Medicine Faculty
Department of Cardiology
Reperfusion therapy and prognosis in
acute ST-segment elevation
myocardial infarction in elderly
patients
Author: Claudia Cifuentes Enríquez de Salamanca
Supervisor: Professor Olivija Gustienė
Table of contents
1. SUMMARY ..………..……….……….….…..……….… 3 2. ACKNOWLEDGEMENT ……….……….….. 4 3. CONFLICTS OF INTERESTS .……….….……….………….………..………..……….….. 4 4. ABBREVIATIONS ………..…………..……….………..……… 5 5. TERMS ..……….……..……… 6 6. INTRODUCTION ..……….. 77. RESEARCH METHODOLOGY AND METHODS …….…….….….…..………….………. 8
8. LITERATURE REVIEW ……….…. 8
8.1 CLINICAL PRESENTATION ……….…………..……… 9
8.2 REPERFUSION THERAPY .……….….………..…….……….…. 10
8.3 FIBRINOLYTIC THERAPY VS. PRIMARY PCI ………..….………..…. 13
8.4 REPERFUSION VS. NON-REPERFUSION ………. 15
8.5 ANTIPLATELET THERAPY……….……….…. 17
8.6 OTHER FACTORS INVOLVED ….…….……….……….…….………..…. 19
8.7 PROGNOSIS ……….…….….……….….…….….………… 20
9. DISCUSSION OF THE RESULTS ……….……….…….…. 22
10. CONCLUSIONS ………..………..……..………..………….….… 23
11. REFERENCES ……….……..………..…..….. 25
1. SUMMARY
This is a final master thesis elaborated by Claudia Cifuentes Enríquez de Salamanca about reperfusion therapy and prognosis in acute ST- elevation myocardial infarction in elderly patients.
The aim of this research is to analyse trends in management of the elderly (≥75 years old) presenting with STEMI and its short and long term outcomes.
Our objectives are:
1. To review the characteristics of fibrinolytic and interventional reperfusion therapies.
2. To analyse trends in elderly patients undergoing it and its benefits and risks in this group of patients.
3. To review and compare the outcomes of these patients treated in an integrated regional system according to the modality of reperfusion given.
2. ACKNOWLEDGMENTS
First of all, I am very grateful to the supervisor of this work, Professor Olivija Gustienė, for guiding me along this way. I would also like to express my deepest gratitude towards my family and friends in Spain and the people in Lithuania that made me feel like home and became my second family. I especially thank Dr. Helena Cifuentes Enríquez de Salamanca for guiding me and being a major support for this thesis. I could never be thankful enough, you have all being fundamental pillars in my life, not only for my professional development but also in my personal growth.
3. CONFLICTS OF INTEREST
4. ABBREVIATIONS
ACS = Acute coronary syndrome AMI = Acute myocardial infarction CHD = Coronary heart disease cTn = Cardiac troponin
DAPT = Double antiplatelet therapy DBP = Diastolic blood pressure ECG = Electrocardiogram ED = Emergency department
ESC = European Society of Cardiology FMC = First medical contact
FT = Fibrinolytic therapy
GFR = Glomerular filtration rate IHD = Ischemic heart disease IRA = Infarction related artery i.v. = Intravenous
LBBB = Left bundle branch block LVEF = Left ventricular ejection fraction MI = Myocardial infarction
NSTEMI = Non-ST-segment elevation myocardial infarction PCI = Percutaneous coronary intervention
p.o. = Per os (orally)
RCT = Randomised clinical trial SBP = Systolic blood pressure s.c. = Subcutaneous
5. TERMS
According to the definitions given by the European Society of Cardiology (ESC) guidelines: 1. First medical contact (FMC) - The time point when the patient is either initially assessed by
a physician, paramedic, nurse or their trained personnel who can obtain and interpret the electrocardiogram (ECG) and deliver initial interventions (e.g. defibrillation). FMC can be either in a prehospital setting or upon the patient’s arrival at the hospital (e.g. emergency department (ED))
2. Primary percutaneous coronary intervention (PCI) - Emergent PCI with balloon, stent or other approved device, performed on the infarction related artery (IRA) without previous fibrinolytic treatment.
3. Pharmacoinvasive strategy - Fibrinolysis combined with rescue PCI (in case of failed fibrinolysis) or routine early PCI strategy (in case of successful fibrinolysis)
4. Primary PCI Strategy - Emergent coronary angiography and PCI of the IRA if indicated. 5. Rescue PCI - Emergent PCI performed as soon as possible in case of failed fibrinolytic
treatment.
6. Routine early PCI strategy after fibrinolysis - Coronary angiography, with PCI of the IRA if indicated, performed between 2 and 24 hours after successful fibrinolysis.
