7.3 Ischemic Heart Disease & Acute Coronary Syndromes (Antiplatelet & Antianginal Therapy)

Ischemic Heart Disease & Acute Coronary Syndromes (Antiplatelet & Antianginal Therapy)

Ischemic heart disease results from a critical mismatch between myocardial oxygen supply and myocardial oxygen demand (MVO2). The underlying pathophysiological driver is coronary atherosclerosis, which progresses along a clinical continuum from stable, predictable chronic coronary disease to life-threatening acute coronary syndromes (ACS). In Canadian pharmacy practice, pharmacists play a pivotal role in triaging chest pain, educating patients on emergency sublingual nitroglycerin protocols, optimizing antianginal pharmacotherapy, preventing stent thrombosis with dual antiplatelet therapy (DAPT), and ensuring long-term secondary prevention adherence.

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The Clinical Spectrum: Stable Angina vs. Acute Coronary Syndromes

                        THE ISCHEMIC HEART DISEASE CONTINUUM
                                          │
         ┌────────────────────────────────┴────────────────────────────────┐
         ▼                                                                 ▼
   CHRONIC CORONARY DISEASE                                     ACUTE CORONARY SYNDROMES
   (Stable Angina)                                              (Plaque Rupture & Thrombosis)
• Fixed stenosis (≥ 70% lumen)                                             │
• Predictable on exertion / cold                                ┌──────────┴──────────┐
• Relieved by rest or SL NTG in < 5m                            ▼                     ▼
• Normal troponin; transient ST changes                  NON-ST-ELEVATION ACS      STEMI
                                                          (UA / NSTEMI)      Transmural necrosis;
                                                                │            ST-elevation ≥ 1 mm;
                                                     ┌──────────┴──────────┐ Emergency Reperfusion
                                                     ▼                     ▼ (PCI ≤ 90m or Lytics)
                                              UNSTABLE ANGINA           NSTEMI
                                              • Rest / crescendo       • Subendocardial necrosis
                                              • Troponin NEGATIVE      • Troponin POSITIVE
                                              • ST-depression/T-inv    • ST-depression/T-inv

1. Chronic Coronary Disease (CCD) / Stable Angina

Characterized by predictable, transient retrosternal chest tightness, pressure, or heaviness brought on by physical exertion, emotional distress, or cold exposure, which resolves completely within 2 to 5 minutes of rest or sublingual nitroglycerin administration. It is caused by fixed atherosclerotic narrowing (> 70% luminal diameter) without acute plaque rupture or thrombosis. Cardiac troponins remain normal.

2. Acute Coronary Syndromes (ACS)

Caused by acute disruption (rupture or erosion) of a vulnerable atherosclerotic plaque, triggering platelet adhesion, activation, aggregation, and acute thrombus formation with varying degrees of coronary luminal occlusion:

• Unstable Angina (UA): Characterized by ischemic chest pain occurring at rest (typically lasting > 20 minutes), new-onset severe angina (Canadian Cardiovascular Society Class III or IV), or accelerating/crescendo angina (more frequent, severe, or provoked by less exertion). Cardiac biomarkers (cardiac troponin I or T) remain strictly negative. The ECG may demonstrate transient ST-segment depression or T-wave inversion.
• Non-ST-Segment Elevation Myocardial Infarction (NSTEMI): Symptoms identical to unstable angina, but myocardial necrosis is confirmed by statistically significant elevation in cardiac troponin above the 99th percentile upper reference limit. ECG demonstrates persistent or transient ST-segment depression, deep T-wave inversion, or may be non-specific, but lacks persistent ST-segment elevation.
• ST-Segment Elevation Myocardial Infarction (STEMI): Complete, acute, transmural coronary artery occlusion resulting in extensive full-thickness myocardial infarction. The hallmark ECG finding is persistent ST-segment elevation ≥ 1 mm in two or more anatomically contiguous leads (or ≥ 2 mm in anterior chest leads V2–V3 in men, or new left bundle branch block [LBBB]). Confirmed by positive troponin curves. STEMI represents a medical emergency requiring immediate coronary reperfusion:
  • Primary Percutaneous Coronary Intervention (PCI): The gold standard; target door-to-balloon time is ≤ 90 minutes (or ≤ 120 minutes from first medical contact).
  • Intravenous Fibrinolysis (e.g., Tenecteplase): Indicated only when primary PCI cannot be accomplished within 120 minutes of medical contact, provided no absolute contraindications exist; target door-to-needle time is ≤ 30 minutes.

