Clincal Resarch Article |
|
Pre-hospital Thrombolysis
Aijaz H Mansoor, Upendra Kaul, Department of Cardiology
Escorts Heart Institute and Research Centre, New Delhi
|
Pre-hospital thrombolysis is the administration of a bolus thrombolytic agent to an eligible patient with acute ST- Elevated Myocardial infarction (STEMI) as soon as possible after the onset of symptoms-- at his home, the nearest health centre or the ambulance.
The concept is attractive, logical and has advantages as well as limitations. It derives from the principle that the earlier the patency and flow of the infarct-related vessel is established, the better the survival of the patient.
STEMI is a major health problem of the world. In 2001, 7.1 million deaths were attributed to ischemic heart disease worldwide, 1 80% of which were in low-income countries.2, 3 Half a million people suffer a STEMI in the US each year.4 The prevalence of CAD is increasing in South Asians. India is expected to have 60% of world’s heart disease by 2010.5 Coronary risk factors are more common in south Asians as compared to the rest of the world and CAD manifests at a younger age.6, 7 The CREATE registry data8 has provided some important insights into the natural history of acute coronary syndromes in India as shown in table 1
Table1. natural history of acute coronary syndromes in India
- Patients are younger at presentation (mean age 57.5 years)
- lower socioeconomic groups are substantially affected (75%)
- STEMI is more common in Indians as compared to the West
- medical attention is received late (median 6 hr after onset of symptoms)
- majority of patients receive thrombolysis (80%)
- Median door-to needle time (DTN) is 50 min
- standard of care medications are received less often
- 30-day mortality is higher as compared to the west
- most patients reach hospital by private/public transpor
- most patients pay directly for their own treatment
The scenario of acute coronary syndromes in India calls for a lot of improvement. The lower rate of education and awareness in the lower socioeconomic strata, infrastructural problems, financial difficulties, lack of ambulance services, suboptimal DTN, and lack of widespread primary PCI programs make pre-hospital thrombolysis a potentially important option here.
|
|
Pathophysiology of STEMI
Formation of an occluding thrombus over a ruptured atherosclerotic plaque in the infarct-related artery results in STEMI in > 90% cases.9 Timely reperfusion interrupts evolving myocardial necrosis, salvages viable myocardium and preserves LV function with consequent improved survival. Every minute counts (time is muscle).
Possible remedies to reduce total ischemia time include public education for early response to symptoms and pre-hospital thrombolysis
Thrombolysis versus primary PCI
Current ACC/AHA guidelines emphasize the provision of timely reperfusion to the patient rather than the mode of reperfusion.10 In the first 3 hr either strategy is acceptable, beyond which Primary PCI is preferred
Primary angioplasty has been shown to be superior to thrombolysis in reducing mortality, recurrent MI and stroke.11 There is a 2% absolute reduction in mortality compared with thrombolysis irrespective of the lytic agent used.12As per ACC/AHA guidelines: if a PCI-capable hospital is accessible (and affordable) to the patient within 30 min and its door-to-balloon time (DTB) is <90 min, then Primary PCI is the choice. The vast majority of patients however, has no access to these facilities, and will consequently benefit more from timely thrombolysis.
