Wednesday, September 16, 2026

Antiseizure Medications

Antiseizure Medication Dosing and Monitoring

Antiseizure Medication Dosing and Monitoring in the ICU

Practical Lecture Notes Based on the 2026 Narrative Review

1. Source and Scope

  • Source: Webb AJ, Barlow B, Seto SL, Maciel CB, Brennan J, Cook AM. Antiseizure medication dosing and monitoring in the intensive care unit: a practical narrative review. Intensive Care Medicine. 2026. DOI: 10.1007/s00134-026-08550-y.
  • Publication date reported in the supplied summary: July 15, 2026.
  • Review type: Practice-oriented narrative review supported by the Research and Scholarship Committee of the Neurocritical Care Society Pharmacy Section.
  • Literature search: MEDLINE from database inception through March 2026.
  • Clinical scope:
    • Antiseizure medication (ASM) pharmacokinetics and pharmacodynamics in critical illness.
    • Status epilepticus (SE), seizure treatment, and seizure prophylaxis.
    • Acute kidney injury, augmented renal clearance (ARC), and hepatic dysfunction.
    • Intermittent hemodialysis, continuous renal replacement therapy (CRRT), extracorporeal membrane oxygenation (ECMO), and plasma exchange (PLEX).
    • Therapeutic drug monitoring (TDM), drug interactions, formulations, and enteral access.
  • Fifteen ASMs are reviewed in detail:
    • Brivaracetam, cannabidiol, carbamazepine, cenobamate, and clobazam.
    • Lacosamide, lamotrigine, levetiracetam, oxcarbazepine, and perampanel.
    • Phenobarbital, phenytoin, topiramate, valproate, and zonisamide.
  • Core principle: ICU dosing cannot be treated as routine outpatient dosing. Critical illness, organ support, and the indication can substantially change drug exposure and response.
  • Evidence caution: These notes summarize the supplied review content. Many ICU recommendations are extrapolated from outpatient data, small cohorts, case reports, pharmacokinetic studies, or expert opinion.

2. Why Outpatient Dosing Can Fail in the ICU

  • Histamine-2 receptor antagonists and proton pump inhibitors raise gastric pH and may reduce absorption of weakly basic drugs.
  • Vasopressors can reduce gastrointestinal perfusion and impair enteral absorption.
  • Large-volume fluid resuscitation can increase the volume of distribution of hydrophilic drugs.
  • Feeding tubes may adsorb selected drugs or create clinically important interactions with enteral nutrition.
  • Hypothermia can reduce the metabolism of drugs that depend on esterase activity.
  • Hypovolemia can reduce the volume of distribution.
  • Hypoalbuminemia increases the unbound fraction of highly protein-bound drugs.
  • Inflammation can increase alpha-1 acid glycoprotein and reduce the unbound fraction of basic drugs.
  • Acute kidney injury reduces clearance of renally eliminated ASMs.
  • ARC increases renal drug clearance and can cause subtherapeutic exposure.
  • Acute hepatic injury reduces clearance of drugs that depend on hepatic metabolism.
  • CRRT increases clearance of dialyzable ASMs. Effluent rates above 3 L/hour may produce supraphysiologic clearance.
  • Intermittent hemodialysis increases clearance of dialyzable drugs and may require a post-dialysis supplemental dose.
  • ECMO can increase the apparent volume of distribution of lipophilic and highly protein-bound drugs.
  • PLEX preferentially removes drugs with a small volume of distribution and high protein binding.

3. Status Epilepticus Changes Pharmacodynamics

  • Persistent seizure activity produces receptor-level changes that make delayed treatment less effective.
  • Calcium-sensitive NMDA and AMPA receptors are upregulated at excitatory synapses, increasing glutamate-driven excitation.
  • Intracellular gamma-aminobutyric acid (GABA) stores and metabolic substrates become depleted, reducing inhibitory tone.
  • Benzodiazepine-sensitive GABA-A receptors are internalized, which contributes to declining benzodiazepine effectiveness as SE continues.
  • Neuronal chloride accumulation can reverse the electrochemical gradient. GABA-A receptor activation may then become excitatory rather than inhibitory.
  • A loading dose has two major purposes in SE:
    • It rapidly achieves therapeutic exposure despite an expanded volume of distribution.
    • It counters the time-dependent pharmacodynamic changes of ongoing seizure activity.
  • Maintenance dosing must reflect the indication:
    • Use the lower end of a dose range for prophylaxis or an isolated seizure.
    • Use the higher end, faster titration, or shorter intervals for SE when clinically appropriate.

4. Organ Function and Clearance

Acute kidney injury

  • Renally cleared ASMs such as levetiracetam, lacosamide, and topiramate have reduced clearance.
  • Start with a lower maintenance dose and titrate according to tolerance, clinical response, and drug concentrations when useful.
  • A clinically appropriate loading dose may still be required because loading is driven mainly by the volume of distribution and urgency of seizure control.

Augmented renal clearance

  • ARC is common in younger neurocritical care and trauma patients.
  • It can cause underexposure to predominantly renally cleared ASMs despite an apparently normal serum creatinine.
  • Consider an 8- to 24-hour urine creatinine collection when ARC is suspected.
  • Higher maintenance doses or more frequent administration may be needed.

Hepatic dysfunction

  • Reduce or cautiously titrate drugs that rely on hepatic metabolism when hepatic clearance is impaired.
  • Avoid valproate in hepatic dysfunction because direct hepatotoxicity makes drug substitution preferable to simple dose reduction.

5. Therapeutic Drug Monitoring: Appropriate Use and Limitations

  • TDM is useful when drug exposure is uncertain, but most ICU ASM targets are not validated against clinical outcomes.
  • For phenytoin and valproate, measure the free concentration whenever possible in critically ill patients.
  • Total concentrations can be misleading when albumin concentration or protein binding is altered.
  • Correction equations are unreliable in critical illness:
    • The Winter-Tozer equation may inaccurately estimate free phenytoin.
    • The Fraser equation may inaccurately estimate free valproate.
  • A published reference range should not be treated as a mandatory target when the concentration-response relationship is unproven.
  • Concentrations above traditional outpatient ranges may occasionally be required for seizure control, especially in SE, but toxicity surveillance must intensify.
  • Reasonable indications for TDM include:
    • Assessment of outpatient adherence at admission.
    • Suspected treatment failure or toxicity.
    • Markedly altered protein binding.
    • ARC, dialysis, CRRT, ECMO, or other major pharmacokinetic uncertainty.
    • Drug interactions expected to change exposure.
  • Do not change a clinically effective and tolerated regimen solely to place a concentration inside an unvalidated reference range.

6. Overall Medication Selection Strategy

  • Integrate four domains before selecting and dosing an ASM:
    • Clinical indication and urgency.
    • Concomitant medications and drug-drug interactions.
    • Renal and hepatic function.
    • Organ support devices and drug delivery route.
  • Levetiracetam, fosphenytoin, and valproate have the strongest practical support as initial non-benzodiazepine choices for established SE in the reviewed material.
  • Other ASMs may be used when first-line choices are unsuitable, but the evidence base is generally smaller.
  • Lamotrigine is difficult to initiate acutely because it requires slow titration. Continue a patient's established regimen when feasible.
  • Cenobamate also requires slow outpatient titration because of the risk of drug reaction with eosinophilia and systemic symptoms (DRESS).
  • Prefer intravenous loading when an IV formulation is available and reliable exposure is essential.
  • Transition to enteral therapy after access and gastrointestinal function are established.
  • Screen for drug-drug interactions whenever an ASM or a major ICU medication is added, discontinued, or substantially changed.