7. ST-segment elevated myocardial infarction (STEMI) - The presence of ST-segment elevation or new left bundle branch block (LBBB) on electrocardiography in addition to suspicion of ongoing ischemia.
6. INTRODUCTION
Worldwide, ischaemic heart disease is the single most common cause of death and its frequency is increasing. However, in Europe, there has been an overall trend for a reduction in ischaemic heart disease mortality over the past three decades.Ischaemic heart disease now accounts for almost 1.8 million annual deaths, or 20% of all deaths in Europe, although with large variations between countries.Probably the most comprehensive European STEMI registry is probably found in Sweden, where the incidence rate of STEMI was 58 per 100000 per year in 2015.In other European countries, the incidence rate ranged from 43 to 144 per 100 000 per year.
Similarly, the reported adjusted incidence rates from the USA decreased from 133 per 100 000 in 1999 to 50 per 100 000 in 2008, whereas the incidence of non-ST-segment elevation myocardial infarction (NSTEMI) remained constant or increased slightly.There is a consistent pattern for STEMI to be relatively more common in younger than in older people, and more common in men than in women (Ibanez et al. [6]).
Nevertheless, a high number of the acute myocardial infarction (AMI) cases still occur in the elderly and this number is constantly increasing as a consequence of ageing populations in the western world. Older patients have more comorbidities and often develop heart failure and other complications when treated aggressively so their care exhibits more challenges than that of younger patients.
Effective and continued opening of the IRA is crucial to protect left ventricular function and to improve prognosis. Reperfusion therapy, including thrombolytic therapy and PCI, is effective in reducing the mortality rate of STEMI patients. If available, PCI is the preferred method, but despite its advantages it is not implemented universally and thrombolysis is still used in many cases (Kristensen et al. [4])
It will become clear at the end of this review that many elderly patients with AMI do not receive any reperfusion therapy in a timely and effective manner or at all, which stresses the need of research focused especially on this part of the population, since they have traditionally been under-represented in randomised clinical trials (RCT). Prior studies suggest that clinical factors and financial concerns, as well as organisational difficulties, are some key factors. To overcome these obstacles, systems of care need to develop and establish regional STEMI networks. In addition, more clinical trials in the elderly are needed to complete the lack of knowledge about the benefit-risk profile in this age range. Last but not least, we ought to improve public
understanding of coronary heart diseases (CHD), including its symptoms, risk factors and the different types of reperfusion therapy available nowadays.
7. RESEARCH METHODOLOGY AND METHODS
A systematic literature search for biomedical publications in English and Spanish language was conducted in Pubmed, Embase and Medline databases.
The following keywords were used: “reperfusion therapy”, “ST-elevation myocardial infarction”, “STEMI”, “elderly”, “prognosis”, “fibrinolysis”, “antiplatelet”, “infarto de miocardio”, “IAM”, “ancianos” and/or “reperfusión”.
Inclusion criteria were:
-
Admission to the hospital within 24 hours of symptoms onset that meet the diagnostic criteria of AMI.- Myocardial infarction with ST-segment elevation or new LBBB on electrocardiography in addition to compatible symptoms.
-
Elderly population treated with a reperfusion therapy after AMI diagnosis.-
Publication dates from January 2000 until March 2020, both included. Exclusion criteria were:- Non ST-segment elevation acute coronary syndrome. - Case reports.
8. LITERATURE REVIEW
8.1 CLINICAL PRESENTATIONPresenting symptoms of acute MI differ in the elderly from those in younger patients. They are more likely to be termed “atypical” because the description differs from the classical one of subesternal pressure with exertion. When pain is the presenting complaint, it may be different in character or location, and sometimes appears as an upper abdomen pain rather than a crushing or squeezing subesternal sensation (Carro et al. [4]). The elderly have changes in pain perception and altered ischemic thresholds, thus the probability that the patient reports chest pain decreases as the patient gets older.
This atypical symptoms, together with common occurrence of heart failure, the higher comorbidity rates and the association of older patients with delayed presentation (although patients with STEMI are more likely to present promptly than those with NSTEMI) can distract us from the suspicion of an acute ischemic event. Late presentation is a powerful predictor of lack of reperfusion therapy.
Other symptoms reported were dyspnea, syncope, shoulder or back pain, weakness, fatigue (mostly in women), acute confusion or epicardial discomfort, and they may be precipitated by concurrent illnesses.
The hemodynamic parameters at admission are worse in the elderly (Câlmâc et al. [25]). They show higher heart rate, lower systolic blood pressure, a Killip class >1 and a lower mean
haemoglobin than the younger counterpart. The Grace score was also higher, usually with a score ≥140.