Survival benefit for thrombolysis
Data from randomized clinical trials involving > 58,000 patients indicates that thrombolysis confers a 20-25% relative mortality benefit.13 Fibrinolytic therapy Trialists collaborative group (FTT) overview of 13 large randomized trials that compared fibrinolytic therapy with control (58,600 patients) 13 revealed that 30 lives are saved /1000 patients treated within 6 hr of symptom onset and 20 lives are saved /1000 patients treated from >6—12 hr. Beyond 12 hr, the life-saving capacity of thrombolysis is lost. The greatest benefit accrues in the first hour (golden hour) wherein 65 lives can be saved/ 1000 patients’ treated.13 Early thrombolysis (within 2-3 hours) therefore has the best prognostic benefit. The CAPTIM study14 compared pre-hospital thrombolysis followed by prompt transfer to a PCI-
|
Correspomdence: Dr.Upendra Kaul, Department of Cardiology, Escort Heart Institute and Research Centre, New Delhi, India
Email: ukaul@vsnl.com |
|
Indian Heart J. 2009; 61:433-436 |
Upendra Kaul et al |
|
capable hospital (for rescue PCI, if needed) versus primary PCI in 845 patients. A trend of lower 30-day mortality in the pre-hospital thrombolysed group was observed in this study, especially in patients managed within the first 2 hr.15 The 5-yr follow-up of CAPTIM has been published.16 At 5 years, the pre-hospital strategy is not inferior to Primary PCI. Importantly, for patients treated within 2 hr of symptom onset, 5-yr mortality was significantly lower with pre-hospital thrombolysis and immediate transfer to a PCI capable hospital for rescue PCI if needed, as compared to Primary PCI. The ASSENT-3 Plus trial17 showed that pre-hospital administration allows up to one-half of patients to be treated within 2 hr of symptom onset. On the other hand, The MI registry data from the USA and Europe indicate that 50% of patients eligible for thrombolysis do not report within 3 hours, 18 and another 25% arrive in the hospital more than 6 hr after onset of symptoms.18, 19 Causes of delay to in-hospital thrombolysis are listed in table 2
Despite emphasis on early reperfusion, the median time to thrombolysis has not improved in large clinical trials of MI (GUSTO-1 (1993) median time 165 min; HERO-2 (2001) median time 198 min)
Table 2. Causes of delay to in-hospital thrombolysis
Patient factors: Delayed reaction of patients to their symptoms.
Transportation factors: Increased transport time (dependence on infrastructure,
Hospital distances, time of day).
Hospital factors: Increased door-to-needle time (DTN) of the hospital.
---------------------------------------------------------------------------------------------------------
The evidence-base for Pre-hospital thrombolysis
A number of randomized trials have compared pre-hospital with in-hospital thrombolytic therapy. Although most of them were small and not powered enough to show statistical significance, together they provide compelling evidence that pre-hospital thrombolysis is safe and effective in properly diagnosed and eligible patients. European Myocardial Infarction project (EMIP) 20, myocardial infarction
Triage and intervention (MITI) Trial21, Grampian Region early anistreplase Trial (GREAT) 22 and ER-TIMI 1923 are some of these trials of note. In all of these trials a trend towards lower mortality in the pre-hospital group was noted. Several registry data provide additional support for pre-hospital thrombolysis.24,25 A meta-analysis of all early trials demonstrated a 17% reduction in mortality in the pre-hospital group.26 Combined data analysis of all trials reveals a one hour gain by Pre-hospital thrombolysis that translates into 20 lives saved /1000 patients treated.27
|
Pre-hospital Thrombolysis Programs in Practice
Many communities in Europe and North America have successful on-going pre-hospital thrombolysis programs. Dutch experience28: Reperfusion in Acute Infarction Rotterdam (REPAIR) program was initiated in 1988, in Rotterdam, the Netherlands. An ambulance nurse initiated pre-hospital thrombolysis followed by transfer to the hospital. Mortality after 30 days, 1 year, 5years and 10 years was 4.9%, 7.3%, 16.2% and 30.1% respectively. These results are gratifying when compared to the mortality figures of recent trials of MI patients (30-day 5.5-7%; 1-yr 9-11% respectively: GUSTO V (2001), HERO-2 (2001) ASSENT 2(1999) and ASSENT 3 (2001)
East Anglican experience29: 1062 patients received paramedic-initiated pre-hospital thrombolysis, and actuarial survival was 93.9% at 30 days and 90.8% at 1-yr, attesting to the safety and efficacy of this program.
Pre-hospital process
General practitioners trained in ECG interpretation and use of bolus thrombolytics can safely and effectively administer pre-hospital thrombolysis. Alternatively, an organized ambulance system can be created wherein trained paramedics reach the patient, obtain an ECG, read it, administer a checklist to r/o contraindications and as per protocol either administer the thrombolytic or fax / tele-transfer the ECG to the base hospital emergency department where a physician interprets it and authorizes thrombolysis. The ambulance then transfers the patient to the hospital.