7. High-Yield Individual Medication Notes

Brivaracetam

  • Routine initiation: 50 mg twice daily.
  • Acute seizure or SE loading: 100 to 400 mg IV.
  • SE maintenance: 200 to 400 mg/day in two divided doses.
  • Prophylaxis: 100 to 200 mg/day in two divided doses.
  • It can be started directly at the target dose because tolerability is generally favorable.
  • When switching from levetiracetam because of neuropsychiatric adverse effects, a brivaracetam-to-levetiracetam ratio of approximately 1:10 to 1:15 has been used.
  • Renal dysfunction: No routine adjustment.
  • Hepatic dysfunction: Reduce the dose; maximum 150 mg/day.
  • TDM: Not routinely needed because interpatient pharmacokinetic variability is relatively low.
  • Evidence note: A small 14-patient SE series reported higher loading doses among responders than nonresponders, but a concentration-guided outcome benefit remains unproven.
  • Proposed but unvalidated concentration range: 0.2 to 2 µg/mL.

Lacosamide

  • Routine initiation: 50 mg twice daily, titrated to 200 to 400 mg/day.
  • Common ICU loading dose: 400 mg IV.
  • Reported higher loading strategies: 8 to 13 mg/kg, with uncertain incremental clinical benefit.
  • Maintenance: 200 to 400 mg/day, beginning 6 to 12 hours after the loading dose.
  • The TRENdS trial used a 400 mg IV bolus and found acceptable efficacy and tolerability compared with fosphenytoin for nonconvulsive seizures.
  • A 25-patient SE cohort reported seizure control in 50% after 400 mg versus 18% after 200 mg loading, with p = 0.2.
  • Cardiac safety:
    • High loading doses may prolong the PR interval.
    • Use caution in patients with conduction disease and monitor the electrocardiogram when risk is increased.
  • Severe renal dysfunction with creatinine clearance below 30 mL/min: Reduce the maintenance dose by approximately 25%.
  • Hepatic dysfunction: An initial 25% reduction with close electrocardiographic monitoring is reasonable.
  • Proposed reference range: 10 to 20 mg/L.
  • TDM: Concentrations have not shown a clear efficacy relationship. Use mainly when toxicity is suspected.

Levetiracetam

  • Routine focal seizure initiation: 500 mg twice daily, titrated to 1,500 mg twice daily.
  • Convulsive SE loading in ESETT: 60 mg/kg, maximum 4,500 mg.
  • Seizures not progressing to SE: A loading dose of 20 to 40 mg/kg may be sufficient.
  • ICU maintenance: 1,000 to 2,000 mg every 6 to 12 hours, individualized to renal clearance and indication.
  • Seizure prophylaxis: 500 to 1,000 mg twice daily.
  • Higher prophylactic doses of 750 to 1,000 mg twice daily may reduce post-traumatic seizures in some studies, but findings are inconsistent.
  • Renal dysfunction: Reduce the maintenance dose, using sedation and tolerance as clinical guides.
  • ARC: Doses as high as 1,500 mg every 6 hours may be required to maintain exposure.
  • Proposed reference range: 12 to 46 mg/L.
  • TDM: Consider for suspected nonadherence, ARC, dialysis, CRRT, or otherwise unpredictable clearance.
  • Concentration-toxicity correlation is weak. In a cohort of 106 patients with concentrations above 80 µg/mL, 45.3% were asymptomatic.

Phenytoin and Fosphenytoin

  • Use is limited by complex pharmacokinetics, numerous interactions, formulation issues, and cardiovascular toxicity.
  • Express all fosphenytoin doses as phenytoin equivalents (mg PE).
  • Acute loading: 15 to 20 mg/kg.
  • Obesity: If actual weight exceeds 125% of ideal body weight, calculate the loading dose using adjusted body weight.
  • Maintenance: 5 to 7 mg/kg/day in divided doses, guided by TDM.
  • Phenytoin has capacity-limited, zero-order elimination near the therapeutic range.
  • Maintenance dose adjustments are not linear:
    • Change by only 25 to 50 mg/day at a time.
    • Recheck concentrations before making further changes.
  • Typical targets:
    • Total concentration: 10 to 20 µg/mL.
    • Free concentration: 1 to 2 µg/mL.
    • Refractory epilepsy may require approximately 25 µg/mL total or 2.5 µg/mL free with close toxicity monitoring.
  • When valproate is coadministered, measure free phenytoin because the drugs compete for albumin binding.

Phenobarbital

  • SE loading: 15 to 20 mg/kg.
  • Maintenance after SE loading: 1 to 2 mg/kg/day in divided doses.
  • Ideal body weight is often used because the volume of distribution is small.
  • In severe or refractory SE, actual body weight may be used with TDM guidance.
  • Transition from prolonged pentobarbital infusion may require exceptionally high phenobarbital doses. The supplied review reports doses up to 120 mg/kg/day and targets above 80 to 100 mg/L in this specialized setting.
  • Mild to moderate renal dysfunction: No routine adjustment.
  • Estimated glomerular filtration rate below 10 mL/min/1.73 m2: Start at 50% to 66% of the usual dose.
  • Mild hepatic dysfunction: No routine adjustment.
  • Child-Pugh class B or C: Start at approximately 50% and titrate using tolerance and TDM.
  • Phenobarbital is a strong CYP3A4 inducer and can increase alpha-1 acid glycoprotein, creating multiple interactions.
  • Usual concentration range: 10 to 40 µg/mL, although selected severe cases may require higher concentrations.
  • Because the half-life is long, peak and trough concentrations differ relatively little.

Valproate

  • Routine initiation: 10 to 20 mg/kg/day in one to four divided doses.
  • TDM-guided maintenance: 20 to 30 mg/kg/day.
  • Acute seizure or SE loading: 20 to 40 mg/kg IV, maximum 3,000 mg.
  • Protein binding is saturable. The free concentration can rise disproportionately relative to the total concentration.
  • When coadministered with phenytoin, measure free concentrations of both drugs.
  • Critical interaction with carbapenems:
    • A single carbapenem dose may reduce valproate concentration by more than 70%.
    • Dose escalation generally cannot overcome this interaction.
    • Avoid the combination and select an alternative antimicrobial or ASM when possible.
  • Typical total concentration range: 50 to 100 µg/mL.
  • A total concentration up to 125 mg/L has been proposed in SE.
  • Free concentration target is not established. Proposed values include 5 to 15 µg/mL and up to 25 µg/mL in SE.
  • Do not rely on albumin correction equations in critically ill patients. Directly measure the free concentration.
  • Avoid in hepatic dysfunction because of direct hepatotoxicity.

Carbamazepine

  • Difficult to initiate in the ICU because absorption is slow, pharmacokinetics are complex, and the therapeutic index is narrow.
  • Initiation: 200 to 400 mg/day in two to four divided doses.
  • Increase every 3 to 5 days toward 800 to 1,200 mg/day after autoinduction develops.
  • Reported oral loading: 8 to 10 mg/kg, with risks of rash, gastrointestinal effects, dizziness, and somnolence.
  • If oral loading is attempted, suspension may be preferable to other formulations.
  • TDM is especially useful during initiation and after interruption:
    • Autoinduction may reduce exposure during continued therapy.
    • De-induction can occur after an interruption as short as 6 to 7 days and may increase toxicity when the prior dose is restarted.
  • Usual concentration range: 4 to 12 µg/mL.
  • Concentration-related adverse effects may appear above 8 µg/mL.
  • Renal dysfunction: No empiric dose adjustment, but consider monitoring carbamazepine-10,11-epoxide.

