14
© SUPPLEMENT TO JAPI • december 2011 • VOL. 59
Pre-Hospital Thrombolysis
Aditi Vaishnav*, Avani Vaishnav*, Santosh Khandekar**, Sudhir Vaishnav***
Abstract
Coronary heart disease (CHD) is a major cause of mortality in India. Patients in India, who have acute coronary
syndromes, have a higher rate of STEMI than do patients in developed countries. Since most of these patients
are poor, they are less likely to get evidence-based treatments, and have a greater 30-day mortality. Reduction
of delays in access to hospital and provision of affordable treatments could reduce this.
Treatment regimes for AMI should aim to open the artery as soon as possible and as wide as possible. In patients
suitable for thrombolytic treatment, time is critical and reperfusion should be initiated as soon as possible. Some
adjunctive therapies are also beneficial, in particular, the antiplatelet agent aspirin, which should be given in the
prehospital setting when a diagnosis of AMI is suspected.
Despite availability of good treatment, mortality from AMI is showing no further reduction due to the prehospital
phase and in-hospital delays. Thrombolysis is almost always delivered to patients after arriving in hospital, losing
valuable time (and hence heart muscle). Newer drugs combined with recognition of improved outcomes have
prompted attempts to decrease the time from symptom onset to treatment delivery via Pre Hospital Thrombolysis
(PHT).
However, PHT is significantly superior to in-hospital thrombolysis (IHT). This is especially important in regions
where PCI is not available.
In the RIKS-HIA and NRMI, PHT had better outcomes than IHT, but patients who received PPCI had lower
mortality and re-infarction rates. They concluded that within 2 h of symptom onset, patients should receive
PHT only if PPCI is not available within 4 h.
In CAPTIM, which compared PPCI and PHT followed by PCI if thrombolysis failed and in GRACIA-1 trial , which
tested the role of systematic PCI within 24 h of thrombolysis, the policy of systematic PCI following thrombolysis
yielded better results than conservative management.
The American Heart Association (AHA) and the American College of Cardiology (ACC) favour the use of PHT
over PCI, placing the emphasis on the time factor rather than on the method of reperfusion. However, if PHT
cannot be administered, the patient should be treated with PPCI within 90 min of first medical contact or therapy
within 30 min such that the total ischaemic time is 120 min.
The National Institute for Clinical Excellence supports reperfusion with fibrinolytics, recommending PHT using
the newer agents, reteplase and tenecteplase, whose bolus application simplifies administration.
PHT constitutes one of the means to shorten delays before the administration of reperfusion therapy. However, it
poses several organizational problems that can find different answers according to each regional/national system
of care. A number of barriers exist that limit the actual use of PHT. Thus the system of care chosen is likely to
have a definite impact on the percentage of STEMI patients in whom PHT can be delivered. Global Trends in Coronary Artery
Disease
Coronary heart disease (CHD) is a major cause of morbidity
and mortality in India like the rest of the world. Although rates
of coronary heart disease have been decreasing over the past
three decades in the western world, this is not true in India where
we are seeing a rising trend. This decreasing trend has not been
consistent across age groups, gender or socio-economic class.
A more rapid reduction has been seen in younger age groups
(45-54 years), in men and in higher socio-economic groups. In
addition, the rate of decline in the UK has been slower then that
in other developed counties (e.g. Denmark, Norway, Australia).1
Indian Scenario
Patients in India, who have acute coronary syndromes, have
a higher rate of STEMI than do patients in developed countries.
Since most of these patients are poor, they are less likely to get
evidence-based treatments, and have a greater 30-day mortality.