Acute Antianginal Pharmacotherapy: Sublingual Nitroglycerin

Short-acting sublingual nitroglycerin (SL NTG) is the universal first-line agent prescribed for all patients with documented ischemic heart disease for the immediate termination of acute angina attacks.

Mechanism of Action & Hemodynamics

Nitroglycerin is an organic nitrate prodrug denitrated in vascular smooth muscle by mitochondrial aldehyde dehydrogenase (ALDH-2) to produce nitric oxide (NO). Nitric oxide activates soluble guanylyl cyclase, increasing intracellular cyclic guanosine monophosphate (cGMP). Elevated cGMP activates protein kinase G, promoting dephosphorylation of myosin light chains and vascular smooth muscle relaxation:

• Venous Capacitance Dilation (Primary Hemodynamic Effect): Profound systemic venodilation reduces venous return to the heart, decreasing left ventricular end-diastolic volume (preload) and ventricular wall tension, which significantly reduces myocardial oxygen demand (MVO2).
• Coronary Artery Vasodilation: Relieves epicardial coronary artery vasospasm, dilates eccentric atherosclerotic stenoses, and redistributes coronary blood flow toward ischemic subendocardial tissue.

Dosage Forms & Administration Technique

• Sublingual Tablets (Nitrostat 0.3, 0.4, 0.6 mg): Dissolved under the tongue; not swallowed or chewed. Must not be placed between cheek and gum.
• Sublingual Pump Spray (Nitrolingual / Rho-Nitro 0.4 mg/metered spray): Sprayed onto or under the tongue; do not inhale. The canister must be held upright during actuation. Must be primed before initial use (1–2 test sprays into air) and reprimed if unused for > 14 days.

                         SUBLINGUAL NTG "5-MINUTE RULE"

               Patient experiences acute ischemic chest discomfort
                                         │
               Sit down immediately (prevents orthostatic syncope)
               Administer 1 dose of SL NTG (0.4 mg tablet or spray)
                                         │
                                   Wait 5 MINUTES
                                         │
                  Has chest pain completely resolved after 5 minutes?
                                         │
                     ┌───────────────────┴───────────────────┐
                     ▼                                       ▼
                    YES                                     NO
            Resume quiet rest                    IMMEDIATELY CALL 911!
            Log incident in diary               (Do NOT wait for 3 doses!)
                                                             │
                                                Administer 2nd SL NTG dose
                                                Wait 5 minutes while ambulance en route
                                                             │
                                                If pain persists, administer 3rd dose
                                                (MAXIMUM 3 doses in 15 minutes)

Stability & Storage Rules (Tablets vs. Spray)

• SL Tablets: Highly volatile and unstable. Tablets degrade rapidly upon exposure to heat, atmospheric air, and moisture. They must be stored in their original amber glass bottle with a tightly sealed metal screw cap. Never carry tablets in plastic pillboxes, medication cassettes, or shirt pockets close to warm body heat. The cotton plug should be removed upon opening and discarded. Follow the product monograph for the in-use period. Many pharmacists still advise replacing an opened bottle every 6 months as a precaution, and patients should never use tablets past the expiry date.
• SL Pump Spray: Encased in a sealed glass/plastic canister that is impervious to atmospheric moisture and light. It maintains chemical stability until the printed manufacturer expiration date (typically 2 to 3 years) and does not require refrigeration. It is preferred for patients who experience infrequent attacks or travel frequently.

Absolute Contraindication: Phosphodiesterase Type 5 (PDE-5) Inhibitors

Co-administration of organic nitrates with PDE-5 inhibitors used for erectile dysfunction or pulmonary arterial hypertension is strictly contraindicated without exception.