The ECG also presents with a variety of differences in elderly patients. They have a tendency to present a LBBB and non-Q wave infarctions. The presence of the ST-segment elevation is less frequent in the elderly compared to their younger counterparts. In addition, elderly people might present preexisting ST-T segment abnormalities that mimic changes related to myocardial ischemia, even in the absence of acute coronary syndrome (ACS) (Carro et al. [5])
Biomarkers, more specifically cardiac troponin (cTn), are widely used as indicators of
myocardial ischemia. Subsequently, cTn together with ECG changes and imaging findings play a main role in the diagnosis of AMI. However, cTn might get increased in patients presenting with a variety of chronic heart conditions and, to a lesser extent, healthy individuals. The most
prevalent comorbidities in old people than can raise troponin levels in the absence of MI are end-stage renal disease, arrhythmias, myocarditis and congestive heart failure.
False positives can also occur in the presence of substances that interfere with the immunoassays such as the presence of rheumatoid factor, heterophiles antibodies, fibrin clots or circulating antibodies (vaccinations, immunotherapy, blood transfusion). Therefore, the detection of a true change in the value of troponin is essential to correctly diagnose an AMI. Clinicians must be aware of the other conditions that can elevate this value in order not to over-diagnose an AMI and miss the real cause.
8.2 REPERFUSION THERAPY
Reperfusion therapy is a medical treatment focused on restoring the blood flow in a blocked artery after a MI. It includes two different modalities: pharmacological and interventional. The pharmacological treatment is based on the use of thrombolytic and fibrinolytic drugs so as to achieve thrombolysis. The interventional approach is performed by a minimally-invasive procedure (PCI) (See annex 1).
The selection of the right reperfusion modality follows a strategy clock (figure 2). STEMI diagnosis should occur within 10 minutes from FMC. Once the diagnosis has been made, the medical team has to evaluate if PCI could be performed in the 110-120 minute range. In case it
cannot be accomplished, the bolus of fibrinolytics should be administered in an optimal target time of 10 minutes.
According to the current guidelines (Ibanez et al. [6]), the use of PCI along with intraprocedural pharmacotherapy is the preferred reperfusion strategy in elderly adults with STEMI up to 12 hours after the onset of the symptoms if crossing the wire of the culprit lesion can be performed within the first 120 minutes from the ECG diagnosis. The main aspects of PCI intervention that have shown favourable results in the elderly are the radial approach as the access route, when performed by an experienced physician, and coronary stenting with a drug-eluting stent (instead of bare metal stents or single balloon angioplasty).
Primary PCI should also be the choice when there is a clinical presentation compatible with an AMI and a non-interpretable ST-segment on the ECG (such as those with bundle branch block or ventricular pacing), as well as in patients with symptoms lasting >12 hours in the presence of: (1) ECG evidence of ongoing ischemia; (2) ongoing or recurrent pain and dynamic ECG
changes; and/or (3) ongoing or recurrent pain, symptoms and/or signs of heart failure, shock or malignant arrhythmias. Routine PCI of an occluded IRA in an asymptomatic patient >48 hours after the onset of symptoms is not indicated.
If the above is not viable, fibrinolysis should be administered in the pre-hospital setting whenever it is available in order to start the pharmacotherapy as soon as possible.
Early mortality decreases if administered particularly in the first 2 hours of symptoms onset. After the administration, they should be transferred immediately to a PCI-capable hospital. Rescue PCI is indicated in case of failed fibrinolysis or if the patient presents hemodynamical or electrical instability, worsening ischemia or persistent chest pain. If the fibrinolysis is successful and the patient meets criteria for reperfusion, a routine PCI should be performed after 2-24 hours from the diagnosis.
Fibrinolytic therapy (FT) is an important reperfusion strategy when primary PCI is not available or cannot be offered in a timely manner. The largest benefit is shown in high-risk people,
including the elderly. This therapy is recommended within 10 minutes from the STEMI diagnosis if primary PCI cannot be performed in the next 120 min and if there are no
contraindications. However, in the presence of contraindications the benefit-risk value should be considered in order to take into account alternative treatment options including delayed PCI.
Table 1. Preferred drug cocktail for pharmacoinvasive therapy.