Reduction of delays in access to hospital and provision of
affordable treatments could reduce morbidity and mortality
in India.2
*
Observer in Cardiology, **Clinical Associate in Cardiology, ***Senior
Interventional Cardiologist, Asian Heart Institute, G/N Block, Bandra
Kurla Complex, Bandra (E), Mumbai 400 051
Pathophysiology of Acute Myocardial
Infarction
Coronary heart disease is usually due to atherosclerotic
narrowing of the coronary arteries supplying the muscle of the
heart (the myocardium). Its first presentation can be an acute
myocardial infarction (AMI). AMI is the result of a thrombus or
clot forming on top of a ruptured atherosclerotic plaque, blocking
the blood flow through the artery. Unless the blood flow can be
quickly restored, the muscle supplied by that artery “infarcts”
due to ischaemia. This can result in sudden cardiac death. In
fact 50% of the patients with an AMI die before they can reach
the hospital. This muscle damage weakens the heart, and may
also cause heart failure either early (within a matter or hours)
or later (over a period of months or years).
Diagnosis of Acute Myocardial
Infarction
According to the World Health Organization, the diagnosis
of AMI requires that at least two of the following three criteria
be met: 1) a clinical history of ischaemic-type chest discomfort,
2) changes on repeated electro-cardiographic (ECG) tracings
usually over two to three days, and 3) a rise and fall in serum
cardiac markers (typically over 1-2 days but new sensitive
markers may allow a diagnosis within 6-12 hours). However,
these criteria may not be suitable for the diagnosis of AMI, within
© SUPPLEMENT TO JAPI • december 2011 • VOL. 59 Table 1 : Differences in 30 day and 1 year mortality between
all pre-hospital thrombolysis, ambulance-transported
pre-hospital thrombolysis, primary percutaneous coronary
intervention, and in-hospital thrombolysis for ST-elevation
myocardial infarction patients in the RIKS-HIA registry
Mean age
(years)
30 day
mortality (%)
1 year
mortality (%)
Ambulancetransported
PHT,
2001–2004
64
All PHTs,
1999–2004
PPCI,
1999–2004
IHT,
1999–2004
66.3
64.2
68.6
5.4
7.6
4.9
11.4
7.2
10.3
7.6
15.9
Data from Bjo¨rklund et al.18 and Stenestrand et al.23
the first 6 hours when interventions to restore blood flow, such as
drugs to dissolve the thrombus, may be of most value to save life.
Changes in ECG readings are useful in the diagnosis of AMI
and ST segment elevation is very specific in identifying patients
requiring reperfusion therapy. These changes may occur in the
“anterior” ECG leads (generally indicating an occlusion in the
left coronary artery, the main supply to the myocardium and
hence affecting more myocardium, with a worse prognosis) or
inferior leads generally implying a smaller infarct with a better
outlook, possibly due to obstruction in the right coronary artery
or circumflex artery unless there is associated right ventricular
infarct. However, as many as 50% of patients with AMI may
not exhibit ST elevation in the early stages and assessment of
change in ST abnormalities has been proposed as a more sensitive
diagnostic marker. Changes in traditional serum cardiac markers
also often occur too slowly to be of immediate value. Newer,
more rapidly available tests are being evaluated.
Current practice for early identification of patients
experiencing an AMI, and who might benefit from reperfusion
therapy, therefore includes a combination of clinical symptoms
and ECG changes. Serial ECG changes are monitored if initial
readings appear normal but clinical symptoms persist or become
worse. Serial readings may also be needed if initial readings are
abnormal but not diagnostic of AMI.
Treatment
15
Medical care for patients experiencing AMI has changed
over the past 40 years. Care in the 1960s and 70s focused on
the treatment of life-threatening arrhythmias. This included
the development of specialist coronary care units to monitor
these patients. The 1980s saw the conduct of large clinical trials
to assess the effectiveness of drugs that broke down the clot
causing the infarct (thrombolysis) followed by trials of primary
angioplasty in the 1990s.
Treatment regimes for patients experiencing AMI have been
presented out in evidence based clinical guidelines established
through a combination of professional and voluntary bodies.3,4
Not all patients are suitable for treatment with thrombolytic
treatment. In the first instance, delay on the part of the patient
following the onset of symptoms may mean that they are not
eligible for treatment. Even for patients seeking help early it
may not be suitable for treatment. The increased risk of bleeding
means that all patients need to be screened. However, even
those appropriately screened who receive treatment may bleed.