Cenobamate

  • Standard initiation: 12.5 mg once daily.
  • Increase every 2 weeks toward 200 mg/day. A maximum of 400 mg/day may be used if tolerated.
  • Antiseizure activity generally requires at least 50 mg/day, which is not reached until approximately week 6 with standard titration.
  • This slow titration limits acute ICU use.
  • DRESS generally appears 2 to 6 weeks after initial exposure.
  • Faster off-label initiation has been described in refractory SE, but ICU loading safety remains uncertain.
  • TDM is not routine because pharmacokinetics are relatively consistent and no validated target exists.
  • Phase 3 data cited in the supplied summary reported mean steady-state concentrations of 10.8 to 19.8 µg/mL among seizure-free patients.

Clobazam

  • Initiation: 5 to 10 mg once or twice daily.
  • Slowly titrate toward 40 to 80 mg/day because the half-life is 36 to 42 hours.
  • Reported SE dosing: 10 to 80 mg/day in divided doses.
  • ICU titration can begin at 10 mg/day and increase with each administration, but delayed somnolence can emerge because of accumulation.
  • Loading doses of 60 to 70 mg, approximately 1 mg/kg, have been reported but evidence is limited.
  • Renal and hepatic dysfunction: No routine adjustment in the supplied review.
  • CYP2C19 poor metabolizers require dose reduction because norclobazam can accumulate.
  • Strong CYP2C19 inhibitors such as cannabidiol may also increase norclobazam exposure.
  • TDM should include both compounds:
    • Clobazam: 30 to 300 ng/mL.
    • Norclobazam: 300 to 3,000 ng/mL.
  • A typical clobazam-to-norclobazam ratio is approximately 1:10.
  • The ratio does not predict efficacy, but an unusual ratio can suggest CYP2C19 poor metabolism. Norclobazam concentration may correlate with toxicity.

Oxcarbazepine

  • Initiation: 150 to 300 mg twice daily.
  • Increase by 300 to 600 mg/day each week to a maximum of 2,400 mg/day.
  • ICU titration may be faster. Two cohorts totaling 78 patients reported that a 30 mg/kg loading dose was tolerated.
  • Conversion from carbamazepine: A carbamazepine-to-oxcarbazepine ratio of approximately 1:1.5 has been used.
  • Severe renal dysfunction: Start at half the target dose and titrate more slowly because 10-hydroxycarbazepine (MHD) accumulates.
  • Hepatic dysfunction: No routine adjustment.
  • TDM is not routine. Consider it with suspected toxicity, older age, interactions, or severe renal dysfunction.
  • Proposed combined oxcarbazepine plus MHD trough range: 15 to 35 µg/mL.

Perampanel

  • Routine initiation: 2 to 4 mg at bedtime.
  • Weekly titration target: 6 to 12 mg/day.
  • Half-life: Approximately 105 hours.
  • Reported loading: 0.25 to 0.5 mg/kg, maximum 36 mg.
  • One SE cohort associated a higher initial dose with SE termination (odds ratio 1.27, 95% confidence interval 1.03 to 1.57).
  • Rapid ICU titration up to 32 mg/day has been reported, but safety documentation is limited.
  • Delayed adverse effects can include sedation and aggressive behavior.
  • Renal dysfunction: No routine adjustment.
  • Mild to moderate hepatic dysfunction: Reduce the initial and maximum dose.
  • Severe hepatic dysfunction: Avoid use.
  • Proposed concentration range: 200 to 600 ng/mL may balance efficacy and adverse effects, but this is not a validated ICU target.
  • Without loading, wait for steady state before measuring a concentration. This may require 2 to 3 weeks.

Topiramate

  • Routine initiation: 50 mg/day.
  • Increase weekly toward 200 to 400 mg/day in one or two divided doses.
  • Reported SE strategy: 400 mg loading followed by 100 to 200 mg twice daily.
  • Creatinine clearance below 70 mL/min/1.73 m2: Start at half the usual dose and titrate to tolerance.
  • Hepatic dysfunction: No routine adjustment in the supplied review.
  • Proposed concentration range: 5 to 20 mg/L.
  • TDM has a limited role because pharmacokinetics are generally predictable.

Zonisamide

  • Routine initiation: 100 mg/day.
  • Increase by 100 mg every 2 weeks toward 400 mg/day.
  • A 34-patient SE cohort used a 300 mg loading dose followed immediately by maintenance dosing without major reported adverse reactions.
  • Renal or hepatic dysfunction: No fixed adjustment in the supplied review, but lower initial doses and slower titration may be prudent.
  • Proposed concentration range: 10 to 40 mg/L.
  • TDM is not routinely required.

Lamotrigine

  • Initiate at 12.5 to 50 mg depending on interacting medications.
  • Increase weekly and reach 200 to 400 mg/day over 6 to 8 weeks.
  • Rapid titration increases the risk of Stevens-Johnson syndrome.
  • If therapy is interrupted for more than five half-lives, approximately 5 days, restart the initial titration schedule.
  • An 11-day rapid microinduction regimen produced rash in 15.1% of a 33-patient cohort, raising safety concerns.
  • Renal and hepatic dysfunction: No routine adjustment in the supplied review.
  • Proposed concentration range: 2.5 to 15 µg/mL.
  • TDM is most useful when the medication history is uncertain and clinicians must determine whether therapy was recently continued.

Cannabidiol

  • Routine initiation: 2.5 mg/kg twice daily.
  • Increase by 5 mg/kg/day each week toward 20 mg/kg/day.
  • Higher doses up to 50 mg/kg/day and faster titration have been reported.
  • Limited ICU SE experience:
    • Start at 5 to 10 mg/kg/day.
    • Titrate over 1 to 2 weeks toward 25 mg/kg/day.
    • Safety and efficacy remain uncertain.
  • Hepatic dysfunction: Reduce to approximately 4 to 10 mg/kg/day.
  • Renal dysfunction: No routine adjustment.
  • Pharmacokinetics are complex, bioavailability is low, and drug interactions are numerous.
  • A proposed concentration range of 47.1 to 157 ng/mL has not been validated and observed concentrations may be higher.
  • In a 100-patient outpatient cohort, responders and nonresponders had similar concentrations, although higher exposure showed a modest association with fewer seizures over 14 days.

Other ASMs to Remember

  • Gabapentin and pregabalin:
    • May be used for periodic or repetitive seizures.
    • Require adjustment in renal dysfunction and kidney replacement therapy.
  • Eslicarbazepine:
    • Similar considerations to oxcarbazepine.
    • Once-daily administration may be convenient.
  • Vigabatrin:
    • Irreversible GABA transaminase inhibitor used for refractory epilepsy.
    • Its role in post-anoxic SE is under investigation.
    • Requires adjustment in renal dysfunction or kidney replacement therapy.
  • Felbamate, stiripentol, rufinamide, tiagabine, and fenfluramine:
    • Have narrow indications.
    • In the ICU, they are most often encountered as continuation of a home regimen.