Bolus thrombolytic agents
Bolus thrombolytics (Tenecteplase and reteplase) are currently recommended. They save additional 10 lives /1000 patients treated as compared to streptokinase with a slightly greater risk of intracranial hemorrhage. The salient features of these agents are shown in table 3
Table 3 Comparison of 2 bolus thrombolytic agents
---------------------------------------------------------------------------------------
agent tenecteplase reteplase
---------------------------------------------------------------------------------------
source recombinant DNA recombinant DNA
technology technology
half-life 20 min 15 min
fibrin specificity ++ +
Allergic reactions + 0
Re-occlusion 5-20% --
PAI-resistance ++ +
Need for I/V heparin yes yes
Dosage weight-based 2 injections, 10 units
Each, 30 min apart
< 60 kg-- 30mg
60-70 kg--35mg
71-80 kg--40mg
81-90 kg—45mg
>90 kg—50mg
----------------------------------------------------------------------------------------------
|
Indian Heart J. 2009; 61:433-436 |
|
| |
Pre-hospital Thrombolysis |
|
ASSENT-130study established the safety of single bolus administration of tenecteplase. ASSENT-231 found tenecteplase and r-tPA (alteplase) equivalent in safety and efficacy
ASSENT-3 Plus32 evaluated tenecteplase + enoxaparin in pre-hospital setting. A time gain of 47 min was observed, allowing 52% of patients to be treated within 2 hours of symptom onset (as against 29% in ASSENT33). Early treatment leads to a lower mortality. The safety and efficacy of indigenously manufactured tenecteplase was recently examined in Indian patients with STEMI.34 Tenecteplase was found safe. (Overall incidence of ICH 0.99%; re-infarction 2.96%) and effective (successful thrombolysis reported in 85.86% within 3 hours of symptom onset). A few more bolus Thrombolytics are in the investigational phase of development. Examples include Amedioplase, Monteplase, Pamitoplase and Saruplase.
5
Adjunctive pre-hospital treatment
The pre-hospital CLARITY-TIMI-28 35 sub-study showed that an oral loading dose of 300 mg clopidogrel together with aspirin, heparin, and a bolus fibrinolytic is safe and associated with earlier and more complete reperfusion of the infarct-related artery.
Risks of thrombolysis
Bleeding is the predominant risk of thrombolytic therapy. Intracerebral hemorrhage (ICH) is the most feared complication (0.5%-1%). The 4 independent predictors of ICH are: old age (>65 yr), weight less than 70kg, female sex and hypertension. Allergic reactions can rarely occur with tenecteplase. Lytic therapy restores normal TIMI 3 flow in <70% of infarct-related arteries.
Current guidelines
1. At this time, the ACC/AHA36 recommends that the pre-hospital fibrinolysis protocol is reasonable in settings in which physicians are present in the ambulance.
2. It is also reasonable to consider pre-hospital fibrinolysis within a well-organized EMS system, which comprises full-time trained paramedics, 12-lead ECG systems in the field, ECG transmission capabilities and a physician in the emergency department who reviews and authorizes thrombolysis.
Post-thrombolysis Management
Two strategies have been found beneficial.
1. CAPTIM strategy: Pre-hospital thrombolysis, especially within 2 hours followed by immediate transfer to a PCI-capable hospital for rescue PCI, if needed. In CAPTIM, 70% of patients initially treated with pre-hospital fibrinolysis underwent PCI within the hospital stay either as rescue PCI (in those not responding to fibrinolysis) or later as elective PCI This strategy of pre-hospital fibrinolysis with immediate transfer to an interventional facility for rescue angioplasty if needed appears to yield long-term survival similar to that of primary angioplasty |
2. TRANSFER-AMI strategy37: Thrombolysis followed by early routine PCI in all patients. This trial demonstrated significant benefit of the pharmaco-invasive strategy as compared to standard treatment. Analysis of the 5 trials of Pharmaco-invasive approach suggest that best results are obtained when early PCI is performed 2-24 hours after thrombolysis.38
Conclusions
Primary PCI currently is the optimal management in STEMI, but is not widely available. Fibrinolysis is still the major reperfusion strategy worldwide, “The earlier the better”. As has been said, ‘it is never too early to reperfuse a STEMI patient’. Patients should be transferred promptly to a PCI capable hospital. If successful Pre-hospital thrombolysis is administered within 2 hr of symptom onset, ischemia-driven PCI is a beneficial option. Otherwise, the pharmaco-invasive approach (thrombolysis followed by early routine PCI) is evidence-based.
References
Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 2006; 367: 1747–57.