One of the most severe bleeds can be within the brain perhaps
causing a catastrophic intracranial haemorrhage. Thrombolysis
is therefore a balance of the benefits and risks, each of which
must be carefully weighed.
All guidelines agree that time is critical and reperfusion
should be initiated as soon as possible.3 The time without
reperfusion to cause infarction can be as little as 1 hour, but
there is still benefit from reperfusion therapy for up to at least
12 hours, decreasing as time goes by.
Thus there is a change in philosophy from passively trying to
manage complications to actively achieve reperfusion.
Hence the aim for treating AMI should be
1. To open the artery
2. To open the artery as soon as possible
3. To open the artery as wide as possible
4. To achieve TIMI 3 flow both at the epicardial and cellular
level.
Some adjunctive therapies are also beneficial, in particular
the antiplatelet agent aspirin. The ISIS-25 study showed an
absolute reduction in mortality of around 3% in patients treated
with streptokinase alone, but of 6% in those treated with both
streptokinase and aspirin. Other studies and meta-analyses have
confirmed the benefits of aspirin, which has become standard
recommended therapy. Aspirin should be ideally given in the
prehospital setting the moment a diagnosis of AMI is suspected.
Today, based on available evidence, patients are also being
loaded with Clopidogrel as soon as the diagnosis is confirmed.
Despite good treatment available mortality from AMI is
showing no further reduction. There are a number of reasons
why the mortality of acute myocardial infarction remains
significant. Most of these pertain to the prehospital phase and
some to in-hospital delays.
1. The most important delay is the time taken by the patient
to recognize that the symptoms are cardiac and they should
seek medical help immediately
2. The logistic delay in Emergency Medical Services
responding and reaching the patient, or the transport delay
due to traffic, weather conditions or geographical terrain.
3. Then, after reaching the delays in the emergency department
of the hospital in making a diagnosis, trying to get a bed
in the ICCU, establishing access and completing lysis in a
timely fashion
4.Delays in the cath lab if occupied and not available
Thrombolysis is almost always delivered to patients after
arriving in hospital, possibly losing valuable time (and hence
heart muscle). Meta-analysis of trials has shown that early
thrombolysis is more effective and that the treatment is of limited
value once irreversible myocardial damage has occurred.8-10
Advances in the speed of action and ease of administration of
newer drugs combined with recognition of improved outcomes
with earlier administration have prompted further attempts to
decrease the time from symptom onset to treatment delivery.
This is where Pre Hospital
Thrombolysis (PHT) comes in
While it seems logical and very attractive is there any evidence
that this would save lives?
Randomised Trials of Prehospital
Thrombolysis vs. In-Hospital
Thrombolysis
Randomized controlled trials (RCTs) have shown PPCI to be
more effective than fibrinolysis for STEMI when performed by an
experienced team within 90 min of first medical contact.8,10 Keeley
et al. evaluated 23 trials comparing PPCI with thrombolysis
using streptokinase or a fibrin-specific agent. Regardless of the
16
Table 2 : Comparison of outcomes at 30 days and 1 year
for ST-elevation myocardial infarction patients treated
within and after 2 h of symptom onset with pre-hospital
thrombolysis, inhospital thrombolysis, or primary
percutaneous coronary intervention
Mean age (years)
30-day mortality
1-year mortality
IHT
<2
8.6
11.9
IHT
>2
11.4
16.3
PHT
<2
5.6
8.0
PHT
>2
8.9
11.8
PPCI
<2
3.8
6.7
PPCI
>2
4.5
7.3
Data from Stenestrand et al.23
thrombolytic agent, PPCI was more effective, even if transfer to
centres with appropriate facilities was necessary.5,11 However, as
documented in a meta-analysis of six randomized trials, PHT is
significantly superior to in-hospital thrombolysis (IHT) in terms
of hospital mortality and it saved 45 min compared with IHT,
which could potentially preserve myocardial tissue and improve
outcomes.11 This is especially important in regions and countries
where PCI is not available either at all, or on a 24 h basis.