• Pathophysiological Mechanism: Organic nitrates stimulate guanylyl cyclase to produce cGMP, while PDE-5 inhibitors block the enzymatic breakdown of cGMP. Co-administration causes massive, uncontrolled, supra-additive accumulation of cGMP in vascular smooth muscle, triggering catastrophic refractory hypotension, loss of coronary perfusion, myocardial reinfarction, and cardiovascular collapse.
• Mandatory Nitrate-Free Washout Intervals:
  • Sildenafil (Viagra) & Vardenafil (Levitra): Minimum 24-hour nitrate-free interval required after the last dose before any nitrate may be administered.
  • Tadalafil (Cialis): Minimum 48-hour nitrate-free interval required after the last dose, mandated by tadalafil's prolonged terminal elimination half-life (t½ ~ 17.5 hours).
  • Riociguat (Adempas, soluble guanylate cyclase stimulator): Concomitant use with nitrates is contraindicated with zero safe time window.

Maintenance Antianginal Pharmacotherapies

When treating chronic stable angina, pharmacotherapy aims to eliminate ischemic symptoms, improve exercise tolerance, and prolong survival by modifying myocardial hemodynamics.

1. First-Line Maintenance: Cardioselective Beta-Blockers

• Agents: Metoprolol tartrate (25–100 mg PO BID), Metoprolol succinate XL (50–200 mg PO daily), Bisoprolol (5–10 mg PO daily), Atenolol (25–100 mg PO daily).
• Mechanism: Competitively block β1-adrenergic receptors in the myocardium, decreasing resting and exercise heart rate, blunting myocardial contractility, and lowering systemic arterial blood pressure, thereby dramatically reducing MVO2. Prolonging diastolic filling time also enhances subendocardial coronary perfusion.
• Titration Target: Titrate dose to achieve a resting heart rate of 55 to 60 bpm, and ensure the exercise heart rate does not exceed 100 bpm during moderate exertion.
• Prognostic Impact: Beta-blockers are the only antianginal class proven to reduce reinfarction, fatal arrhythmias, and all-cause mortality in patients with previous myocardial infarction or heart failure with reduced ejection fraction.

2. Second-Line / Add-On: Calcium Channel Blockers (CCBs)

• Dihydropyridines (Amlodipine 5–10 mg daily, Felodipine 5–10 mg daily): Potent coronary and systemic arteriolar vasodilators that decrease left ventricular afterload. Safe and highly synergistic when added to beta-blockers because beta-blockers suppress the reflex sympathetic tachycardia induced by DCCB vasodilation.
• Non-Dihydropyridines (Diltiazem CD 120–360 mg daily, Verapamil SR 120–360 mg daily): Reduce heart rate, slow AV nodal conduction, and depress myocardial contractility. Excellent alternative antianginals for patients who have true contraindications to beta-blockers (e.g., severe active reactive airway disease / asthma). Critical Safety Rule: Combining a non-dihydropyridine CCB with a beta-blocker is hazardous due to additive negative chronotropic and dromotropic actions, risking severe symptomatic sinus bradycardia, sinus arrest, and high-degree AV block. Non-DCCBs are strictly contraindicated in HFrEF (LVEF ≤ 40%) due to negative inotropy precipitating acute pulmonary edema.

3. Long-Acting Nitrates & The Nitrate Tolerance Phenomenon

• Agents: Oral Isosorbide Mononitrate (ISMN, 30–120 mg daily), Oral Isosorbide Dinitrate (ISDN, 10–40 mg TID), Transdermal Nitroglycerin Patches (0.2–0.8 mg/hr).
• Mechanism of Nitrate Tolerance: Continuous, uninterrupted, round-the-clock administration of organic nitrates leads to rapid development of complete hemodynamic and antianginal tolerance within 24 to 48 hours. Tolerance results from depletion of essential intracellular sulfhydryl (-SH) donor groups in ALDH-2, neurohormonal counter-regulation (sympathetic activation, intravascular fluid retention via RAAS), and increased vascular production of reactive oxygen species (superoxide anion inactivating nitric oxide).
• The Mandatory Nitrate-Free Interval: To prevent tolerance and maintain therapeutic antianginal efficacy, all long-acting nitrate regimens must incorporate an eccentric dosing schedule that provides a 10- to 12-hour nitrate-free interval each day, typically scheduled during the night when the patient is at physical rest:
  • Transdermal Nitroglycerin Patches: Apply the patch in the morning (e.g., 08:00) and remove the patch at bedtime after 12 to 14 hours (e.g., 20:00 to 22:00), providing an overnight 10- to 12-hour patch-free washout interval.
  • Oral Isosorbide Mononitrate (Immediate-Release 20 mg): Dosed twice daily, but administered 7 hours apart (e.g., 08:00 and 15:00) rather than every 12 hours, creating a 17-hour nighttime washout period.
  • Oral Isosorbide Mononitrate (Sustained-Release 30–120 mg): Formulated to release active drug over 10 to 12 hours followed by subtherapeutic evening/nocturnal plasma concentrations; administered once daily in the morning.

