Pharmacologic considerations in the management of acute coronary syndrome in elderly patients

KEYWORDS:

• Acute coronary syndrome (ACS)
• antiplatelets
• elderly
• fibrinolytics
• pharmacotherapy

1. Introduction

Despite having a high prevalence of acute coronary syndromes (ACS) and higher ACS related mortality rates than younger patients, elderly patients are often underrepresented in ACS clinical trials. Elderly patients are not a homogenous group. Some patients >75 years are frail, have several comorbid conditions, and may not tolerate aggressive pharmacotherapy. Other patients in this age group are otherwise healthy and fully functional. Pathophysiologic changes associated with aging alter the pharmacokinetic and pharmacodynamic responses to certain drugs [1], necessitating special considerations and individualization of pharmacotherapy (Table 1) in the elderly [1–14].

Table 1. Drug-specific considerations for elderly patients [1–14].

Drug	Renal Dose Adjustments	Special Considerations in the Elderly
Fibrinolytics
Tenecteplase		Age ≥75 years: with invasive strategy reduce dose by 50% More fibrin-specific agents preferred in elderly due to reduced risk of bleeding
Alteplase		Increased risk of bleeding versus tenecteplase in the elderly
Anticoagulants
Unfractionated Heparin		Can be used in severe renal impairment Lower doses may be required for older patients
Low Molecular Weight Heparin	CrCl <30 mL/min: reduce frequency to 1 mg/kg once daily	May be more effective than UFH in elderly patients with adequate renal function Age ≥ 75 years: reduce dose to 0.75 mg/kg b.i.d.; avoid 30-mg IV bolus with fibrinolysis
Fondaparinux	CrCl 30 to 50 mL/minute: use with caution CrCl <30 mL/minute: contraindicated	Increased bleeding risk in age ≥75 years, renal impairment and low body weight <50 kg
Bivalirudin	CrCl 30 to 59 mL/minute: reduce infusion rate to 1.4 mg/kg/hour CrCl <30 mL/minute: avoid use	Improved safety profile over UFH + GP 2b/3a inhibitors in patients ≥75 years
P2Y12 Inhibitors
Clopidogrel		Age ≥75 years: no loading dose with fibrinolysis for STEMI
Prasugrel		Age ≥75 years: use not recommended; may be considered in high-risk situations (patients with diabetes or history of MI)● 5mg daily dose EMA approved for patients ≥75 years if use is necessary Caution patients <60 kg due to increase bleeding risk
Ticagrelor		BID dosing regimen; consider compliance in elderly patients
Glycoprotein IIb/IIIa Inhibitors
Abciximab		Preferred in renal impairment Increased bleeding risk
Eptifibatide	CrCl 30 to 50 mL/min: reduce infusion dose by 50% CrCl <30 mL/min: contraindicated	Increased bleeding risk
Tirofiban	CrCl ≤30 mL/min: reduce dose by 50%	Increased bleeding risk
Post-ACS Pharmacotherapy
Beta-Blockers	Avoid atenolol in renal impairment	Increased risk of orthostatic hypotension Potential increased risk of CNS side effects with lipophilic beta-blockers (bisoprolol, carvedilol, metoprolol, propranolol)
Statins		Potentially no benefit of high-intensity over moderate intensity statins Start at low doses and titrate slowly Hydrophilic statins (pravastatin, rosuvastatin) may decrease risk of myalgias
ACE Inhibitors	Avoid use in renal impairment	Increased risk of hyperkalemia in elderly patients with renal dysfunction Increased risk of orthostatic hypotension

ACE = angiotensin converting enzyme; BID = twice daily; CNS = central nervous system; CrCl = creatinine clearance; EMA = European Medicines Agency; IV = intravenous; kg = kilogram; mg = milligram; MI = myocardial infarction; Min = minute; mL = milliliter; STEMI = ST-segment elevation myocardial infarction; UFH = unfractionated heparin

2. Acute treatment of ACS

ACS guidelines recommend primary percutaneous coronary intervention [PPCI] or fibrinolytic strategy over less aggressive strategies regardless of age, with PPCI preferred over thrombolytic reperfusion [2–5]. PPCI provides increased rates of perfusion, decreased need for subsequent reperfusion procedures and decrease risk of bleeding compared to fibrinolysis. Age >75 years and reduced baseline renal function are risk factors for radiocontrast-induced nephropathy associated with coronary angiography. Mitigating strategies such as hydration and use of lower osmolarity contrast agents in the smallest amount necessary reduce the risk of nephrotoxicity [6].