Comparison of Angioplasty and
Prehospital Thrombolysis in Acute
Myocardial Infarction (CAPTIM)
CAPTIM, compared PHT and PPCI. Patients who received
thrombolysis within 2 h of symptom onset showed a strong trend
towards lower 30 day mortality than those who had undergone
PPCI. Beyond 2 h, the difference between the groups was almost
reversed in favour of PPCI.12
The findings from CAPTIM are consistent with those from
PRAGUE-2, which showed that within 3 h of symptom onset,
mortality rates were almost identical, but in patients randomized
after 3 h, mortality following thrombolysis was much higher.12
The investigators concluded that if STEMI patients can be
transferred within 20–30 min, they should receive PPCI. If
this cannot be performed within 60 min, thrombolysis can be
administered up to 3 h after onset. Beyond 3 h, thrombolysis
should not be used, and patients should be transferred for PPCI.
Likewise, in the Primary Coronary Angioplasty vs. Thrombolysis
(PCAT)-2 Trialists Collaborative Group meta-analysis, 30 day
mortality doubled in the fibrinolysis group as the time delay
increased from 1 to 6 h. The re-infarction rate was also higher
in this group and increased with the time delay (not observed
in the PPCI group). Thus, the time delay to reperfusion remains
central to the choice of strategy.13
Do registry data also suggest the same
conclusions?
In the large RIKS-HIA (Register of Information and
Knowledge about Swedish Heart Intensive Care Admissions),
PHT had better outcomes than IHT, but patients who received
PPCI had lower mortality and re-infarction rates and shorter
hospital stays.14 However, only a few months before, the same
group reported the results of thrombolysis in the same patients
treated in the ambulance before hospital admission. In this latter
group, mean age was comparable with the age of patients treated
with PPCI. Interestingly, comparing 30 day and 1 year results
between the ambulance-managed PHT patients and the primary
angioplasty group shows that both reperfusion methods yield
very similar mortality figures: 5.4 vs. 4.9% at 30 days and 7.2 vs.
7.6% at 1 year, respectively (Table 1).14,15
Time delay to reperfusion appeared very important in the
thrombolysis groups, as mortality increased sharply beyond 2
© SUPPLEMENT TO JAPI • december 2011 • VOL. 59
PCI-related delay (DB/DN) where
PCI and ﬁbrinolytic mortality are equal (min)
0-120 pre-hospital delay (min)
180
168
179
120
148
107
103
58
60
0
121+
40
20 424 10 614
Non-Ant MI
65+ Years
9812
3739
Ant MI
65+ Years
41 774 16 119 19 517
Non-Ant MI
<65 Years
43
5296
Ant MI
<65 Years
Fig. 1 : Comparison of time windows in which PCI-related
delay (DB-DN time) offers an advantage over thrombolysis
for different patient populations depending on age, site of
infarction, and pre-hospital time delay (data from Pinto et al.18).
h. The difference was less dramatic for PPCI (Table 2). Overall,
time delay was central to the benefit incurred by any type of
reperfusion, but loss of benefit with increasing delay was less
pronounced with PPCI. Therefore, the authors concluded that
within 2 h of symptom onset, patients should receive PHT only
if PPCI is not available within 4 h. This conclusion, however,
did not take into account the results of PHT in ambulancetransported patients.
The National Registry of Myocardial Infarction (NRMI)
registries studied the impact of the difference in time delays
between the administration of thrombolysis and PPCI in 192509
patients. Overall, PPCI yielded more favourable results than
thrombolysis, but increasing DB minus DN times were associated
with increasing mortality rates (P 0.001).16 The time point at
which PCI lost its survival advantage over fibrinolysis varied
considerably between various subgroups: from 40 min in patients
65 years of age with an anterior infarction, presenting within 2
h of symptom onset, to179 min in patients 65 years of age with
a non-anterior infarct, presenting after 2 h of symptom onset
(Figure 1). The effect of thrombolysis was greatest in patients
presenting with a large infarction, short duration of symptoms,
and low bleeding risk. The prolonged time window gained
for PCI in the elderly appeared related to the increased risk of
intracerebral haemorrhage with fibrinolysis.16,17
Is there a need for PCI after PHT?