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Dual Antiplatelet Therapy (DAPT) in Acute Coronary Syndromes

Dual Antiplatelet Therapy—combining acetylsalicylic acid (ASA) with an oral P2Y12 platelet adenosine diphosphate (ADP) receptor antagonist—is the mandatory foundation of post-ACS management, preventing catastrophic stent thrombosis and recurrent myocardial infarction.

                           P2Y12 INHIBITOR COMPARISON (ACS)

         CLOPIDOGREL                      TICAGRELOR                       PRASUGREL
    ┌────────────────────┐          ┌────────────────────┐          ┌────────────────────┐
    │ • Thienopyridine   │          │ • Cyclo-pentyl-    │          │ • Thienopyridine   │
    │   prodrug          │          │   triazolo-pyrimid.│          │   prodrug          │
    │ • Irreversible     │          │ • REVERSIBLE       │          │ • Irreversible     │
    │ • 2-step CYP2C19   │          │ • Active drug      │          │ • 1-step bioactiv. │
    │   bioactivation    │    vs    │   (non-prodrug)    │    vs    │ • Potent, rapid    │
    │ • High variable    │          │ • PLATO Trial:     │          │ • TRITON-TIMI 38   │
    │   resistance       │          │   Superior to Clop │          │ • CONTRAINDICATED  │
    │ • Dose: 75 mg daily│          │ • Dose: 90 mg BID  │          │   in prior stroke  │
    │ • Omeprazole inter.│          │ • Side effects:    │          │   or TIA!          │
    └────────────────────┘          │   dyspnea, pauses  │          │ • Dose: 10 mg daily│
                                    │ • ASA ≤ 100 mg cap │          └────────────────────┘
                                    └────────────────────┘

1. P2Y12 Receptor Antagonists: Clinical Comparison

Ticagrelor (Brilinta)

• Pharmacology: A direct-acting, reversible P2Y12 receptor antagonist. It does not require hepatic enzymatic biotransformation to become active.
• Dosing in ACS: Initial loading dose of 180 mg PO, followed by a maintenance dose of 90 mg PO twice daily (with or without food).
• Pivotal Evidence (PLATO Trial): In 18,624 ACS patients, ticagrelor significantly reduced cardiovascular death, myocardial infarction, and stroke compared to clopidogrel (9.8% vs 11.7%, p < 0.001), with a statistically significant reduction in cardiovascular death (4.0% vs 5.1%) and definite stent thrombosis, with no increase in overall major bleeding (though non-CABG bleeding was increased). The CCS antiplatelet guideline prefers ticagrelor (or prasugrel for PCI-treated patients) over clopidogrel in ACS.
• Adverse Effects & Unique Pearls:
  • Dyspnea (10% to 15%): Occurs early (typically within 3 to 5 days). Caused by ticagrelor inhibiting cellular adenosine reuptake via equilibrative nucleoside transporter-1 (ENT-1), increasing circulating plasma adenosine and stimulating pulmonary vagal C-fibers. It is self-limiting, does not cause bronchospasm or heart failure decompensation, and does not impair pulmonary function. Most cases resolve over several weeks without drug cessation. Reassure the patient unless severe or accompanied by objective heart failure signs.
  • Ventricular Pauses / Bradycardia: Usually asymptomatic nocturnal sinus pauses.
  • Hyperuricemia: Mild elevation in serum uric acid; caution in active gout.
  • The ASA Dosing Restriction: Concomitant maintenance ASA must not exceed 100 mg daily (81 mg daily in Canada). In the PLATO trial North American subgroup, high maintenance ASA (≥ 300 mg daily) eliminated ticagrelor's clinical benefit due to paradoxical prostanoid pathway antagonism.

