What it is:Ischemic heart disease is a supply-demand mismatch at the myocardium. Coronary plaque narrows the pipe (fixed supply problem), and everyday exertion asks the heart to work harder (demand goes up). When demand outstrips what the narrowed vessel can deliver, you get angina. This chapter is about the chronic, stableversion, not the emergency (ACS/STEMI/NSTEMI is a different chapter).
The core problem:Every anginal episode is myocardial oxygen demand (MVO2) briefly exceeding a fixed, plaque-limited oxygen supply. Nothing about that changes acutely, it's a mechanical ceiling.
What you do about it:Two levers only, lower demand or raise supply, plus stop the plaque from getting worse. Beta blockers and non-DHP CCBs lower demand. Nitrates and DHP CCBs raise supply. Antiplatelets, statins, and BP/glucose control slow the disease underneath it all.
Frame the whole chapter as "two levers on one equation."MVO2 (demand) is driven by heart rate, contractility, and wall tension. Supply is driven by coronary diameter and diastolic filling time. Almost every antianginal drug class maps cleanly onto one side of that equation, and once you see the equation the drug choices stop being a memorization exercise.
"Chest pain" is not one diagnosis. Sorting it correctly changes the whole treatment plan, and mixing these up is a common trap.
| Type | Mechanism | Who gets it |
|---|---|---|
| Typical (obstructive CAD) angina | Fixed epicardial stenosis, usually >70%, limiting flow during exertion | Classic risk-factor patient, exertional, predictable |
| Microvascular angina (INOCA) | Small resistance vessels can't dilate enough, despite open epicardial arteries | Often women; angina-equivalent dyspnea common |
| Vasospastic (Prinzmetal) angina | Coronary artery spasm, often with little or no fixed plaque | Younger, smokers, cocaine users, Raynaud's/migraine history |
Constricting discomfort in the chest, neck, jaw, shoulder, or arm, plusprecipitated by exertion, plusrelieved by rest or SL nitroglycerin within about 5 minutes. Missing any one of the three makes it atypical, not typical. Chest pain lasting only seconds or lasting hours is usually not angina at all.
This chapter covers stableIHD: predictable, exertional, reproducible symptoms. Unstable angina and STEMI/NSTEMI are acute coronary syndromes and live in a different treatment pathway entirely, don't confuse the algorithms.
Angina happens when MVO2 rises faster than a plaque-limited coronary can supply. Understand the vessel anatomy and the drug classes stop being arbitrary.
| Epicardial stenosis | What's happening |
|---|---|
| <50–70% | Resistance vessels compensate easily. Usually no ischemia, no angina, even with exertion. |
| ≥70% | Resistance vessels are near maximally dilated at rest just to maintain baseline flow. Minimal exertion now tips the balance into ischemia. This is where exertional angina starts. |
| ≥90% ("critical stenosis") | Coronary flow reserve is exhausted. Even resting flow may be marginal. |
The plaques that cause stable, predictable anginaare the big, heavily stenotic ones (≥70%). The plaques that cause heart attacksare often small, lipid-rich, thin-capped ones that were never tight enough to cause symptoms, they just rupture. Severity of stenosis predicts angina; plaque composition predicts rupture. A "mild" lesion on angiography is not a "safe" lesion.
Once stenosis passes roughly 70%, repeated ischemic episodes trigger release of VEGF and basic fibroblast growth factor, which combine with endogenous vasodilators like nitric oxide and prostacyclin to enlarge existing collateral channels (arteriogenesis) and grow new ones (angiogenesis). This is a genuine adaptive response, it's why some patients with severe angiographic disease have surprisingly preserved function.
Many patients have a fixed stenosis andsuperimposed vasospasm at the site of endothelial damage caused by that plaque. This produces variable threshold angina, the same level of exertion doesn't always trigger symptoms because the dynamic vasospasm component varies. Circadian release of vasoconstrictors makes ischemic episodes more common in the morning; cold exposure and emotional stress are classic triggers. Patients with true Prinzmetal angina usually lack an obstructive plaque at all, their ischemia is almost purely vasospasm-driven.