Another important point is the role of subsequent PCI after
PHT. In CAPTIM, 70% of patients in the thrombolysis group
underwent PCI before day 30, with 26% requiring rescue PCI.
Therefore, the actual comparison in this trial was between PPCI
and PHT followed by PCI if thrombolysis failed. Furthermore,
the role of systematic PCI within 24 h of thrombolysis was tested
in the Grupo de Analisis de la Cardiopatia Isquemica Aguda
(GRACIA-1) trial19 and in the CARESS-in-AMI trial.20 In both
instances, the policy of systematic PCI following thrombolysis
yielded better results than conservative management. The WEST
(Which Early ST-elevation myocardial infarction Therapy) study
extended this concept and compared tenecteplase alone with
tenecteplase and mandatory PCI within 24 h and PPCI with a
loading dose of clopidogrel.The results suggested that rapidly
applied pharmacological reperfusion with follow-up (rescue and
routine) PCI within 24 hproduced equivalent results to PPCI.21
The American Heart Association (AHA) and the
AmericanCollege of Cardiology (ACC) favour the use of PHT
over PCI, placing the emphasis on the time factor rather than on
the method of reperfusion. AHA/ACC guidelines state that PHT
should be performed only following the confirmation of STEMI
© SUPPLEMENT TO JAPI • december 2011 • VOL. 59 on a 12-lead ECG, interpreted by a physician on site or after
transmission to a specialist. A reperfusion checklist should also
be completed to ensure that the patient has no contraindications
to thrombolytics and to identify high-risk patients who would
benefit more from PPCI. PHT should be performed within 30
min of the arrival of the emergency services. If PHT cannot
be administered and the patient is subsequently transported
to a hospital that has no PCI facility, the door-to-needle time
(arrival at the hospital to the administration of thrombolytic,
DN) should be 30 min. If, however, the hospital can offer PCI,
the door-to-balloon time (arrival to PCI, DB) should be 90 min.
The recent update of the ACC/AHA guidelines3 insists that
patients presenting to a hospital with PCI capability should be
treated with PPCI within 90 min of first medical contact (level
of evidence A). In patients presenting to a hospital without PCI
capability and who cannot be transferred to a hospital centre
and undergo PCI within 90 min of first medical contact, therapy
should be administered within 30 min of hospital presentation
unless contraindicated (level of evidence B). The goal is to
organize systems of care such that the total ischaemic time be
120 min.The goals for each management step are the following:
1. time from symptom onset to first call to emergency medical
service (EMS): 5 min,
2. with 1 min EMS dispatch;
3. EMS on scene within 8 min,
4. ECG on scene and consider pre-hospital fibrinolytic therapy
by EMS if capable and time to lytic therapy, 30 min;
5. if transportation to a hospital without PCI capability, DN
time, 30 min;
6. if transportation to ahospital with PCI capability, EMS-toballoon time, 90 min (if patientself-transport: DB time, 90
min).
The National Institute for Clinical Excellence supports
reperfusion with fibrinolytics, recommending PHT using
the newer agents, reteplase and tenecteplase, whose bolus
application simplifies administration.
“People with symptoms of a possible heart attack should receive help
from an individual equipped with and appropriately trained in the use
of a defibrillator within eight minutes of calling for help, to maximize
the benefits of resuscitation should it be necessary and...
People thought to be suffering from heart attack should be assessed
professionally and, if indicated, receive aspirin. Thrombolysis should
be given within 60 minutes of calling for professional help.”
There has been recognition that a goal of providing
thrombolysis within this 60-minute time window may be difficult
when transport distances (or times) are long. To address this
issue the NSF states:
“...usually hospital will be the best place to give thrombolysis.