<75 years old patients ≥75 years old patients
• Tenecteplase single i.v. bolus1:
30 mg (6000 IU) if <60 kg 35 mg (7000 IU) if 60 to <70 kg 40 mg (8000 IU) if 70 to <80 kg 45 mg (9000 IU) if 80 to <90 kg 50 mg (10000 IU) if ≥90 kg
• Enoxaparin 30 mg i.v. bolus followed 15 minutes later by 1 mg/kg s.c. every 12 hours until revascularization or spill discharge for a maximum of 8 days (max. 100 mg per injection for the first two s.c. doses)
- Patients with eGFR <30 mL/min/1.73 m2,
regardless of age, the s.c. doses are give once every 24 hours
• Clopidogrel loading dose of 300 mg orally (maintenance dose of 75 mg/day)
• Aspirin 150 to 300 mg orally or 75-250 i.v. if oral ingestion is not possible (maintenance dose of 75-100 mg/ day)
• Tenecteplase single i.v. bolus, half-dose1
• Enoxaparin no i.v. bolus, start first s.c. 0.75 mg/kg (max. 75 mg per injection for the first two s.c. doses)
- Patients with eGFR <30 mL/ min/1.73 m2, regardless of
age, the s.c. doses are give once every 24 hours
• Clopidogrel loading dose of 75 mg orally (maintenance dose of 75 mg/ day)
• Aspirin 150 to 300 mg orally or 75-250 i.v. if oral ingestion is not possible (maintenance dose of 75-100 mg/day)
Elderly people are prone to present, to some kind of extent, renal dysfunction (defined as an eGFR <30 mL/min/1.73 m2) as a comorbidity. On that account, it is important to estimate the
GFR as soon as possible in case it is needed to adjust the dose for FT, although the decision on reperfusion therapy must be made before any renal function assessment is available. Contrast agents should be limited and medication needs to be modified appropriately (See annex 2). However, routine PCI is not indicated in totally occluded IRA beyond the first 48 hours from symptom onset due to the increased risk of late complications. Early echocardiography with LVEF assessment is indicated in all patients. Medical therapy should include double antiplatelet therapy (DAPT), anticoagulation and secondary prevention therapies. In patients in whom PCI is finally performed, ticagrelor or prasugrel are preferred,while in patients who do not undergo PCI, clopidogrel is indicated.Anticoagulation, preferably with fondaparinux, is indicated until coronary revascularisation is done or hospital discharge. Elderly patients are often undertreated. Therefore, it is important to emphasize that they should all receive the same secondary
prevention medical therapies as those who receive timely reperfusion.
The 75-year cut-off age is artificial, it does not take into consideration the biological age nor the comorbidities of the patient. The bleeding risk in FT starts to increase around the age of 60 years. In frail STEMI patients between 60-74 year old, is worth considering the administration of the reduced cocktail used in patients ≥75 years old.
Absolute contraindications to the FT according to ESC guidelines (Ibanez et al. [6]) include: previous intracranial haemorrhage or stroke of unknown origin at anytime, ischemic stroke in the preceding 6 months, central nervous system damage or neoplasm or arteriovenous
malformations, recent major trauma/surgery/head injury (within in the preceding month), known bleeding disorder (excluding menses), aortic dissection and non-compressible punctures in the last 24 h (e.g. lumbar puncture, liver biopsy). Relative contraindications are transient ischemic attack in the preceding 6 months, oral anticoagulant therapy, pregnancy or within 1 week
postpartum, refractory hypertension (SBP >180 mmHg and/or DBP >110 mmHg), advance liver disease, infective endocarditis, active peptic ulcer and prolonged or traumatic resuscitation.
8.3 FIBRINOLYTIC THERAPY VS. PRIMARY PCI
There is a limited amount of trials comparing both of the reperfusion strategies, primary PCI and FT, in elderly patients. However, the latest evidence favours primary PCI as the preferred
In patients over 80 years old thrombolytic therapy is indeed hazardous mainly due to bleeding risks. PCI is one of the most effective strategies to open the IRA, improve left ventricular function, reduce intracerebral haemorrhages and increase the survival rate of elderly patients with STEMI.
Some patients with a history of angina do not receive effective reperfusion therapy because (1) these patients were accustomed chest pain and can miss the golden window for PCI by
dismissing their symptoms or (2) symptoms of angina masked those of AMI, which is especially common in diabetic patients.
An analytical study published in The American Geriatrics Society journal (Turk et al. [8]) showed that the percentage of participants receiving timely reperfusion therapy decreases with age, accounting for 44.6% of participants younger than 75, 36.8% of those aged 75 to 84
(OR=0.73, 95% CI=0.62–0.86), and 29.9% of those aged 85 and older (OR=0.53, 95% CI=0.41– 0.69). Lower percentages of primary PCI provision within 60 minutes of FMC for older adults presenting to PCI-capable hospitals or early presenters mainly determined this decreasing trend, in contrast with all other participants undergoing primary PCI within 90 minutes of FMC. Median time to primary PCI consistently increased with age, whereas median delay in intravenous fibrinolysis did not differ according to age.
This prospective regional hospital-based clinical registry aimed to compare the delivery of any reperfusion therapy in STEMI older patients in 23 hospitals in northern France. Patients were categorised into three different groups according to age (<75, 75–84 and ︎85+ years old). Overall, 91.3% of participants received any reperfusion therapy, 65.4% received primary PCI and 26.0% received intravenous fibrinolysis. Although percentages of participants undergoing primary PCI increased with age, the rates of any reperfusion therapy decreased (See annex 3). The
explanation given for this apparent contradiction was a decreasing trend in the use of intravenous fibrinolysis with advancing age.