Macrophages and T-lymphocytes in the plaque produce cytokines and growth factors that activate endothelium, worsen vasoreactivity, and drive smooth muscle proliferation. hs-CRP tracks this and correlates with future cardiovascular events. This is the biologic rationale behind anti-inflammatory strategies like colchicine (see Inflammationbelow), on top of the standard lipid/BP/glucose targets.
Chest pain that's squeezing, crushing, heavy, or tight, brought on by exertion or daily activity, radiating to the arm, shoulder, back, abdomen, or jaw. It typically lasts 5 to 20 minutesand resolves with rest or SL NTG. Diaphoresis, nausea, and dyspnea can accompany it.
Women, older adults, and patients with diabetesare the classic groups that present atypically: midepigastric discomfort, effort intolerance, dyspnea, and unusual fatigue instead of classic chest pressure. Diabetic neuropathy can blunt pain sensation entirely ("silent ischemia"). Don't anchor on textbook chest pain when screening these groups.
Prinzmetal anginalooks different: younger patients, chest pain at rest, often early in the morning, sometimes with transient ST-elevation on ECG during the episode that resolves once the spasm passes.
History drives this: quality, precipitants, location, duration, radiation, and response to rest or nitroglycerin. Because anginal pain can mimic GI, musculoskeletal, and other noncardiac pain, history alone is often not enough.
| Nonmodifiable | Modifiable |
|---|---|
| Age, sex, family history of premature ASCVD (first-degree relative: male <55, female <65) | Hypertension, diabetes, dyslipidemia, smoking |
Cardiac troponin is not typically elevated in stable IHD.If troponin is up, you're not looking at stable angina anymore, you're looking at an acute coronary syndrome and a different workup and treatment pathway entirely.
Short-term goal:eliminate or nearly eliminate anginal chest pain and get the patient back to normal activity.
Long-term goal:slow atherosclerosis progression and prevent MI, heart failure, stroke, and death. Antianginals treat the symptom; risk-factor therapy treats the disease.
Daily physical activity (≥150 min/week moderate or ≥75 min/week vigorous aerobic, plus resistance training twice weekly), healthy body weight, smoking cessation, limiting alcohol and avoiding other illicit substance use, and minimizing air pollution and extreme heat exposure. None of the studied supplements (vitamin C, D, E, beta-carotene, calcium, most fish oil) change outcomes here, don't recommend them for this indication.
PCI (with or without stent) or CABG restores flow mechanically. Outside of an active STEMI, revascularization and optimal medical therapy produce equivalent outcomesfor stable disease, revascularization is not automatically "better," it's a tool for refractory symptoms or high-risk anatomy. Either way, the patient still needs the drugs that improve endothelial function and stabilize plaque.
Everyone starts on the foundation below (see Foundational Therapy). If angina symptoms remain uncontrolled, escalate stepwise:
If the patient has vasospastic angina, skip the beta-blocker-first logic. CCBs are first-line for vasospasm regardless of where you are in the algorithm, and beta blockers can actually make vasospasm worse (see Vasospastic Angina).
This layer doesn't relieve chest pain today, it's what keeps the patient alive and out of the cath lab long-term. Don't skip it just because symptoms are controlled.
NSAIDs compete with aspirin for the same COX-1 binding site. Taken together (especially ibuprofen before aspirin), the NSAID can physically block aspirin from reaching the enzyme, blunting its irreversible antiplatelet effect. If both are needed, aspirin should be dosed first.
In IHD these stabilize plaque, improve endothelial function, and inhibit vascular smooth muscle proliferation, but they do notrelieve anginal symptoms directly, that's not their job here.