However, where the ‘call-to-hospital’ time cannot be reduced
below 30 minutes, it may be more appropriate to plan to give
thrombolysis before admission to hospital.”
Pre-hospital thrombolysis: advantages
and limitations
PHT constitutes one of the means to shorten time delays
before the administration of reperfusion therapy. However, it
poses several organizational problems that can find different
answers according to each regional/national system of care. A
number of barriers may exist and limit the actual use of PHT.
Finally, there remains a discussion on the optimal system
of prehospital care, with the on-site involvement of physicians
17
or with the involvement of paramedics without physicians.
A study of 641 consecutive STEMI patients in Finland found
that the clinical results achieved with an EMS with the on-site
involvement of physicians were superior to those of an EMS
with only paramedics on site.22 Obviously, the system of care
chosen is likely to have a definite impact on the percentage
of STEMI patients in whom PHT can be delivered. In the
recent French registry of MI in 2005, PHT was used in 19%
of the STEMI patients admitted to intensive care units within
48 h of pain onset, representing two-thirds of those treated
with intravenous thrombolysis.23 From a practical standpoint,
emergency ambulances in France are physician-staffed and PHT
is administered by physicians who decide on its use after the
initial clinical and ECG work-up.24
Feasibility of PHT in India
It depends on multiple factors
1. Availability of Emergency medical services
2. Accessibility to EMS
3. Trained paramedics and emergency physicians
4. Thrombolytics- Infusion vs. bolus
5. Role of telemedicine
6. Organized PHT program
It is terms like ‘The Golden Hour’ that typify the importance
of Emergency Medical Services (EMS) all over the world. It
is a well-accepted fact that a patient who receives PHT from
trained professionals and is transported to the nearest healthcare
facility in case of PPCI has the greatest chance of survival.
However, the state of EMS varies drastically from developed to
developing countries like India. In spite of the development in
the healthcare sector over the past decade, India is yet to create
a single, comprehensive EMS that can be accessed throughout
the country.
Scenario in India
As compared to developed countries with proper emergency
systems in place, there is no single system which could play a
major role in managing emergency medical services in India.25
There is a fragmented system in place to attend the emergencies
in the country. 102 is the emergency telephone number for
ambulance in parts of India. There are different emergency
numbers in India’s 28 states and seven Union Territories.
Hospitals in the country provide different telephone numbers
for ambulance services. Clearly, India is in need for proper
emergency medical service that can be accessed from anywhere
in the country. India requires a better emergency medical
service to meet the growing number of emergencies. What exists
currently in the form of fragmented services across the country
falls way short of meeting the requirement. More recently, NGOs
and hospitals have come forward to provide their own EMSs.
There have been considerable efforts by states across India to
develop emergency services.
In 2007, with the extension of Ambulance Access for All
(AAA)’s services, American Association of Physicians of Indian
Origin (AAPI) founded Emergency Medical Service (EMS) for
Mumbai. AAPI has collaborated with the Confederation of
Indian Industries (CII) and signed a MoU to endorse the growth
of the healthcare sector in India, especially in rural areas. This
agreement is to provide knowledge and technology transfer and
provide EMS to develop healthcare facilities in India.
Another such facility, Life Support Ambulance Service
(LSAS) operating in Mumbai for three years in association with
18
London Ambulance Service, UK, has now made inroads into
Kerala and has 500 ambulances that can be reached on a toll
free number 1298.
Legislation for emergency services The demand for legislation for EMS has been rising steadily in
India. Supporters of such legislation opine that it would mandate
a common access number, formation of an EMS council, trained
paramedics, gradation of ambulance and hospitals, network of
hospitals and define physical and human resources needed for
the service. This could help save lives by making access easy
for all the patients. Methods, technology, personal skills need
to be standardized with formation of legislation in emergency
services to provide protection for the providers.
Recent introduction of bolus form of thrombolytic agents and
role of telemedicine in decision making would help to form the
organized PHT program in India.
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