A review of 23 trials comparing PCI versus FT with longer follow-up (6 to 18 months) found PCI to be superior for the reduction of death, reinfarction, stroke and ischemic heart disease (ICH) (Keeley et al. [9]). There was a benefit with PCI, particularly if the patient arrived 2 hours after the symptom onset or if the patient was ≥65 years of age. A subgroup analysis indicated that the absolute mortality advantage of PCI increased with age from 1% at 65 years to 6.9% at ≥85 years of age. In the elderly, PCI is appealing because it can be applied in the absence of clear ST- segment elevation or chest pain and is effective despite hemodynamic status. Two
considerations deserve special consideration: timing and availability of PCI and cardiogenic shock at presentation.
Another study aimed to identify characteristics and outcomes of FT received within 24 hours of admission in STEMI octogenarians (≥80 years) (Ogunbayo et al. [26]). They found that patients who received FT had eight times more risk for hemorrhagic stroke than those who did not receive it, being hemorrhagic stroke an independent predictor of mortality, whether they underwent rescue PCI or not.
A combination of various factors explained why FT has low effectiveness and associates with high bleeding risk in the elderly. Some of these are: endothelial dysfunction, increased platelet activation and hyperreactivity, reduced activity of ADAMTS-13, increased activity of secondary hemostasis, increase in natural anticoagulants, decreased plasminogen and plasminogen
activator inhibitor-1, oxidative stress, marked accelerated atherosclerosis, vascular dysfunction and reduction in antioxidant gene expression. All of these contribute to increase the risk of thrombosis and the prevalence of obstructive coronary artery disease. Due to comorbidities, elderly patients are usually on medications that may increase bleeding risk. Thus, all the data suggests that PCI may be the preferred reperfusion strategy for elderly patients.
8.4 REPERFUSION VS. NON-REPERFUSION THERAPY
Reperfusion therapy has been associated with lower mortality rates and years gained over the long term. In multivariable analysis (Yi et al. [13]), provision of timely reperfusion therapy remained independently associated with lower in-hospital mortality. In mediation analysis, failure to provide timely reperfusion therapy explained most of in-hospital mortality for patients aged 75 and older compared with patients younger than 75.
Patients who, for specific reasons (e.g. long delay), fail to receive reperfusion therapy within the recommended time (12 hours), should be immediately examined to rule out any clinical
hemodynamical or electrical instability. If 12-48 hours from the symptoms onset have passed and the patient is stable and asymptomatic but there is a presence of signs and/or symptoms suggesting an ongoing myocardial ischemia, hemodynamic instability to life-threatening
arrhythmia and/or heart failure, a primary PCI strategy is indicated. After that time, either a non-invasive test to check the presence of residual myocardial ischemia to decide a late non-invasive strategy or elective coronary angiography should be considered.
Many other potential reasons why older STEMI patients do not receive reperfusion therapy include absolute or relative contraindications to fibrinolysis, atypical presentation, delayed presentation, cognitive status, individual preference, physician reluctance to use invasive therapy because of high bleeding risk and age-related discrimination. Moreover, some studies suggest the fact that older people die faster and therefore do not get the chance to be treated, yet the trend towards decreasing rates of reperfusion therapy with advancing age remained significant after removing participants who died within 12 hours of the FMC.
A data registry created to evaluate the quality of MI care (Forman et al. [10]) analysed the reasons why some patients did not receive reperfusion therapy. It is evident that there are age-associated contraindications, but the sum of increased absolute and relative contraindications only explained 9% of the age-related discrepancy. In patients ︎<75 years old, reperfusion was most likely to be contraindicated due to symptoms, timing, electrocardiographic criteria and coronary anatomy, whereas in patients ≥85 years old reperfusion was more likely to be contraindicated based on patient preferences. Even in eligible older patients with STEMI without contraindications, reperfusion was less likely to be performed. Patients, their families and/or medical providers may opt to avoid reperfusion even when contraindications are not identified.
A study registered in the Beijing Military General Hospital No. 5, based on demographic characteristics of patients, compared the reception or not of reperfusion therapy (Yi et al. [13]). This study pinpointed five factors (age, history of angina, right ventricle MI, unbearable
symptoms and medical insurance) with statistically significant p-values related to the likelihood of receiving reperfusion therapy.