All patients need access to SL nitroglycerin 0.3–0.4 mgtablets or spray for acute anginal episodes, and can also use it prophylactically 2–5 minutes before an activity known to trigger symptoms (protection lasts up to 30 minutes with NTG, up to an hour with SL ISDN).
| Class / Drug | Usual Dosage Range | Notes |
|---|---|---|
| Antiplatelet | ||
| Aspirin | 75–162 mg daily (81 mg typical) | Indefinite, first-line |
| Clopidogrel | 75 mg daily | Aspirin allergy/intolerance |
| ACE Inhibitors | ||
| Lisinopril | 2.5–40 mg once daily | Use if HTN, DM, LVEF ≤40%, or CKD |
| Enalapril | 2.5–40 mg daily (1–2 doses) | |
| Ramipril | 2.5–10 mg daily (1–2 doses) | |
| Captopril | 6.25–50 mg three times daily | |
| Fosinopril | 10–80 mg daily (1–2 doses) | |
| Perindopril / Quinapril / Trandolapril | 4–8 mg daily / 5–20 mg BID / 1–4 mg daily | |
| ARBs | ||
| Candesartan | 4–32 mg once daily | If ACEi intolerant |
| Valsartan / Telmisartan | 80–320 mg daily (1–2 doses) / 20–80 mg once daily | |
| Beta Blockers | ||
| Metoprolol | 50–200 mg BID (or once daily if extended release) | β1-selective |
| Bisoprolol | 2.5–10 mg once daily | β1-selective |
| Atenolol | 25–200 mg once daily | β1-selective, renally cleared |
| Carvedilol | 3.125–25 mg BID (or 10–80 mg once daily, phosphate form) | Nonselective + α1 |
| Nadolol / Propranolol / Timolol | 40–120 mg daily / 20–120 mg BID / 10–20 mg BID | Nonselective |
| Nebivolol | 5–10 mg once daily | β1-selective, ↑ NO |
| Calcium Channel Blockers - Non-DHP | ||
| Diltiazem ER | 120–360 mg once daily | Rate + contractility + vasodilation |
| Verapamil ER | 180–480 mg once daily | Strongest node/contractility effect; constipation ~8% |
| Calcium Channel Blockers - DHP | ||
| Amlodipine | 5–10 mg once daily | Safe in HFrEF |
| Felodipine ER | 5–10 mg once daily | Safe in HFrEF |
| Nifedipine ER | 30–90 mg once daily | ER only, never short-acting |
| Nicardipine | 20–40 mg three times daily | Short-acting |
| Nitrates | ||
| SL nitroglycerin | 0.3–0.6 mg PRN, repeat q5min ×3 | Acute attack; onset 1–3 min |
| Nitroglycerin transdermal | 0.2–0.8 mg/h, on 12–14h / off 10–12h | Daily nitrate-free interval required |
| Nitroglycerin ER capsule | 2.5–27 mg three times daily | 10–12h nitrate-free interval |
| Isosorbide dinitrate | 5–80 mg IR (TID, e.g. 7am/noon/5pm) or 40–160 mg ER | ≥14h (IR) or ≥18h (ER) nitrate-free interval |
| Isosorbide mononitrate | 5–20 mg BID (doses 7h apart) or 30–120 mg ER once daily | ER gives built-in nitrate-free window |
| Other | ||
| Ranolazine | 500 mg BID, up to 1000 mg BID | 500 mg daily start if CrCl <30; cap 500 mg BID with moderate CYP3A4 inhibitors |
| Colchicine | 0.5 mg daily | Adjunct for residual inflammatory risk, not a substitute for GDMT |
↓ HR, ↓ contractility, ↓ wall tension
Coronary + collateral vasodilation
Late INa blockade, doesn't touch HR/BP
Beta blockers competitively block catecholamine effects at β-receptors. Blocking cardiac and renal β1 receptors lowers HR, contractility, and BP, which directly lowers MVO2. They're recommended ahead of CCBsas initial therapy for stable angina. Target resting HR 50–60 bpm and exercise HR <100 bpm; in patients who can't tolerate that range (often older adults), go as low as tolerated above 50 bpm.
Only carvedilol, metoprolol succinate, and bisoprololhave mortality data in HFrEF. If your angina patient also has HFrEF, pick from that list only, don't reach for atenolol or metoprolol tartrate.