8. Dosing During Organ Support

Intermittent hemodialysis and CRRT

  • No routine adjustment reported for brivaracetam, cannabidiol, carbamazepine, cenobamate, clobazam, lamotrigine, or perampanel. Much of this guidance is based on expert opinion.
  • Phenytoin and valproate:
    • No routine dialysis adjustment.
    • Monitor free concentrations.
  • Lacosamide:
    • Hemodialysis: Give 50% of the maintenance dose after dialysis.
    • CRRT effluent below 2 L/hour: 50 to 200 mg every 12 hours.
    • CRRT effluent 2 to 3 L/hour: 50 to 200 mg every 8 to 12 hours.
    • CRRT effluent above 3 L/hour: 100 to 200 mg every 6 to 12 hours.
  • Levetiracetam:
    • Hemodialysis: Give 50% of the maintenance dose after dialysis, or use 250 to 750 mg every 12 hours as described in the review.
    • CRRT effluent below 2 L/hour: 250 to 1,000 mg every 12 hours.
    • CRRT effluent 2 to 3 L/hour: 500 to 1,250 mg every 12 hours.
    • CRRT effluent above 3 L/hour: 500 to 1,500 mg every 6 to 12 hours.
  • Oxcarbazepine:
    • Slow the titration rate.
    • No other routine adjustment reported.
  • Phenobarbital:
    • Hemodialysis: Give 50% of the maintenance dose after dialysis.
    • CRRT: Consider a higher initial maintenance dose of 2 to 3 mg/kg/day.
  • Topiramate and zonisamide:
    • Hemodialysis: Give 50% of the maintenance dose after dialysis.
    • CRRT: Consider starting at 25 to 50 mg every 12 hours and titrate to tolerance.
    • Approximate CRRT upper doses in the review: topiramate 200 mg every 12 hours and zonisamide 300 mg every 12 hours.

ECMO

  • Cannabidiol and carbamazepine may require higher doses based on limited data and expert opinion. Use TDM when possible.
  • No routine adjustment reported for clobazam, lacosamide, levetiracetam, oxcarbazepine, phenobarbital, topiramate, or zonisamide.

Plasma exchange

  • Administer carbamazepine and clobazam after PLEX when feasible.
  • No routine adjustment reported for cannabidiol or phenobarbital.

9. Formulation and Administration Pearls

Cannabidiol

  • Do not administer through a polyvinyl chloride (PVC) feeding tube because the formulation can harden and crack the tubing.
  • A non-PVC tube may be used.
  • The formulation contains no carbohydrate and should not disrupt ketosis.

Carbamazepine

  • Do not administer oral suspension simultaneously with other medications because precipitation may occur.
  • Extended-release capsules may be opened and sprinkled on soft food.
  • Intact beads may be administered through a sufficiently large-bore tube.

Cenobamate

  • The 12.5 mg strength is available only in prefilled titration packaging.
  • A 25 mg tablet may be split.

Clobazam and Lamotrigine

  • Clobazam oral film and lamotrigine orally disintegrating tablets are not absorbed through the buccal mucosa.
  • The dissolved medication and saliva must be swallowed for absorption.

Lacosamide

  • Maximum IV administration rate: 80 mg/minute.
  • IV-to-oral conversion: 1:1.

Oxcarbazepine

  • Compared with immediate-release dosing, the extended-release formulation produces approximately 19% lower peak and 16% lower trough concentrations.
  • A 1:1 conversion can be used, but the extended-release dose may need to be higher based on clinical response.

Perampanel

  • The IV formulation is available only in Japan according to the supplied review.
  • Infuse over at least 30 minutes.

Phenobarbital

  • IV formulation pH: 9.2 to 10.2.
  • It is incompatible with acidic medications such as midazolam.
  • The formulation contains propylene glycol. High doses may disrupt ketogenic therapy.
  • Undiluted high-dose administration may cause irritation.
  • Maximum IV bolus: 260 mg.
  • Infusion rate: 50 to 100 mg/minute.

Phenytoin and Fosphenytoin

  • Maximum phenytoin IV infusion rate: 50 mg/minute.
  • Maximum fosphenytoin infusion rate: 150 mg PE/minute.
  • Fosphenytoin may be administered intramuscularly.
  • For enteral phenytoin:
    • Hold tube feeding for 1 hour before administration.
    • Hold tube feeding for 1 hour after administration.
  • Products labeled as extended-release capsules do not use a true extended-release mechanism.
  • When converting from phenytoin sodium in capsules or IV solution to phenytoin base in suspension or chewable tablets, reduce the dose by approximately 8% to 10%.
  • IV phenytoin contains propylene glycol and may disrupt ketogenic therapy at high doses.
  • IV phenytoin can precipitate with multiple medications and dextrose-containing fluids.

Valproate

  • Maximum IV infusion rate: 500 mg/minute.
  • Total daily IV-to-oral conversion: 1:1.
  • Because IV therapy has no delayed absorption, divide the IV daily dose into three or four administrations.
  • Conversion between extended-release and delayed-release formulations: Approximately 1:0.8 to 0.9, depending on the direction of conversion.

General enteral principle

  • Do not crush or administer an extended-release formulation through a feeding tube unless product-specific information explicitly permits it.

10. Practical Bedside Framework

  • Step 1: Define the indication.
    • SE requires rapid loading and aggressive maintenance.
    • Prophylaxis usually uses the lower end of the dose range.
  • Step 2: Choose the agent.
    • Match spectrum, evidence, adverse-effect profile, and available route.
    • Avoid valproate in hepatic dysfunction.
    • Avoid initiating lamotrigine or cenobamate when rapid effect is required.
  • Step 3: Give an appropriate loading dose.
    • Base loading primarily on urgency and volume of distribution.
    • Do not reflexively reduce a necessary loading dose solely because maintenance clearance is reduced.
  • Step 4: Design maintenance therapy.
    • Account for kidney function, hepatic function, ARC, CRRT effluent rate, ECMO, PLEX, and dialysis schedule.
    • Use more frequent dosing when rapid renal clearance is expected.
  • Step 5: Confirm delivery.
    • Verify formulation compatibility, feeding-tube material, nutrition holds, infusion rate, and IV compatibility.
  • Step 6: Screen interactions.
    • Treat carbapenem plus valproate as a high-risk combination that usually requires avoidance rather than valproate dose escalation.
  • Step 7: Monitor response and toxicity.
    • Use electroencephalography and the clinical examination as appropriate.
    • Use TDM when it answers a specific clinical question.
    • Prefer free phenytoin and free valproate concentrations in critical illness.

11. Five Executive Takeaways from the Review

  • Critical illness changes ASM pharmacokinetics. Volume of distribution, organ dysfunction, ARC, CRRT, ECMO, and PLEX can all move exposure away from outpatient expectations.
  • Loading doses are essential in SE because they rapidly achieve exposure and address time-dependent pharmacodynamic resistance. ICU maintenance doses and titration rates may exceed outpatient labeling.
  • TDM is valuable but limited. Free phenytoin and free valproate concentrations are more informative than total concentrations, while most newer ASMs lack validated ICU concentration-response targets.
  • Drug interactions must be screened proactively. Carbapenems can reduce valproate concentrations by more than 70%, and increasing valproate usually does not solve the problem.
  • Evidence gaps remain substantial. Many ICU strategies are extrapolated from outpatient studies, small observational cohorts, pharmacokinetic modeling, or expert opinion.

12. Final Take-Home Message

  • Do not import outpatient ASM doses and titration schedules into the ICU without reassessment.
  • Treat SE early and aggressively with an appropriate loading dose.
  • Reduce maintenance exposure when clearance is impaired, but increase it when ARC or high-effluent CRRT causes excessive clearance.
  • Measure free phenytoin and free valproate when protein binding is altered.
  • Avoid carbapenem and valproate coadministration whenever possible.
  • Verify the formulation and route because administration details can determine whether the intended dose reaches the patient.
  • Apply individualized clinical judgment and close monitoring because the evidence base remains incomplete.

Educational summary based solely on the source material supplied by the user. It is not a substitute for local protocols, specialist consultation, product labeling, or patient-specific clinical judgment.

at

Management of Myocardial Infarction

Management of Myocardial Infarction

Clinical Management of Myocardial Infarction: High-Yield Lecture Notes

Source and Scope

  • Primary source: Landi A, Malik FTN, Chieffo A, Valgimigli M. Clinical Management of Myocardial Infarction. Circulation. 2026;154(11):1036-1051.
  • Online publication: September 14, 2026. Issue publication: September 15, 2026.
  • DOI: https://doi.org/10.1161/CIRCULATIONAHA.126.079317
  • Scope: Diagnosis, risk stratification, acute reperfusion, antithrombotic treatment, revascularization, cardiogenic shock, secondary prevention, and myocardial infarction with nonobstructive coronary arteries (MINOCA).
  • The review is a state-of-the-art synthesis, not a clinical practice guideline. Recommendations should be reconciled with current guidelines, local protocols, contraindications, and patient-specific ischemic and bleeding risks.