Patients were distributed into two groups. After social analysis, data showed that most of the patients in the non-reperfusion therapy group were older (77 ± 7 vs. 73 ± 5 years, P = 0.000) and had higher rates of history of angina (OR = 0.492, P = 0.006). Other factors such as larger medical insurance coverage (OR = 2.393, P = 0.002), higher incomes (OR = 1.521, P = 0.032) and well-educated backgrounds (OR = 1.424, P = 0.049) were also found to be more frequently associated to the reperfusion therapy group.
According to clinical characteristics of patients undergoing reperfusion therapy, they showed more unbearable symptoms (OR = 2.272, P = 0.002), polypnea (OR = 0.530, P = 0.036) and excessive perspiration (OR = 1.891, P = 0.021). This was likely related to a realisation of the severity and nature of their symptoms.
The journal of the American Geriatrics Society published in 2018 a registry of differences in the rates of reperfusion and non-reperfusion therapy stratified by age (Turk et al. [8]). Although the overall reperfusion rate was as high as 91.3%, older adults were less likely to receive any reperfusion therapy, a finding that was consistent with previous research. They identified 6 primary cohort studies that reported use of any reperfusion therapy at baseline and short-term mortality for 10,058 unselected individuals with STEMI aged 75 and older and 39,840 individuals younger than 75 who were enrolled between 2005 and 2015 in Europe.
The median percentage of reperfusion therapy recipients across primary studies was 61.3% (range, 43.6–86.1%) for patients 75 years or older compared with 80.5% (range, 73.9–92.9%) for patients younger than 75 years. It is likely that between-study heterogeneity in the use of reperfusion therapy (range 63.3– 91.3%) reflected differences in times from symptom onset to enrolment (range <12 to <72 hours) and recruitment periods (range 2005–2015). Overall, the summary odds ratio estimate of receiving any reperfusion therapy was 0.37 (95% CI 0.33–0.41) for 63.3% individuals aged 75 and older compared with 82.3% individuals younger than 75. Timely delivery of reperfusion therapy was associated with lower in-hospital mortality with an adjusted odds ratio of 0.63 (95% CI 0.46-0.85).
8.5 ANTIPLATELET THERAPY
Patients need to receive a DAPT the moment STEMI is diagnosed in the form of aspirin plus a P2Y12 inhibitor. This can go up to 1 year after undergoing fibrinolysis and/or subsequent PCI in
order to prevent sudden clotting. Co-therapy for PCI
Patients undergoing primary PCI should receive a DAPT, and a parenteral anticoagulant. A dose of 150-300 mg of aspirin, preferably orally (if not, i.v.), is required to ensure the complete inhibition of thromboxane A2-dependent platelet aggregation. There is limited knowledge about when to initiate the P2Y12 inhibitor, if during the transfer to a PCI- capable centre or right before
the angiography. Nonetheless, the latest data suggest that an early administration, particularly for long delays, may be preferable in favor of achieving superior efficacy. However, when STEMI diagnosis is not clear, delaying P2Y12 inhibitor loading dose until the anatomy is known should
The preferred P2Y12 inhibitors are:
• Prasugrel → <75 years old - 60 mg loading dose and 10 mg maintenance dose once daily per os (p.o.); ≥75 years old - not recommended. However, if needed, a reduced dose (5 mg) is recommended or,
• Ticagrelor → 180 mg loading dose and 90 mg maintenance dose twice daily p.o.
-
Although these drugs, prasugrel and ticagrelor, have a quicker onset of action, greater potency and superior in clinical outcomes compared to clopidogrel, neither should be used in patients with a history of haemorrhagic stroke, moderate-to-severe liver disease or patients on oral anticoagulants. Therefore, they might not be the preferable ones for elderly patients.• Clopidogrel → 300 mg loading dose p.o. should be given if the two above are not available or contraindicated.
All P2Y12 inhibitors should be used with caution in patients at high risk of bleeding or with
significant anaemia. Three RCT have assessed cangrelor, a potent i.v. reversible P2Y12 inhibitor
with a rapid onset and offset of action, and showed that it reduced periprocedural ischaemic complications at the expense of an increased risk of bleeding (Steg et al. [24]). Ergo, cangrelor may only be considered in patients not pre-treated with oral P2Y12 receptor inhibitors at the time
of PCI or in those who are considered unable to absorb oral agents.
Despite the routine use in the catheterisation lab of glycoprotein (GP) IIb/IIIa inhibitors, their use in pre-hospital routine settings before primary PCI have not proved to offer any benefit and adds bleeding risk. Overall, there is no evidence to recommend the routine use of intracoronary nor i.v. GP IIb/IIIa inhibitors for primary PCI.