Selecting an agent by comorbidity:β1-selective agents (metoprolol, bisoprolol, atenolol, nebivolol) are preferred with COPD, PAD, diabetes, dyslipidemia, or sexual dysfunction, since sparing β2 avoids bronchoconstriction and peripheral vasoconstriction. Combined α1/β-blockers (carvedilol, labetalol) work well for IHD too. Agents with intrinsic sympathomimetic activity barely lower resting HR and aren't preferred.
Beta blockers can worsen glucose control, roughly a 0.75% A1C risevia decreased insulin secretion and increased gluconeogenesis, both mediated through α1/β2 receptors. Carvedilol is the exception: by blocking α1 it may actually protect against new-onset diabetes, while pure β1-selective agents carry more of this risk. Beta blockers also mask hypoglycemia symptoms except sweating, worth saying out loud to a diabetic patient.
COPD isn't an automatic contraindication.COPD and CV disease share risk factors and commonly coexist. Cardioselective agents are reasonably safe even with some airway reactivity, and withholding a beta blocker that's genuinely indicated can cause more harm (MI, HF) than the bronchospasm risk it avoids. Reserve real caution for uncontrolled asthma.
Post-MI without ongoing angina:benefit is uncertain in the first year and likely unnecessary beyond it if the patient is otherwise asymptomatic, this is a shift from the old "beta blocker forever post-MI" teaching.
Contraindications:preexisting bradycardia or hypotension, 2nd/3rd degree AV block without a pacemaker, uncontrolled bronchospastic disease, severe PAD, unstable HFrEF, and diabetes with frequent hypoglycemia. Never stop abruptly, taper over 2–3 weeks; abrupt withdrawal up-regulates myocardial beta receptors and can precipitate rebound ischemia or MI. The most common reason patients quit on their own is perceived intolerance: fatigue, orthostasis, depression, sexual dysfunction, bradycardia, insomnia, so ask about these directly at follow-up.
All CCBs block L-type calcium channels, reducing intracellular calcium available for the actin-myosin contractile apparatus. Where they act determines the clinical effect.
| Vascular vasodilation | Cardiac contractility | SA/AV node | |
|---|---|---|---|
| Verapamil | ++++ | ↓↓↓↓ | ↓↓↓↓↓ |
| Diltiazem | +++ | ↓↓ | ↓↓↓↓ |
| Nifedipine (DHP) | +++++ | ↓ (minimal) | none |
Dihydropyridines(amlodipine, felodipine, nifedipine ER) act almost purely on vascular smooth muscle: vasodilation, minimal effect on contractility, and often reflex tachycardia from arterial dilation since they don't blunt the SNS response. That reflex tachycardia is exactly why only extended-release nifedipineshould ever be used for angina, short-acting DHPs drop BP fast enough to trigger dangerous reflex tachycardia and worsen ischemia.
Non-dihydropyridines(verapamil, diltiazem) act mainly on the myocardium and conduction system: lower HR, lower contractility, lower MVO2, with much less vasodilation. Initial therapy with a long-acting non-DHP instead ofa beta blocker is a reasonable alternative when beta blockers aren't tolerated.
Most CCBs are contraindicated in HFrEF due to negative inotropy, especially the non-DHPs. Amlodipine and felodipine are the exceptions, they're considered safe in HFrEF because they spare contractility.
Interactions:verapamil and diltiazem inhibit CYP3A4, raising levels of carbamazepine, cyclosporine, lovastatin/simvastatin, and benzodiazepines. Both inhibit P-glycoprotein too, verapamil more than diltiazem, raising digoxin and cyclosporine levels (verapamil also directly reduces digoxin clearance). CYP3A4 inducers blunt the effectiveness of any CCB. Verapamil causes constipation in roughly 8% of patients.