2 Yusuf S, Reddy S, Ounpuu S, Anand S. Global burden of cardiovascular diseases: part I: general considerations, the epidemiologic transition, risk factors, and impact of urbanization. Circulation 2001; 104: 2746–53.
3 Reddy KS. Cardiovascular disease in non-Western countries. N Engl J Med 2004; 350 (24): 2438–40.
.
4. American Heart Association. Heart disease and stroke statistics – 2008 update
Available at www.americanheart.org/downloadable/heart/1200082005246HS_Stats%202008.final.pdf.
5. Ghaff ar A, Reddy KS, Singhi M. Burden of non-communicable diseases in South Asia. BMJ 2004; 328: 807–10.
6. Mohan V, Deepa R, Rani SS, Premalatha G. Prevalence of coronary artery disease and its relationship to lipids in a selected population in South India: The Chennai Urban Population Study (CUPS No. 5). J Am Coll Cardiol 2001; 38: 682–87.
7. Joshi P, Islam S, Pais P, et al. Risk factors for early myocardial infarction in South Asians compared with individuals in other countries. JAMA 2007; 297: 286-94
8. Treatment and outcomes of acute coronary syndromes in India (CREATE): a prospective analysis of registry data. Denis Xavier, Prem Pais, P J Devereaux, Changchun Xie, D Prabhakaran, K Srinath Reddy, Rajeev Gupta, Prashant Joshi, Prafulla Kerkar, S Thanikachalam, K K Haridas, T M Jaison, Sudhir Naik, A K Maity, Salim Yusuf; on behalf of the CREATE registry investigators Lancet 2008; 371: 1435–42
9. DeWood MA, Spores J, Notske R, et al. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med 1980; 303: 897–902
10. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the
management of patients with ST-elevation myocardial infarction—executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1999 guidelines for
the management of patients with acute myocardial infarction). J Am Coll Cardiol 2004; 44: 671–719. |
|
Indian Heart J. 2009; 61:433-436 |
| |
Upendra Kaul et al |
|
11. Keeley EC, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet 2003; 361:13–
12. Weaver WD, Simes RJ, Betriu A et al. Comparison of primary coronary angioplasty and intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review. JAMA 1997; 278:2093–8.
13. Fibrinolytic Therapy Trialists’ Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomized trials of more than 1,000 patients. Lancet 1994; 343:311–322.
14. Bonnefoy E, Lapostolle F, Leizorovicz A, et al. Primary angioplasty versus prehospital fibrinolysis in acute myocardial infarction. Lancet 2002;360:825-829.
15. Steg PG, Bonnefoy E, Chabaud S, et al. Impact of time to treatment on mortality after prehospital fibrinolysis or primary angioplasty: data from the CAPTIM randomized clinical trial Circulation 2003;103:2851-2856.
16. Bonnefoy E, Steg PG, Boutitie F et al. Comparison of primary angioplasty and prehospital fibrinolysis in acute myocardial infarction (CAPTIM) trial: a 5-year follow-up: Eur Heart J 2009; july: 1598-1608
17. Wallentin L, Goldstein P, Armstrong PW, et al. Efficacy and safety of tenecteplase in combination with the low molecular- weight heparin enoxaparin or unfractionated
heparin in the prehospital setting: the Assessment of the Safety and Efficacy of a New Thrombolytic Regimen(ASSENT)-3 PLUS randomized trial in acute myocardial
infarction. Circulation 2003; 108: 135–42.
18. Weaver WD. Time to thrombolytic treatment: factors affecting delay and their
influence on outcome. J Am Coll Cardiol 1995; 25(suppl):3S-9S.
19. Hasdai D, Behar S, Wallentin L et al. A prospective survey of the characteristics,
treatments and outcomes of patients with acute coronary syndromes in Europe and
the Mediterranean Basin: The Euro Heart Survey of Acute Coronary Syndromes.
Eur Heart J 2002; 23:1190–201
20. European Myocardial Infarction Project Group. Prehospital thrombolytic therapy in
patients with suspected acute myocardial infarction. N Engl J Med 1993; 329:383-9
21. Weaver WD, Cerqueira M, Hallstrom AP et al. for the Myocardial Infarction
Triage and Intervention Project Group. Prehospital-initiated vs hospital-initiated
thrombolytic therapy. The Myocardial Infarction Triage and Intervention trial.