Co-therapy for fibrinolysis
Patients undergoing fibrinolysis should also receive a DAPT: oral or i.v. aspirin plus clopidogrel. Clopidogrel is added to aspirin to reduce the risk of early thrombotic complications
(reocclusion) and overall mortalityand should be added to aspirin as an adjunct to lytic therapy. P2Y12 antagonists (ticagrelor, prasugrel, cangrelor) have shown no benefit in association with
8.6 OTHER FACTORS INVOLVED
A wide variety of factors participate in the development of an AMI and the therapy finally given. Gender
AMI remains as a leading cause of death in men. ACS occurs around 4 times more often in men in patients up to the age of 60, but after the age of 75, the majority is represented by women. Some studies indicate that women usually undergo fewer interventions than men and receive reperfusion less frequently. This can be explained by the higher tendency of women to present atypical symptoms (up to 30% in some registries) and to present them later. Therefore, it is important to maintain a high degree of awareness for AMI in women that present potential symptoms of ischemia.
Age
Only round 10% of the oldest old (≥85 years old) are cited as having absolute or relative
contraindications (Forman et al. [10]). Even in reperfusion-eligible patients, the oldest old were less likely to receive it. PCI failure (thrombolysis in MI flow 0 or 1 after PCI) was observed more often with increasing age. In the older group a lower proportion of patients present <12 hours after symptom onset and there is a higher prevalence of comorbidities. The oldest-old are mostly not recent smokers, have less diabetes mellitus and less hyperlipemia but they have a higher prevalence of hypertension and end-organ comorbidity. Lower creatinine clearance and higher B-type natriuretic peptide levels are also shown in the elderly compared to the younger age strata (75-84 vs. <75). Younger ones have a higher rate of body mass index >30 kg/m2 (Fach et al. [15]).
Social status & education
Different socioeconomic and cognitive backgrounds affect reperfusion therapy rates. Patients with widely educated and with higher incomes are more likely to receive reperfusion therapy (Yi et al. [13]) and in a more efficient way. They have greater probabilities of recognising their own symptoms when the acute cardiac event occurs and asking for help; they are also aware of the availability of treatments for CHD that can potentially open a narrowing or blockage in the IRA. Comorbidities
It is a known fact that elderly patients have more comorbidities than younger ones.
Hypertension, anaemia, end-organ damage, diabetes or hyperlipemia are some of the most common. They can mask real CHD symptoms delaying the correct diagnosis and therefore, the necessary treatment. Also, patients with multiple concomitant diseases are usually under-treated
since they are perceived as being frail and often developing procedural complications, prolonged recoveries and functional decline.
Insurance
In countries like the United States of America where a public universal healthcare system is not always available, patients must seek private insurance plans to meet their health care needs. Patients covered by a medical insurance are more prone to receive reperfusion therapy
effectively and in time compared to those who do not have one. This finding could potentially have an impact on medical insurance systems and how they manage elderly patients with AMI.
8.7 PROGNOSIS
The oldest-old population have a fourfold higher odds of in-hospital mortality compared to younger patients, a hazard that persists after medication adjustment and is irrespective of reperfusion status. Therefore, it is clear that both logistic and intrinsic factors contribute to poor outcomes in the oldest.
Diverse factors, other than procedure-related variables (e.g. failure of PCI), have been related to an increased in-hospital mortality related to ageing (Turk et al. [8]); being these: impaired microcirculation, greater myocardial susceptibility to ischemia-reperfusion injury, poorer functional recovery after ischemia and complex coronary anatomy related to a higher incidence of post-procedural distal embolisation.
Various studies that took place around the year 2000 showed a clear age-related increase in intracranial haemorrhage rate when tenecteplase or alteplase were used. Tenecteplase tended to cause fewer cases, but the difference was not significant. In the STREAM trial (Armstrong et al. [12]), the initial excess in intracranial haemorrhage in patients ≥75 years was reduced after the protocol amendment to reduce the dose of tenecteplase by 50%. Consequently, this dose reduction is now well-accepted in all the guidelines and has now become the gold standard. FT in patients 80 years or older presenting with STEMI was proved to be associated with an eight-fold increase in hemorrhagic stroke and no mortality advantage, both with or without rescue PCI (Ogunbayo et al. [26]). Hemorrhagic stroke is an independent predictor of mortality (OR 2.44 95% CI 1.29-4.58) and discharge to a skilled nursing facility (OR 8.51 95% CI 3.66-19.80).
In-hospital mortality in octogenarians and STEMI patients <80 years old were evaluated based on data from the prospective Belgian STEMI registry (Vandecasteele et al. [14]). The benefit of PCI concerning mortality was maintained in haemodynamically stable octogenarians. Moreover, ischemic time and door-to-needle/balloon time was longer for octogenarians. In-hospital
mortality for octogenarians was 17.8 versus 5.5 % in the younger group. In octogenarians with cardiac failure, in-hospital mortality was extremely high independently of the chosen
reperfusion therapy.