Nitrates donate nitric oxide, raising vascular cGMP and dropping intracellular calcium, causing smooth muscle relaxation. At low doses this is mostly venodilation, reducing preload and wall tension (lowering demand). At higher doses arterial dilation kicks in, which can trigger reflex tachycardia that eats into the antianginal benefit, that's blunted by adding a beta blocker. Nitrates also directly dilate epicardial and collateral vessels, adding a genuine supply-side benefit on top of the demand-side one.
Acute attack:fast-onset SL NTG (0.3–0.4 mg, onset 1–3 min, "time is myocardium"). Chronic prevention:long-acting formulations (transdermal patch, ISMN, or ISDN) layered onto other antianginals, never as the acute rescue.
Nitrate-free interval is mandatory.Continuous exposure over 24–36 hours causes tolerance (tachyphylaxis), likely from a mix of RAAS/SNS compensation, nitrate-driven ROS production worsening endothelial function, and phosphodiesterase upregulation normalizing cGMP levels. Build in 10–14 hours nitrate-free every day, usually overnight since MVO2 is lower during sleep. The tradeoff: this leaves a gap in coverage that lines up with the circadian early-morning ischemia risk described in pathophysiology, which is why nitrates should never be monotherapy.
Adverse effects:headache (about two-thirds of users, treat with acetaminophen, usually resolves after ~2 weeks), hypotension, dizziness, syncope, and with transdermal patches, skin erythema (minimize by rotating application sites and starting low).
SL tablets should never be transferred to another container, the drug seeps into plastic. Once opened, a bottle is only good for 6 months, ambient moisture degrades it. When dispensing, open the bottle for the patient, the cap is intentionally tight and someone mid-MI may not have the grip strength. If chest pain lasts more than 10 minutes and isn't relieved by NTG, that's a medical emergency, call 911, don't keep dosing at home.
Ranolazine selectively inhibits the late sodium current (late INa), reducing intracellular sodium and downstream calcium overload. That improves diastolic relaxation and myocardial perfusion without changing HR, BP, contractility, or coronary blood flow, it's the one antianginal that doesn't work by manipulating the demand/supply equation directly.
Where it fits:add-on therapy for patients who've hit target HR/BP but still have exertional angina, patients who can't reach those hemodynamic targets due to side effects, or patients already maxed on traditional agents with persistent symptoms. It's rarely used as monotherapy, and only when patients can't tolerate first-line agents at all.
| Trial | Design | Result |
|---|---|---|
| MARISA | Monotherapy, dose-ranging | Dose-dependent ↑ exercise duration and time to angina/ST depression |
| CARISA | Add-on to beta blocker or CCB | ↑ exercise tolerance, fewer angina episodes |
| ERICA | Add-on to amlodipine | Further symptom reduction on top of a CCB |
Dosing:start 500 mg BID, increase to 1000 mg BID over 1–2 weeks if tolerated. If CrCl <30 mL/min, start 500 mg daily, max 500 mg BID. Moderate CYP3A4 inhibitors (diltiazem, verapamil, erythromycin, fluconazole) cap the dose at 500 mg BID rather than being outright contraindicated.
Potent CYP3A4/P-gp inhibitors(ketoconazole, itraconazole, protease inhibitors, clarithromycin, nefazodone) and potent inducers(phenytoin, phenobarbital, carbamazepine, rifampin/rifabutin/rifapentine, St. John's wort) are both contraindicated, one drives ranolazine levels dangerously high, the other makes it ineffective.
Adverse effects:constipation, nausea, dizziness, headache, and dose/concentration-dependent QTc prolongation, worse with hepatic impairment, congenital long QT, or other QTc-prolonging drugs. Also bradycardia, orthostasis/syncope, and excess sweating.
Ivabradine slows the SA node via the Ifcurrent, lowering HR without touching contractility, which sounds like it should help stable CAD. It doesn't. A large outcomes trial in stable CAD patients (with and without prior MI, most already on antiplatelets, statin, and a beta blocker) found no benefit in preventing cardiovascular events, and a signal toward possible harm. This is a useful contrast with heart failure, where ivabradine has a defined role in HFrEF with a resting HR ≥70 despite maximized beta blocker. In plain stable IHD without that HFrEF context, it isn't part of the algorithm.