Important 2026 Terminology Update

  • The review describes the Fourth Universal Definition of Myocardial Infarction and its numeric types 1 through 5.
  • The Fifth Universal Definition of Myocardial Infarction was published in August 2026 and replaced the numeric system with 3 clinical categories:
    • Primary myocardial infarction: A spontaneous presentation caused by an acute coronary process, including atherothrombosis, spontaneous coronary artery dissection, embolism, vasospasm, or late stent or graft failure.
    • Secondary myocardial infarction: Acute ischemic myocardial injury caused by oxygen supply-demand imbalance from another acute condition.
    • Procedure-related myocardial infarction: Myocardial infarction occurring as a complication of a percutaneous or surgical cardiac procedure.
  • The older type 1, type 2, type 3, type 4, and type 5 labels remain common in prior literature and clinical communication, but learners should recognize that the current universal definition uses the newer clinical classification.

Core Clinical Takeaway

  • Modern myocardial infarction care follows a sequence:
    • Recognize ischemia rapidly and obtain an electrocardiogram (ECG).
    • Identify patients who require immediate reperfusion without waiting for biomarker confirmation.
    • Confirm acute myocardial injury with serial cardiac troponin and determine whether ischemia is present.
    • Identify the underlying mechanism because atherothrombotic, supply-demand, procedure-related, and nonobstructive presentations require different treatment.
    • Balance ischemic and bleeding risks when choosing antithrombotic intensity and duration.
    • Start secondary prevention before discharge and ensure early follow-up and cardiac rehabilitation.
  • The greatest remaining gaps are delayed reperfusion, high mortality from cardiogenic shock, incomplete implementation of secondary prevention, and imprecise diagnosis of occlusive myocardial infarction that does not meet classic ST-elevation criteria.

Pathophysiology and Diagnostic Framework

Atherothrombotic Myocardial Infarction

  • Plaque rupture or plaque erosion exposes tissue factor and subintimal material to circulating blood.
  • This activates coagulation and platelet aggregation, producing an intracoronary thrombus that may partially or completely obstruct flow.
  • Calcified nodules are another less common substrate for acute coronary thrombosis.
  • Not every troponin elevation represents myocardial infarction. Acute myocardial injury becomes myocardial infarction only when there is evidence of acute myocardial ischemia.

Diagnostic Criteria

  • Under the Fourth Universal Definition, acute myocardial infarction required:
    • A rise and/or fall in cardiac troponin, with at least 1 value above the 99th-percentile upper reference limit.
    • At least 1 feature of myocardial ischemia:
      • Ischemic symptoms.
      • New ischemic ECG changes.
      • New pathologic Q waves.
      • Imaging evidence of new loss of viable myocardium or a new regional wall-motion abnormality in an ischemic pattern.
      • Identification of a coronary thrombus by angiography, intracoronary imaging, or autopsy.
  • Serial high-sensitivity cardiac troponin should be interpreted with the clinical context, timing of symptoms, assay-specific thresholds, ECG findings, and alternative causes of myocardial injury.
  • Common nonischemic causes of troponin elevation include myocarditis, heart failure, pulmonary embolism, renal dysfunction, tachyarrhythmia, critical illness, and sepsis.

ECG First, Troponin Second

  • Obtain and interpret the ECG immediately in suspected acute coronary syndrome.
  • Persistent ST-segment elevation or an equivalent high-risk occlusion pattern should trigger an immediate reperfusion pathway.
  • Absence of classic ST-segment elevation does not exclude acute coronary occlusion.
  • Repeat ECGs, posterior leads, right-sided leads, bedside echocardiography, and urgent cardiology review may be necessary when symptoms persist or the initial ECG is nondiagnostic.
  • The occlusive myocardial infarction (OMI) framework highlights patients with acute coronary occlusion who do not meet traditional ST-elevation myocardial infarction (STEMI) criteria. OMI is an emerging diagnostic concept and has not replaced guideline-based STEMI and non-ST-segment elevation myocardial infarction (NSTEMI) pathways.

Historical Numeric Classification

  • Type 1 myocardial infarction:
    • Spontaneous atherothrombotic infarction caused by plaque rupture, erosion, or a calcified nodule.
    • Typical management includes coronary angiography when appropriate, revascularization, dual antiplatelet therapy (DAPT), acute anticoagulation, and secondary prevention.
  • Type 2 myocardial infarction:
    • Ischemic injury caused by oxygen supply-demand imbalance from conditions such as anemia, hypoxemia, hypotension, sepsis, severe hypertension, or tachyarrhythmia.
    • Treat the precipitating condition and reassess for underlying coronary disease. Automatic activation of an atherothrombotic treatment pathway may expose patients to harm when acute coronary thrombosis is absent.
  • Type 3 myocardial infarction:
    • Cardiac death with symptoms or ECG evidence suggesting ischemia before cardiac biomarkers can be obtained or before they become abnormal.
  • Type 4 myocardial infarction:
    • Related to percutaneous coronary intervention, stent thrombosis, or restenosis under the Fourth Universal Definition.
  • Type 5 myocardial infarction:
    • Related to coronary artery bypass grafting under the Fourth Universal Definition.
  • High-sensitivity troponin assays increased recognition of acute myocardial injury and secondary myocardial infarction while making true unstable angina less common.

Risk Stratification

Why Risk Stratification Matters

  • Estimate short-term mortality and recurrent ischemic risk.
  • Identify patients who may benefit from closer monitoring or earlier invasive management.
  • Estimate bleeding risk before selecting antithrombotic intensity and duration.
  • Risk scores supplement rather than replace clinical judgment, hemodynamic assessment, ECG interpretation, frailty assessment, and evaluation of comorbid disease.

Ischemic Risk Tools

  • Global Registry of Acute Coronary Events (GRACE) score:
    • Uses age, Killip class, systolic blood pressure, heart rate, ST-segment deviation, cardiac arrest at presentation, serum creatinine, and cardiac biomarkers.
    • A GRACE score greater than 140 identifies a high-risk group frequently used in trials and guidelines when considering invasive timing.
  • Thrombolysis in Myocardial Infarction (TIMI) score for unstable angina or NSTEMI:
    • Includes age 65 years or older, at least 3 coronary risk factors, known coronary stenosis of at least 50%, ST-segment deviation, at least 2 anginal episodes in 24 hours, aspirin use within 7 days, and elevated cardiac biomarkers.
    • Predicts 14-day risk of death, myocardial infarction, or urgent revascularization.
  • TIMI score for STEMI:
    • Estimates 30-day mortality using readily available clinical variables.

Bleeding Risk Tools

  • PRECISE-DAPT uses age, creatinine clearance, hemoglobin, white blood cell count, and previous spontaneous bleeding.
  • A PRECISE-DAPT score of at least 25 indicates high bleeding risk, but its meaning depends on the population and treatment context.
  • Academic Research Consortium High Bleeding Risk (ARC-HBR) criteria define high bleeding risk as at least 1 major criterion or at least 2 minor criteria.
  • Major ARC-HBR examples include:
    • Long-term oral anticoagulation.
    • Severe or end-stage chronic kidney disease.
    • Hemoglobin below 11 g/dL.
    • Recent serious spontaneous bleeding.
    • Moderate or severe thrombocytopenia.
    • Cirrhosis with portal hypertension.
    • Active malignancy.
    • Previous spontaneous intracranial hemorrhage.
    • Recent major ischemic stroke.
    • Nondeferrable major surgery during DAPT.
  • Minor ARC-HBR examples include age at least 75 years, moderate chronic kidney disease, mild anemia, remote spontaneous bleeding, chronic steroid or nonsteroidal anti-inflammatory drug use, and previous ischemic stroke not meeting a major criterion.