Prasugrel (Effient)

• Pharmacology: An irreversible thienopyridine prodrug requiring a single-step hepatic bioactivation (predominantly CYP3A4 and CYP2B6). Achieves faster, more potent, and more consistent platelet inhibition than clopidogrel.
• Dosing in ACS: Loading dose 60 mg PO, followed by 10 mg PO daily (reduced to 5 mg PO daily if patient weight is < 60 kg or age ≥ 75 years).
• Pivotal Evidence (TRITON-TIMI 38): Demonstrated superior ischemic event and stent thrombosis reduction compared to clopidogrel in ACS managed with PCI.
• Absolute Contraindications: Strictly contraindicated in patients with a history of stroke or Transient Ischemic Attack (TIA). In TRITON-TIMI 38, patients with prior stroke/TIA experienced significant net clinical harm, driven by a massive increase in fatal intracranial hemorrhage.

Clopidogrel (Plavix)

• Pharmacology: An irreversible thienopyridine prodrug requiring two sequential hepatic bioactivation steps involving CYP2C19. Up to 30% of patients carry CYP2C19 loss-of-function alleles (e.g., *2 or *3), leading to diminished active metabolite formation, "clopidogrel resistance," and increased stent thrombosis.
• Clinical Role in ACS: Reserved as a second-line agent for ACS patients who have contraindications to ticagrelor or prasugrel, require oral anticoagulation (triple/dual therapy), or have excessively high bleeding risks.
• Drug Interaction with Proton Pump Inhibitors (PPIs): Omeprazole competitively inhibits CYP2C19, decreasing clopidogrel active metabolite concentrations by ~45% and blunting platelet inhibition. If gastroprotection with a PPI is required in a patient taking clopidogrel, pantoprazole is the evidence-based agent of choice because it does not significantly inhibit CYP2C19.

2. DAPT Duration Stratification Post-ACS

• Standard Guideline Duration: 12 months of DAPT (ASA 81 mg daily + P2Y12 inhibitor) is recommended for all ACS patients, whether managed medically or revascularized with PCI/stents.
• High Bleeding Risk (HBR) Stratification: In patients identified as having high bleeding risk (e.g., PRECISE-DAPT score ≥ 25, advanced age ≥ 75, concurrent oral anticoagulation, recent major bleed, or severe thrombocytopenia), shortened DAPT duration (3 to 6 months) followed by single antiplatelet monotherapy (P2Y12 inhibitor or ASA) is recommended to mitigate hemorrhagic stroke and fatal gastrointestinal bleeding.
• Extended DAPT (> 12 Months): In patients who tolerate 12 months of DAPT without bleeding and have high ischemic risk features (e.g., multiple prior MIs, diabetes, complex multivessel stenting, DAPT score ≥ 2), extended DAPT up to 36 months (e.g., ticagrelor 60 mg PO BID per the PEGASUS-TIMI 54 trial) significantly reduces recurrent atherothrombotic events.

Secondary Prevention Guideline-Directed Medical Therapy ("The Post-MI Cocktail")

Every patient discharged following an acute myocardial infarction or revascularization must receive the evidence-based four-pillar secondary prevention medical cocktail, unless an absolute clinical contraindication exists:

                          THE POST-MI SECONDARY PREVENTION COCKTAIL

         PILLAR 1                      PILLAR 2                      PILLAR 3                      PILLAR 4
       ANTIPLATELET                  STATIN GDMT                  BETA-BLOCKER                  ACEi or ARB
   ┌──────────────────┐          ┌──────────────────┐          ┌──────────────────┐          ┌──────────────────┐
   │ • ASA 81 mg/day  │          │ • Atorvastatin   │          │ • Metoprolol     │          │ • Ramipril       │
   │   indefinitely   │          │   80 mg daily, or│          │   or Bisoprolol  │          │   or Perindopril │
   │ • Plus P2Y12     │   AND    │   Rosuvastatin   │   AND    │ • Titrate to     │   AND    │ • Indicated for  │
   │   inhibitor for  │          │   40 mg daily    │          │   HR 55–60 bpm   │          │   LVEF ≤ 40%,    │
   │   12 months      │          │ • Add-on if LDL-C│          │ • Duration: 1–3  │          │   HTN, DM, CKD,  │
   │   (Ticagrelor    │          │   ≥ 1.8 mmol/L   │          │   years post-MI, │          │   or all CAD     │
   │   preferred)     │          │   (CCS 2021)     │          │   indefinitely if│          │ • Halts adverse  │
   │ • Prevents stent │          │ • Stabilizes     │          │   LVEF ≤ 40%     │          │   ventricular    │
   │   thrombosis     │          │   plaque         │          │ • Prevents sudden│          │   remodeling     │
   └──────────────────┘          └──────────────────┘          │   arrhythmias    │          └──────────────────┘
                                                               └──────────────────┘