This is the one place the standard algorithm flips. Vasospasm-driven ischemia doesn't respond to the same first-line logic as fixed obstructive disease.
Beta blockers are not useful for vasospasmand may actually worsen it. Blocking β2-mediated vasodilation leaves α-mediated vasoconstriction unopposed, which can induce or prolong coronary vasoconstriction. This is the opposite of their role in typical obstructive angina, don't reflexively reach for a beta blocker just because the patient has "angina."
Typical patient profile: younger, smoker or cocaine user, history of Raynaud's phenomenon or migraines, normal exercise tolerance (symptoms happen at rest, not with exertion), often early morning. Cold exposure can trigger an episode, and spasm can even be provoked intentionally during cath lab testing (e.g., with acetylcholine) to confirm the diagnosis.
Some patients keep having events despite well-controlled LDL, BP, and A1C. That's residual inflammatory risk, and it's an active area of practice change worth knowing at a conceptual level.
| Trial | Population | Result |
|---|---|---|
| LoDoCo(2013) | Stable CAD, clinically stable ≥6 months | Composite ACS/arrest/stroke reduced (5.3% vs 16%) |
| COLCOT(2019) | MI within 30 days, on GDMT | Composite endpoint reduced (5.5% vs 7.1%) |
| LoDoCo2(2020) | Stable CAD, clinically stable ≥6 months | Composite CV death/MI/stroke/revasc reduced (6.8% vs 9.6%) |
| CLEAR SYNERGY(2024) | Post-PCI for ACS | Neutral, no benefit despite lowering hs-CRP |
Colchicine 0.5 mg daily works by blocking the NLRP3 inflammasome. The pattern across trials: benefit shows up in stable, chronicCAD, but the most recent large trial in the acute post-PCI/ACSsetting was neutral. Don't treat this as a universal "add colchicine to every CAD patient" answer, the evidence is population-specific. It's an adjunct on top of GDMT, never a substitute for antiplatelets, statins, or BP control.
Aspirin itself has an anti-inflammatory endothelial effect independent of its antiplatelet action, part of why it's recommended for known CAD even outside pure thrombosis prevention. Statins carry their own pleiotropic anti-inflammatory effects (↓ ROS, ↓ fibrosis, ↑ nitric oxide, ↓ smooth muscle proliferation) beyond LDL lowering.
| Parameter | When | Watching for |
|---|---|---|
| Resting/exercise HR | Baseline and every beta blocker or non-DHP CCB titration | Target resting 50–60 bpm, exercise <100 bpm; bradycardia if too aggressive |
| Blood pressure | Every visit and titration | Goal ≤130/80; symptomatic hypotension is the usual titration limiter |
| Angina frequency & SL NTG use | Every visit | The best real-world marker of control; rising use = escalate therapy |
| Exercise capacity | Every visit (subjective) or repeat stress testing if needed | Should improve over 2–4 weeks once optimized |
| Lipid panel | 4–12 weeks after statin start/change, then periodically | ≥50% LDL reduction or LDL <70–100 mg/dL |
| A1C | Periodically per diabetes plan | Individualized goal, usually ≤7% or <8% |
| Renal function / potassium | Baseline and after starting/titrating ACEi or ARB | Renal decline, hyperkalemia |
| QTc | Baseline and with dose changes on ranolazine | Especially with hepatic impairment or other QTc-prolonging drugs |
| Adverse effects by class | Every visit | Headache/dizziness (nitrates), fatigue/depression (beta blockers), edema/constipation (CCBs), constipation/dizziness (ranolazine) |
Once optimized, symptoms typically improve over 2–4 weeks. Follow up every 1–2 months until target endpoints are met, then every 6–12 months. Standardized tools like the Seattle Angina Questionnaire, Specific Activity Scale, or Canadian Cardiovascular Society classification help make symptom tracking reproducible across visits instead of relying on vague "better/worse."