JAMA 1993; 270:1211–16.
22. GREAT Group. Feasibility, safety, and efficacy of domiciliary thrombolysis by
general practitioners: Grampian Region Early Anistreplase Trial. BMJ 1992; 305:
548–53.
23. Morrow DA, Antman EM, Sayah AJ, et al. Evaluation of the time saved by prehospital initiation of reteplase for ST-elevation myocardial infarction: results of the Early Retevase-Thrombolysis in Myocardial Infarction (ER-TIMI)-19 trial. J Am Coll Cardiol 2002;40:71-77.
|
24. Danchin N, Blanchard D, Steg PG, Sauval P, Hanania G, Goldstein P, Cambou JP, Gueret P, Vaur L, Boutalbi Y, Genes N, Lablanche JM: Impact of prehospital thrombolysis for acute myocardial infarction on 1-year outcome: results from the French Nationwide USIC 2000 Registry. Circulation 2004; 110:1909-1915.
25. Bjorklund E, Stenestrand U, Lindback J, Svensson L, Wallentin L, Lindahl B: Pre-hospital thrombolysis delivered by paramedics is associated with reduced time delay and mortality in ambulance-transported real-life patients with ST-elevation myocardial infarction. Eur Heart J 2006; 27:1146-1152.
26. Morrison LJ, Verbeek PR, McDonald AC, Sawadsky BV, Cook DJ: Mortality and prehospital thrombolysis for acute myocardial infarction: A meta-analysis JAMA 2000; 283:2686-2692.
27. Morrison LJ, Verbeek PR, McDonald AC, et al. Mortality and prehospital thrombolysis for acute myocardial infarction. JAMA 2000;283:2686-2692.
28. Boersma E. Pre-hospital fibrinolytic therapy. In Verheugt F. Ed. Fibrinolytic Th erapy in Clinical Practice. London. Martin Dunitz,(Taylor & Francis Group plc). 2005:103-122
29. 29. Khan SN, Murray P, Me Cormick L, et al. Paramedic–led Pre-hospital thrombolysis is safe and effective. The East Anglican experience. Emergency Medicine Journal 2009; 26 : 452 - 455
30. van de Werf FJ, Cannon CP, Luyten A, et al. Safety assessment of single-bolus administration of TNK tissue-plasminogen activator in acute myocardial infarction: the
ASSENT-1 trial. The ASSENT-1 Investigators. Am Heart J 1999; 137:786–791.
31. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial
infarction: the ASSENT-2 double-blind randomised trial. Assessment of the Safety and
Efficacy of a New Thrombolytic Investigators. Lancet 1999; 354:716–722.
32. Wallentin L, Goldstein P, Armstrong PW, et al. Efficacy and safety of tenecteplase in combination with the lowmolecular- weight heparin enoxaparin or unfractionated
heparin in the prehospital setting: the Assessment of the Safety and Efficacy of a New Thrombolytic Regimen(ASSENT)-3 PLUS randomized trial in acute myocardial
infarction. Circulation 2003; 108: 135–42.
33. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3 randomised trial in acute myocardial infarction. Lancet 2001; 358: 605–13
34. Satyamurtthy I, Srinivasan KN, Jayanthi K et al. Efficacy and safety of Tenecteplase in Indian patients with ST-segment elevation Myocardial Infarction.Indian heart Journal 2008:60;(6);554-557
35. Montalescot G, Verheugt F, Sabatine MS, et al. Prehospital fibrinolysis with dual antiplatelet therapy in ST-elevation myocardial infarction. The prehospital CLARITY-TIMI-28 substudy. Circulation 2005;112:Suppl II:567 (abstract).
36. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction—executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1999 guidelines for
the management of patients with acute myocardial infarction). J Am Coll Cardiol 2004; 44: 671–719.
37. Cantor WJ, Fitchett D, Borgundvaag B et al, Routine Early Angioplasty after Fibrinolysis for Acute Myocardial Infarction. the TRANSFER-AMI Trial Investigators N Engl J Med 2009;360:2705-18.
38. Verheugt FWA. Routine Angioplasty after Fibrinolysis — How Early Should “Early” Be? Editorial. N Engl J Med 2009;360:2779-81
|
Indian Heart J. 2009; 61:249-253 |
|