic effects.In contrast to non-DHPs, DHPs are preferably combined with a β-blocker to counteract any potential reflex tachycardia.DHPs are the first-choice antianginal therapy in patients with bradycardia and the second choice in patients already on β-blockers.Examples are amlodipine 2.5-10 mg Qday, felodipine 2.5-10 mg Qday, and nifedipine XL 30-90 mg Qday.
D. Choice of antianginal drugs
β-Blockers are first-line agents. If β-blockers are contraindicated because of bronchospasm, use a non-DHP; if β-blockers are contraindicated because of bradycardia, use a DHP. A long-acting nitrate or ranolazine is used as a second- or third-line agent. The combination DHP + nitrates may be used but is less favored, as both agents are vasodilators.
If one 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