1. Antiplatelet Therapy: ASA 81 mg daily indefinitely, combined with a P2Y12 inhibitor (ticagrelor 90 mg BID preferred) for 12 months.
2. High-Potency Statin: Atorvastatin 80 mg daily or rosuvastatin 40 mg daily started immediately, irrespective of baseline lipid levels, adding ezetimibe and/or a PCSK9 inhibitor if LDL-C stays at or above 1.8 mmol/L (CCS 2021 threshold).
3. Cardioselective Beta-Blocker: Initiated within the first 24 hours of hemodynamically stable presentation. Continued for a minimum of 1 to 3 years in patients with normal left ventricular function, and continued indefinitely in patients with left ventricular systolic dysfunction (LVEF ≤ 40%) or chronic heart failure.
4. ACE Inhibitor or ARB: Initiated early post-infarction. Strongly indicated for patients with left ventricular ejection fraction ≤ 40%, hypertension, diabetes, or anterior wall infarction to suppress neurohormonal activation, prevent progressive adverse ventricular remodeling, and reduce heart failure hospitalizations (SAVE, AIRE, TRACE trials). Clinical trials (HOPE, EUROPA) support long-term ACE inhibitor therapy in all patients with established coronary artery disease.

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Clinical Decision-Making Scenario: Managing Early Post-ACS Therapy & Adverse Effects

A 59-year-old male was discharged from the hospital 5 days ago following an acute anterior STEMI treated with primary PCI and deployment of two drug-eluting stents (DES) in the left anterior descending (LAD) coronary artery. His discharge ejection fraction was 42%. His discharge prescription regimen consists of:

• ASA 81 mg PO daily
• Ticagrelor 90 mg PO BID
• Atorvastatin 80 mg PO daily
• Metoprolol tartrate 50 mg PO BID
• Ramipril 5 mg PO daily
• Nitroglycerin 0.4 mg/metered sublingual spray PRN

He visits the community pharmacy today complaining of a persistent sensation of shortness of breath and mild air hunger that began 2 days ago while resting on the couch watching television. He denies chest pain, palpitations, orthopnea, paroxysmal nocturnal dyspnea, and ankle swelling. His vital signs in the pharmacy: BP 122/76 mmHg, HR 58 bpm (regular), SpO2 98% on ambient room air. The patient is anxious and asks if his newly placed coronary stents are clotting off, and wonders if he should stop all his medications.

Pharmacist Clinical Assessment & Action Plan:

1. Differential Diagnosis: The sudden onset of mild dyspnea at rest with normal oxygen saturation, normal heart rate, no chest pain, and clear lung sounds 5 days post-ACS strongly points to ticagrelor-induced dyspnea. Heart failure decompensation is ruled out by normal vitals, absence of orthopnea, and normal physical findings. Stent thrombosis presents with severe acute ischemic chest pain and ST-segment elevation, which is completely absent.
2. Pharmacological Mechanism Explanation: Explain to the patient that ticagrelor inhibits adenosine reuptake by red blood cells, causing transient local accumulation of adenosine in the lungs that stimulates breathing nerve receptors. It occurs in 10% to 15% of patients, is completely self-limiting, peak symptoms occur in the first week, and it does not harm the lungs or heart.
3. Patient Counseling & Reassurance: Strongly advise the patient NEVER to discontinue ticagrelor or ASA. Premature discontinuation of ticagrelor within the first 30 days post-PCI carries a catastrophic risk of acute stent thrombosis, leading to massive reinfarction and death. Reassure him that the shortness of breath typically subsides over the next 2 to 4 weeks. Instruct him to contact his cardiologist immediately or go to the emergency department only if dyspnea worsens significantly, or if he develops chest pain, orthopnea, or ankle swelling.
4. Nitroglycerin Counseling Reinforcement: Reiterate the 5-minute rule: if acute chest pain occurs, sit down, take 1 spray under the tongue, and if pain is unresolved after 5 minutes, call 911 immediately before taking a second dose.