High Ischemic Risk After PCI

  • Clinical enhancers include medically treated diabetes, recurrent myocardial infarction, multivessel coronary disease, premature or rapidly progressive disease, systemic inflammatory disease, polyvascular disease, and chronic kidney disease.
  • Procedural enhancers include treatment of multiple lesions, implantation of multiple stents, long total stent length, left main intervention, complex bifurcation intervention, chronic total occlusion, last remaining vessel intervention, and previous stent thrombosis during antiplatelet therapy.
  • Practical implementation remains poor. Automated risk calculation linked to specific treatment choices may improve uptake, but prospective evidence that automation improves outcomes is still needed.

STEMI: Reperfusion Is the Priority

Primary Percutaneous Coronary Intervention

  • Primary percutaneous coronary intervention (PCI) is the preferred reperfusion strategy when it can be performed promptly by an experienced team.
  • For patients presenting within 12 hours of symptom onset, immediate reperfusion is a Class I recommendation.
  • Selected patients presenting 12 to 24 hours after symptom onset may still benefit from primary PCI, particularly when symptoms or ischemia persist.
  • Patients with ongoing ischemia, hemodynamic instability, life-threatening arrhythmia, or cardiogenic shock require urgent invasive evaluation regardless of delay from symptom onset.

Fibrinolysis and the Pharmaco-Invasive Strategy

  • If primary PCI cannot be achieved within the guideline time target, generally 120 minutes from first medical contact, and there is no contraindication, administer fibrinolysis as early as possible in an eligible patient presenting within 12 hours.
  • Transfer the patient immediately to a PCI-capable center after fibrinolysis.
  • Suspect failed fibrinolysis when ST-segment resolution is less than 50% at 60 to 90 minutes, or when pain, instability, or arrhythmia persists.
  • Failed fibrinolysis requires urgent angiography and rescue PCI.
  • Even after successful fibrinolysis, routine angiography with possible PCI is recommended within 2 to 24 hours.

Procedural Strategy

  • Radial access is preferred over femoral access in most patients because it reduces major bleeding, vascular complications, and mortality.
  • Slow flow and no-reflow may persist despite opening the epicardial artery because of distal embolization, microvascular obstruction, reperfusion injury, edema, and vasoconstriction.
  • Routine manual thrombus aspiration is not recommended. Newer thrombectomy systems and real-time detection methods remain investigational.

Myocardial Infarction With Cardiogenic Shock

  • Cardiogenic shock remains a major cause of early mortality after myocardial infarction.
  • Immediate revascularization of the infarct-related artery is essential.
  • In multivessel disease with shock, the initial PCI strategy should generally treat the culprit vessel only. Routine immediate PCI of nonculprit vessels increased harm in CULPRIT-SHOCK.
  • Intra-aortic balloon pump:
    • Routine use does not improve survival in myocardial infarction-related cardiogenic shock.
    • It may still have selected roles, such as mechanical complications or individualized hemodynamic support.
  • Venoarterial extracorporeal membrane oxygenation:
    • ECLS-SHOCK did not reduce 30-day mortality with routine early use.
    • Bleeding and peripheral vascular complications increased.
    • These data argue against unselected routine use, not against carefully selected rescue use in experienced shock systems.
  • Percutaneous microaxial flow pump:
    • DanGer-Shock randomized 360 patients with STEMI-related cardiogenic shock.
    • Impella CP reduced 180-day all-cause mortality compared with standard care, but serious adverse events were more frequent.
    • The trial used restrictive eligibility criteria. The result supports protocolized selection rather than indiscriminate device placement.
  • Shock care should include rapid identification of mechanical complications, serial perfusion assessment, echocardiography, invasive hemodynamics when useful, and early multidisciplinary shock-team involvement.

Acute Antiplatelet and Anticoagulant Therapy

STEMI Undergoing PCI

  • DAPT consists of aspirin plus an oral P2Y12 inhibitor.
  • Ticagrelor or prasugrel is generally preferred over clopidogrel for patients undergoing PCI when bleeding risk is acceptable and no contraindication is present.
  • Prasugrel is contraindicated in patients with previous stroke or transient ischemic attack.
  • Clopidogrel remains appropriate when potent P2Y12 inhibition is contraindicated, unavailable, or not tolerated, and it is used with fibrinolytic therapy.
  • CELEBRATE evaluated subcutaneous zalunfiban at first medical contact in STEMI:
    • Zalunfiban improved a hierarchical 30-day composite outcome and pre-PCI infarct-related artery flow.
    • Severe or life-threatening bleeding was not significantly increased, but mild to moderate bleeding increased.
    • Zalunfiban remains an emerging strategy rather than routine standard care.
  • PCI anticoagulant options include unfractionated heparin, bivalirudin, and enoxaparin.
  • Parenteral anticoagulation should usually stop after successful PCI unless another indication exists. A protocolized post-PCI bivalirudin infusion is a specific exception when that strategy is selected.

NSTE-ACS

  • Routine oral P2Y12 pretreatment before defining coronary anatomy is not recommended when early angiography is planned because ischemic benefit is uncertain and bleeding or surgical delay may increase.
  • Pretreatment has not completely disappeared:
    • The 2025 US guideline states that clopidogrel or ticagrelor may be considered when angiography is expected to occur more than 24 hours after presentation.
    • Decisions should reflect bleeding risk, diagnostic certainty, and the probability of urgent coronary artery bypass grafting.
  • Anticoagulant options include unfractionated heparin, enoxaparin, fondaparinux, and bivalirudin.
  • When an invasive strategy will be delayed beyond 24 hours, fondaparinux or enoxaparin may be preferred over unfractionated heparin.
  • If a patient receiving fondaparinux proceeds to PCI, additional unfractionated heparin is required during the procedure to reduce catheter thrombosis.
  • Stop parenteral anticoagulation after revascularization unless another indication remains.

Complete Revascularization

  • Approximately half of patients with myocardial infarction have multivessel coronary disease.
  • In hemodynamically stable STEMI with multivessel disease, complete revascularization reduces major adverse cardiovascular events, particularly spontaneous myocardial infarction and unplanned revascularization.
  • A consistent isolated mortality benefit has not been established across all trials, so the benefit should not be summarized simply as a reduction in death.
  • Immediate versus staged treatment remains individualized:
    • BIOVASC and MULTISTARS AMI supported immediate complete revascularization as noninferior to staged treatment in selected patients.
    • OPTION-STEMI did not demonstrate noninferiority of immediate complete revascularization.
    • Differences in enrolled populations, clinical stability, lesion complexity, and outcome definitions limit direct comparison.
  • Angiographic severity, intracoronary imaging, and physiologic assessment can each inform treatment. The optimal guidance strategy is not settled for every acute myocardial infarction population.
  • In cardiogenic shock, do not extrapolate stable-patient complete revascularization data to justify routine immediate multivessel PCI.