The balance of benefits and risks of fibrinolytic therapy in the elderly is unclear due to the exclusion of patients ≥75 years in most thrombolytic studies. However, given that patient and myocardial survival in ACS goes down exponentially over time, fibrinolytic therapy should not be withheld due to age alone. If fibrinolytics are utilized, contraindications and precautions for fibrinolytics are more common in the elderly and need to be elucidated. Low body weight, elevated diastolic blood pressure and recent head trauma are associated with an increased rate of fibrinolytic induced intracranial hemorrhage (ICH) [7].

Tenecteplase and alteplase are the most commonly used fibrinolytics in the setting of ACS. In head-to-head comparisons, tenecteplase was associated with lower rates of ICH compared to alteplase in patients ≥ 75 years of age [8]. Additionally, data from the Strategic Reperfusion Early after Myocardial Infarction (STREAM) study support age adjusted dosing for tenecteplase [9]. A protocol amendment in the STREAM study reduced the dose of tenecteplase by 50% in patients > 75 years of age and led to a significant reduction in ICH events with no significant changes in efficacy [9]. This dosing strategy was adopted into the most recent European guidelines [5].

Antithrombotic regimens are utilized in medical management of ACS and play a large role in reducing the risk of major bleeding in elderly patients undergoing invasive treatment strategies with PCI. Precise weight-based dosing and assessment of renal function are important factors in the management of anticoagulants in elderly ACS patients. Most of these agents are renally excreted, which could lead to overdosing and accumulation in elderly patients with declining renal function. Enoxaparin, fondaparinux and bivalirudin each require renal dose adjustments. Unfractionated heparin (UFH) however, is not renally excreted and is titrated to a prespecified level of anticoagulation so it may be the preferred agent in ACS in patients with renal dysfunction [10]. It is also important to consider the setting in which these agents are used, as the recommended dosing regimens differ in the setting of concomitant fibrinolytic administration or PCI. The Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction (ExTRACT)-Thrombolysis in Myocardial Infarction (TIMI) 25 study showed similar rates of bleeding and superior efficacy in patients ≥ 75 years old compared to UFH using enoxaparin dose adjusted for age and renal function [11]. In the setting of concomitant fibrinolytic therapy it is recommended to forgo the initial bolus dose of enoxaparin as well as reduce the dose of enoxaparin in patients ≥ 75 years old [10].

Aspirin is recommended in the acute setting for all patients irrespective of age and concomitant therapy. In patients ≥ 65 years of age it is recommended to administer a proton pump inhibitor in the setting of dual antiplatelet administration to reduce the risk of gastrointestinal bleed [10].

In a substudy of the PLATelet inhibition and patient Outcomes (PLATO) trial, ticagrelor was shown to maintain the significant clinical benefit without an increased risk of major bleeding compared to clopidogrel in patients >75 years of age [12]. Prasugrel contains a black box warning for the use in patients ≥75 years of age and in patients < 60 kg due to a higher risk of bleeding. However, prasugrel may have efficacy advantages in patients with diabetes or prior myocardial infarction that are more common in the elderly. The European Medicines Agency approved a 5 mg daily dose of prasugrel for patients ≥ 75 years of age. This is based largely on a pharmacokinetic substudy of the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction (TRITON–TIMI) 38, which showed a significantly higher concentration of the active metabolite in patients ≥ 75 years old [13]. Clopidogrel is the only P2Y12 inhibitor recommended in the setting of concomitant fibrinolytic use but patients ≥ 75 years should not receive the loading dose [5].