The RESIM registry (Dacosta et al. [20]), found 17 variables associated with patients’ prognosis. The dependent variable was 30-days mortality following admission to the ED. Data was
collected through medical history or contact, either with the patient or her/his family, between the 31st and 60th day after the ED visit. In total, 29.9% patients died during the first 30 days. The study showed that mortality of STEMI in patients older than 70 years was directly related to 10 variables: age, Killip III or IV classification, the existence of previous stroke, diabetes
mellitus, previous peripheral vascular disease, female sex, the time from the onset of symptoms to the arrival at the hospital greater than 120 minutes, the previous location of the STEMI, the administration of fibrinolytic treatment and primary PCI. However, in this group of patients, only advanced age, Killip III or IV classification, previous location and non-performance of primary angioplasty maintained a statistical significance after the logistic regression analysis. Other registries, such as REGICOR (Gil et al. [21]), also describe the increase in age as a hazard element closely related to mortality: the risk of death in patients between 75 and 84 years and between 85 and 94 years was much higher than in the youngest age group (between 34-64 years) regardless of any other baseline clinical characteristic. They included 227,598 patients observing that, in patients with STEMI, the independent variables associated with mortality at 30 days were age over 70 years, a Killip classification higher than 1 and the absence of reperfusion signs. Regarding to healthcare facilities, various studies (Allison et al. [22], Burke et al. [24]) showed that elderly patients with ACS who were admitted to teaching hospitals had better quality of life and lower mortality at 30, 60 and 90 days than those attended at non-teaching hospitals. In an international clinical trial that included 41,021 patients with AMI (Carro et al. [5]), the
multivariate analysis pointed age as the main the factor that influenced most mortality at 30 days, and was 1.1% in the youngest decile (< 45 years) and 20.5% in patients over 75 years.
9. DISCUSSION OF RESULTS
Although elderly patients frequently associate multiple comorbidities that may interact with reperfusion therapy suitability or treatment, this must not prevent physicians from delivering the recommended treatment according to the latest guidelines. Reticences in this aspect should not interfere with the decision-making process because, even in aged patients, the benefits of a timely reperfusion are clear regarding reduced mortality rates.
The high frequency of atypical MI presentation and unrecognized infarctions among older patients constantly rises their mortality. This atypical symptomatology must be suspected mainly in women and diabetics. As the number of physicians who are conscious about this changes in the perception of pain increase the difficulties in achieving an adequate and timely treatment will be easier to overcome.
Continued improvements in equipment and pharmacological therapies can reduce associated risks such as blood vessels damages, arrhythmias or hemorrhagic strokes. This will eventually happen when elderly patients are taking more into consideration in the design of clinical trials and their participation increments.
Even though elderly patients have a higher risk of bleeding if they undergo FT, the alternative of not performing any reperfusion therapy is almost always associated with very poor survival results, in some cases even poorer than those related with hemorrhagic complications. Thus, the benefit-risk assessment is to a greater degree crucial for survival compared to younger patients. Teaching hospitals seem to have lower mortality rates in comparison to non-teaching ones. This provision of a better quality care could be explained by the need of physicians to continuously update with the most recent evidence-based medicine so as to teach seminars, clinical sessions and courses aimed to students and also fellow doctors and residents. Teaching hospitals are probably earlier adopters of ultimate technologies and cutting-edge treatments that yield better outcomes. Further studies are necessary to fully understand the reasons of these differences.
10. CONCLUSION
1. Primary PCI is the preferred method in all STEMI patients, regardless their age, up to 12 hours after the onset of symptoms if crossing the wire of the culprit lesion can be
performed within 120 minutes of the ECG diagnosis. If this is not possible, immediate FT should be given and transferred to a PCI-capable hospital.
2. PCI has shown its superior efficacy (over 90% restoration of TIMI 3 flow), safety (less stroke/bleeding), long term outcomes (less reinfarction/restenosis) and the provision of better results in high-risk patients. It is also less impacted by additional factors, such as symptom’s onset, compared to thrombolysis.
3. Elderly patients frequently receive a less aggressive or an incomplete reperfusion therapy. This is mostly due to the multiple comorbidities, intrinsic risks associated with ageing and the atypical presentation of AMI that difficult the diagnosis and delay the initiation of treatment.
4. The outcomes worsens as the patient’s age increases. The mortality and risk of complications increase as well in a exponential way with age.
5. Older age remains a strong independent predictor of short-term mortality in the contemporary era of STEMI management, even for individuals receiving timely
reperfusion therapy. More variables that affect survival rates, aside from advanced age, are Killip classification higher than 1, the presence of a cardiogenic shock or previous MI.
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12. ANNEXES
2. Recommended doses of antithrombotic agents in acute care of patients with chronic kidney disease.