NSTEMI: Invasive Timing Should Be Individualized

  • Immediate invasive management is indicated for hemodynamic instability, ongoing or recurrent refractory ischemia, life-threatening arrhythmia, or mechanical complications.
  • For other patients, trials comparing early and delayed angiography have not shown a consistent overall mortality or major adverse cardiovascular event benefit from an early strategy.
  • A GRACE score greater than 140 has shown a survival signal with earlier invasive treatment in subgroup analyses. This signal supports risk-based prioritization but is not proof that a single score should determine timing in isolation.
  • Contemporary interpretation is limited by older trial eras, mixed unstable angina and NSTEMI populations, variable definitions of early and delayed intervention, and differences in antiplatelet exposure.
  • Older adults:
    • A routine invasive strategy may reduce recurrent myocardial infarction or urgent revascularization without clearly reducing mortality.
    • Frailty, cognition, comorbidity, functional status, bleeding risk, life expectancy, and patient goals should be assessed explicitly.
  • Low-risk patients with uncertain NSTE-ACS may undergo selective invasive evaluation after coronary computed tomography angiography or functional testing when clinically appropriate.

Inpatient Level of Care and Transition to Discharge

  • Non-high-risk NSTE-ACS may be managed in an intermediate-care setting with continuous rhythm monitoring.
  • STEMI and high-risk NSTE-ACS require a higher-acuity setting when there is recurrent ischemia, malignant arrhythmia, cardiogenic shock, resuscitated cardiac arrest with coma, heart failure requiring ventilation, or acute kidney injury requiring renal replacement therapy.
  • Shorter hospital stays make discharge planning part of acute care rather than a final-day task.
  • Before discharge:
    • Document left ventricular ejection fraction.
    • Reconcile antithrombotic indications, duration, dose, interactions, and bleeding precautions.
    • Start intensive lipid-lowering therapy.
    • Address smoking and substance use.
    • Refer to cardiac rehabilitation.
    • Arrange early follow-up and repeat laboratory testing when needed.
    • Provide clear instructions for recurrent chest pain, dyspnea, syncope, bleeding, and medication intolerance.

Secondary Prevention

Cardiac Rehabilitation and Lifestyle

  • Cardiac rehabilitation should begin early after the acute event.
  • A comprehensive program includes exercise training, nutrition counseling, psychosocial support, medication adherence, smoking cessation, and risk-factor management.
  • Participation reduces cardiovascular hospitalization and may reduce recurrent myocardial infarction and cardiovascular mortality.
  • Return to exercise, work, and sexual activity should be individualized according to ventricular function, residual ischemia, arrhythmia, functional capacity, and the physical demands of the activity.
  • Cocaine and other stimulants are established triggers for myocardial infarction. Cannabis exposure is associated with cardiovascular risk in observational data, but causal estimates and dose-response relationships remain less certain.

Antithrombotic Therapy After Discharge

  • For patients with acute coronary syndrome who are not at high bleeding risk, the 2025 US guideline still recommends DAPT for at least 12 months as the default strategy.
  • Ticagrelor monotherapy after abbreviated DAPT is an evidence-based alternative after PCI:
    • In patients who have tolerated ticagrelor-based DAPT, transition to ticagrelor monotherapy at least 1 month after PCI is a Class I, Level A strategy to reduce bleeding.
    • This recommendation does not mean that 12-month DAPT is obsolete.
  • Other de-escalation strategies, including switching to clopidogrel after 1 month or using single antiplatelet therapy after 1 month in high bleeding risk, have weaker or more conditional recommendations.
  • Patients requiring long-term oral anticoagulation after PCI:
    • Keep triple therapy as short as possible, commonly 1 to 4 weeks depending on ischemic and bleeding risk.
    • Continue oral anticoagulation plus a single P2Y12 inhibitor, preferably clopidogrel, for the selected dual-therapy period.
    • Beyond 12 months, oral anticoagulation alone is appropriate for many stable patients, but the plan must be individualized.
  • Long-term single antiplatelet therapy:
    • Randomized trials and meta-analyses increasingly suggest that clopidogrel may reduce ischemic events compared with aspirin after successful completion of DAPT.
    • Most supporting trials enrolled post-PCI populations, and several were conducted largely in East Asian cohorts.
    • Clopidogrel should be viewed as an increasingly supported option, not a universal guideline-mandated replacement for aspirin in every patient with previous myocardial infarction.

Lipid Lowering

  • Start a high-intensity statin in all eligible patients with myocardial infarction.
  • Check baseline and follow-up low-density lipoprotein cholesterol (LDL-C), adherence, and tolerance.
  • Add nonstatin therapy early when the expected statin response will not achieve the treatment goal.
  • Options include ezetimibe, a proprotein convertase subtilisin/kexin type 9 inhibitor, and bempedoic acid.
  • Initiating ezetimibe during the index hospitalization is reasonable in very-high-risk patients or when baseline LDL-C makes goal attainment with statin monotherapy unlikely.
  • The exact LDL-C goal depends on the governing guideline. The operational principle is early, intensive, and sustained lowering rather than slow sequential escalation over many months.

Beta Blockers

  • Continue beta blockers when there is a clear indication such as reduced left ventricular ejection fraction, heart failure, angina, arrhythmia, or hypertension.
  • Preserved ejection fraction:
    • An individual-patient data meta-analysis of 5 randomized trials and 17,801 patients with ejection fraction at least 50% found no reduction in death, recurrent myocardial infarction, or heart failure.
  • Mildly reduced ejection fraction:
    • An individual-patient data meta-analysis of 4 randomized trials and 1,885 patients with ejection fraction 40% to 49% found a lower composite risk of death, recurrent myocardial infarction, or heart failure with beta-blocker therapy.
  • Long-term discontinuation:
    • SMART-DECISION found discontinuation noninferior to continuation in selected stable patients at least 1 year after myocardial infarction, with ejection fraction at least 40% and no heart failure.
    • ABYSS did not establish noninferiority of interruption in a different population and used a broader cardiovascular hospitalization endpoint.
  • Practical interpretation:
    • Reduced ejection fraction or another indication: Treat.
    • Ejection fraction 40% to 49%: Current randomized evidence supports treatment, although guideline integration continues to evolve.
    • Ejection fraction at least 50% without another indication: Routine indefinite treatment has no demonstrated prognostic benefit and should be reassessed rather than continued automatically.

SGLT2 Inhibitors

  • Sodium-glucose cotransporter 2 inhibitors have established indications in heart failure, chronic kidney disease, and type 2 diabetes with appropriate cardiovascular or renal risk.
  • DAPA-MI and EMPACT-MI did not establish a routine hard-outcome indication solely for uncomplicated myocardial infarction without diabetes, chronic kidney disease, or heart failure.
  • Use an SGLT2 inhibitor for a proven comorbid indication, not simply because myocardial infarction occurred.

Renin-Angiotensin-Aldosterone System Therapy

  • Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are strongly indicated after myocardial infarction when there is left ventricular systolic dysfunction, heart failure, hypertension, diabetes, or chronic kidney disease, unless contraindicated.
  • Mineralocorticoid receptor antagonists have an established post-myocardial infarction role in selected patients with left ventricular dysfunction plus heart failure or diabetes, with careful monitoring of potassium and renal function.
  • CLEAR did not show that routine spironolactone improves its coprimary clinical outcomes in an unselected contemporary myocardial infarction population.
  • Later meta-analyses have produced conflicting conclusions about broader use. Routine mineralocorticoid receptor antagonist therapy for all myocardial infarction survivors is therefore not established.