Strong caution is advised for patients ≥ 70 years old receiving Glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors given the increased risk of life-threatening bleeding and uncertain and potentially unfavorable net benefit. It is recommended that GPIIb/IIIa inhibitor use be restricted, and that preventative measures (transradial approach, proton pump inhibition, limited duration of administration) be taken [10]. Abciximab may be the preferred agent in elderly patients with renal dysfunction as eptifibatide and tirofiban are renally excreted and require dose adjustments and avoidance in severe renal dysfunction.

3. Long-term pharmacotherapy

Age related changes may play an important role in agent selection and individual patient response in post-ACS pharmacotherapy. Elderly patients exhibit alterations in gastrointestinal absorption of various drugs, decrease in lean mass and total body water content, decline in renal function and a decrease in serum protein levels [1]. These alterations may affect the absorption, metabolism, distribution and/or excretion of certain drugs.

Beta-blockers provide greater prevention of recurrent myocardial infarction and death in elderly versus younger patients. The aforementioned age related physiologic changes may play a role in beta-blocker selection and dosing. Renally eliminated beta-blockers such as atenolol should be avoided in elderly patients with renal dysfunction [14]. Age related alterations to hepatic mass and blood flow may lead to decreased first pass and ultimate metabolism, increasing the bioavailability and half-life in elderly patients [1]. Elderly patients should be initiated on lower doses of beta-blockers and titrated slowly. Additionally, lipophilic beta-blockers may more readily cross the blood brain barrier in elderly patients, potentiating the central nervous system side effects associated with these drugs [14].

The 2018 blood cholesterol guidelines [15] address statin use in the elderly with the recommendation that starting a moderate- to high-intensity statin is reasonable in patients >75 with clinical atherosclerotic cardiovascular disease. It is also recommended to continue high-intensity statins in elderly patients that previously tolerated high-intensity statins. Hydrophilic statins such as pravastatin and rosuvastatin may be preferred in elderly patients due a possible association with lower rates of myalgia than the lipophilic statins [14]. Statins should be initiated at low doses and titrated slowly in elderly patients to avoid potential side effects. It is also important to know the pharmacokinetic properties of the different statins and individualize statin therapy in the elderly since tolerability of different statins may vary.

Angiotensin receptor enzyme (ACE) inhibitors are beneficial in elderly patients, especially in those with heart failure or reduced left ventricular function and hypertension. The primary concerns with the use of ACE inhibitors in the elderly are related to decreases in renal function and the increased potential of developing hyperkalemia. Renal function should be closely monitored for this reason [14]. Additionally, elderly patients are more prone to postural changes in blood pressure. ACE inhibitors should be initiated at lower doses and titrated slowly to prevent orthostatic hypotension and reduce the risk of falls.

4. Expert opinion

Patients >75 years are not a homogeneous group. Some elderly patients are nearing death from other causes and cardiovascular events are unlikely to shorten their lifespan. Some patients have severe dementia and prolonging their life is really just prolonging their suffering. Some patients are very fragile and cannot tolerate aggressive therapy but will benefit from modest doses of pharmacotherapy. Finally, some patients are otherwise healthy and fully functional and denying them therapy that can prolong their independence and their lifespan would be misguided.

I appreciate how the American Heart Association/American College of Cardiology guidelines are increasingly taking age into consideration and that the decision to treat or how intensively to treat is variable based on the specific type of elderly patient the clinician is treating. With the national movement to create performance measures and the implicit pressure that places on clinicians and health-systems to achieve them, not having multiple acceptable treatment options in this heterogeneous population is dangerous to patient health.

With the flexibility that the new guidelines are giving to clinicians, they need to share the decision with the patient or their caregivers. For a variety of reasons, elderly patients or their caregivers might not be able to tolerate or comply with a cardiovascular drug regimen or parts of the regimen. If education, technology, or other support services cannot alleviate their issues, it is best to respect their wishes.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was not funded.