Practical Cardiovascular Medicine. Elias B. Hanna

oxygen demands are related to the following four factors: inotropism, chronotropism, afterload, and preload. Each antianginal agent targets some of these factors. Nitrates and vasodilatory calcium channel blockers reduce ischemia by reducing preload and afterload, and, except in vasospastic angina, the coronary vasodilatory effect is a less important effect.

      A. β-Blockers

      1 In patients with established CAD and angina, β-blockers are first-line therapy as they reduce mortality in the first year after MI (class I). However, in stable CAD without prior MI or HF, or with MI>1 year, there is no evidence of mortality reduction and the main benefit is angina relief.40,41 Without angina, prior MI, or HF, the recommendation for β-blocker therapy is weak (class IIb).

      2 A tight rate control <70 bpm has proven beneficial in HFrEF, but not in stable CAD, angina, HTN, AF, or HFpEF.42,43 In fact, in the SIMPLIFY trial, stable CAD patients with baseline pulse >70 bpm (most of whom had MI >3 months prior), did not derive a benefit from slowing the sinus rate with ivabradine, even when angina CCS was ≥II. Thus, tight heart rate control <70 bpm may not need to be pursued in stable CAD with normal EF, except possibly in severe angina.

      3 Myocardial β1-receptors have a positive inotropic and chronotropic effect, thus increasing myocardial O2 demands. β2-Receptors mainly have vasodilatory and bronchodilatory effects, with a limited inotropic and chronotropic effect at baseline. However, the latter effect is exaggerated when β1-receptors are blocked. Thus, β2-blockade may be useful in patients requiring a comprehensive blockade of all myocardial adrenergic receptors, such as HF (carvedilol), but may induce harmful vasoconstrictive and bronchospastic effects.

      4 Four types of β-blockers:Non-selective β1- and β2-blockers (e.g., propranolol).Selective β1-blockers (e.g., metoprolol, atenolol, bisoprolol). Selectivity is lost at high doses. β-Blockers with intrinsic sympathomimetic activity – β-blockade does not occur at rest, and rather occurs during catecholamine surges; these agents do not decrease mortality and are preferably avoided.β-Blockers with combined α- and non-selective β-blocker activity (carvedilol, labetalol) have a vasodilatory effect and, thus, a more pronounced antihypertensive effect. However, the α-blocking effect gets attenuated with time, particularly with labetalol.⁴⁴

      5 ContraindicationsBradycardia <55 bpm or symptomatic bradycardia- PR interval >0.24 s, or any second- or third-degree AV block.Decompensated HF (start β-blockers once HF is compensated).History of clinically severe asthma, even if the patient is currently stable, or actively decompensated COPD with wheezes. A low or moderate dose of a selective β-blocker, such as metoprolol 100 mg/day, may be used in stable, mild/moderate asthma.Use caution in diabetic patients with hypoglycemic episodes.

      6 Doses:Metoprolol tartrate 25 mg BID titrated every 3–7 days to a target dose of 50–100 mg BID if tolerated (maximum 200 mg BID). Metoprolol succinate (Toprol XL): the once-daily dose of Toprol XL is almost equivalent 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.

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