Anti-Inflammatory Therapy

  • Low-dose colchicine has reduced ischemic events in some coronary disease trials, including COLCOT, but results are inconsistent.
  • CLEAR randomized 7,062 patients after myocardial infarction and found no reduction in cardiovascular death, recurrent myocardial infarction, stroke, or ischemia-driven revascularization.
  • Meta-analyses that combine heterogeneous acute and chronic coronary populations may show benefit, but they do not erase the neutral result of the largest acute myocardial infarction trial.
  • Colchicine remains an optional, selective therapy rather than routine treatment for every patient after myocardial infarction.
  • Canakinumab reduced recurrent cardiovascular events in CANTOS but increased fatal infection and has not become routine post-myocardial infarction therapy.
  • Interleukin-1 and interleukin-6 pathway therapies remain investigational. ARTEMIS is evaluating ziltivekimab after acute coronary syndrome.
  • High-sensitivity C-reactive protein identifies residual inflammatory risk, but evidence is insufficient to mandate routine serial testing or to assign a specific anti-inflammatory drug solely from the result.

MINOCA: A Working Diagnosis, Not Reassurance

Definition

  • MINOCA requires:
    • Fulfillment of myocardial infarction criteria.
    • No coronary stenosis of 50% or greater in a major epicardial vessel at angiography.
    • No immediately apparent alternative explanation for the presentation.
  • Troponin elevation plus symptoms alone is not sufficient.
  • Myocarditis, takotsubo syndrome, pulmonary embolism, and other nonischemic conditions may initially mimic MINOCA and should be actively investigated.

Diagnostic Strategy

  • Reassess the angiogram for missed distal occlusion, embolism, spontaneous coronary artery dissection, or subtle plaque disruption.
  • Cardiac magnetic resonance imaging should be performed early when feasible because diagnostic yield decreases over time.
  • Intravascular ultrasound or optical coherence tomography may identify plaque rupture, plaque erosion, thrombus, or spontaneous coronary artery dissection.
  • Coronary function testing may identify epicardial spasm or coronary microvascular dysfunction.
  • Echocardiography and targeted evaluation for embolic sources, thrombophilia, arrhythmia, and structural heart disease should be guided by the clinical presentation.

Mechanism-Directed Treatment

  • Plaque disruption:
    • Treat as atherosclerotic myocardial infarction with antiplatelet therapy and intensive lipid lowering. PCI is reserved for an appropriate target lesion.
  • Coronary thromboembolism:
    • Search for atrial fibrillation, left ventricular thrombus, valve disease, endocarditis, tumor, paradoxical embolism, and selected thrombophilias.
    • Choose antiplatelet or anticoagulant therapy according to the confirmed mechanism.
  • Spontaneous coronary artery dissection:
    • Conservative management is preferred when the patient is stable and flow is preserved.
    • Use antiplatelet therapy selectively and consider beta-blockade. Avoid unnecessary PCI because intervention is technically difficult and may extend the dissection.
  • Epicardial coronary spasm:
    • Calcium channel blockers are first-line therapy.
    • Nitrates may be added for symptoms.
    • Provocative acetylcholine testing should be performed in experienced centers.
  • Coronary microvascular dysfunction:
    • Treatment is individualized and may include beta blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, statins, and antianginal therapy.
  • Reported frequencies of MINOCA mechanisms vary widely by population, geography, testing strategy, and timing. Percentages from different studies should not be treated as mutually exclusive or universally applicable.
  • PROMISE supports the concept that a mechanism-directed diagnostic and treatment strategy can improve angina status, but large randomized trials powered for major clinical events remain limited.

Emerging Directions

  • Artificial intelligence-assisted ECG interpretation may improve detection of acute coronary occlusion that does not meet traditional STEMI criteria.
  • TITAN-OMI and DIFOCCULT-3 are evaluating whether AI-assisted OMI recognition improves clinical outcomes. Until outcome data are available, AI should support rather than replace expert ECG interpretation and clinical judgment.
  • Parenteral antiplatelet treatment before PCI is being revisited:
    • Zalunfiban is administered by a clinician at first medical contact.
    • Selatogrel is being studied as patient self-administration after recurrent symptoms in patients with previous myocardial infarction.
  • The central challenge is not only developing new drugs or devices. Systems must also reduce first-medical-contact-to-reperfusion delay and reliably deliver proven secondary prevention.

Practical Myocardial Infarction Checklist

First Minutes

  • Obtain and interpret a 12-lead ECG immediately.
  • Repeat the ECG and obtain posterior or right-sided leads when indicated.
  • Assess airway, breathing, circulation, perfusion, arrhythmia, and heart failure.
  • Activate reperfusion immediately for STEMI or a convincing occlusion pattern.
  • Draw serial high-sensitivity troponin without delaying reperfusion when the ECG already establishes the need.

Acute Treatment

  • Give aspirin unless contraindicated.
  • Select P2Y12 inhibition according to reperfusion strategy, bleeding risk, stroke history, oral anticoagulation, and likelihood of coronary artery bypass grafting.
  • Choose anticoagulation according to STEMI or NSTE-ACS strategy and expected timing of angiography.
  • Prefer radial access for PCI when feasible.
  • In shock, revascularize the culprit artery and avoid routine immediate nonculprit PCI.

Before Discharge

  • Confirm the mechanism of myocardial infarction rather than relying only on the STEMI or NSTEMI label.
  • Document left ventricular function and heart failure status.
  • Write an explicit antithrombotic plan with start date, stop date, and reasons.
  • Start high-intensity statin therapy and add early nonstatin treatment when needed.
  • Reassess the need for beta blockers, renin-angiotensin system therapy, mineralocorticoid receptor antagonists, and SGLT2 inhibitors according to ejection fraction and comorbid indications.
  • Refer to cardiac rehabilitation and arrange early follow-up.

Final Take-Home Points

  • ECG determines urgency, while serial troponin and clinical evidence determine whether acute myocardial injury is myocardial infarction.
  • Acute coronary occlusion may occur without classic ST-segment elevation. Persistent ischemic symptoms with a nondiagnostic ECG require repeated and expanded assessment.
  • STEMI care is a race to reperfusion. Use primary PCI when timely; otherwise use fibrinolysis followed by immediate transfer and a pharmaco-invasive strategy in eligible patients.
  • Cardiogenic shock requires culprit-vessel revascularization and selective, protocolized use of mechanical support rather than routine device placement.
  • Complete revascularization benefits stable multivessel disease, but the timing and method of lesion selection remain individualized.
  • For NSTEMI, invasive timing depends on instability, recurrent ischemia, overall risk, frailty, and the expected delay to angiography. Earlier is not automatically better for every stable patient.
  • Twelve-month DAPT remains the default for patients without high bleeding risk. Ticagrelor monotherapy after at least 1 month is a validated bleeding-reduction option after PCI, not a universal replacement for standard DAPT.
  • Long-term beta-blocker benefit depends strongly on left ventricular ejection fraction and other indications.
  • MINOCA is a working diagnosis that requires cardiac magnetic resonance imaging, careful angiographic review, intracoronary imaging, and/or coronary function testing to identify a treatable mechanism.
  • Secondary prevention should begin during the index hospitalization and should be treated with the same urgency as reperfusion.

Selected References

Educational summary. Confirm current guidelines, contraindications, dosing, renal function, bleeding risk, and local reperfusion protocols before clinical use.

at
Subscribe to: Posts (Atom)

Diabetic Ketoacidosis Management

Diabetic Ketoacidosis: Treat Ketones, Not Just Glucose Diabetic Ketoacidosis: Treat Ketones, Not Just Glucose Diagnostic...

  • Preexcited Atrial Fibrillation
    Preexcited Atrial Fibrillation Lecture Notes Preexcited Atrial Fibrillation Definition and Mechanism Preexcited a...
  • Ketamine vs Etomidate
    Induction Agents: Ketamine vs Etomidate Induction Agents: Ketamine vs Etomidate Core Clinical Message Neither ke...
  • Hydrocortisone in CAP
    Hydrocortisone in Severe Community-Acquired Pneumonia (CAP) - Lecture Notes Hydrocortisone in Severe Community-Acquired Pneumo...