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Little is known about thrombolytic therapy patterns in patients with ST-elevation myocardial infarction (STEMI) in the Middle East. The objective of this study was to evaluate the clinical profile and mortality of STEMI patients who arrived in hospital within 12 hours from pain onset and received thrombolytic therapy.
This was a prospective, multinational, multi-centre, observational survey of consecutive acute coronary syndrome patients admitted to 65 hospitals in six Middle Eastern countries during the period between October 2008 and June 2009, as part of Gulf RACE-II (Registry of Acute Coronary Events). Analyses were performed using univariate statistics.
Out of 2,465 STEMI patients, 66% (n = 1,586) were thrombolysed with namely: streptokinase (43%), reteplase (44%), tenecteplase (10%), and alteplase (3%). 22.7% received no reperfusion. Median age of the study cohort was 50 (45-59) years with majority being males (91%). The overall median symptom onset-to-presentation and door-to-needle times were 165 (95- 272) minutes and 38 (24-60) minutes, respectively. Generally, patients presenting with higher GRACE risk scores were treated with newer thrombolytic agents (reteplase and tenecteplase) (P < 0.001). The use of newer thrombolytic agents was associated with a significantly lower mortality at both 1-month (0.8% vs. 1.7% vs. 4.2%; P = 0.014) and 1-year (0% vs. 1.7% vs. 3.4%; P = 0.044) compared to streptokinase use.
Majority of STEMI patients from the Middle East were thrombolysed with streptokinase and reteplase in equal numbers. Nearly one-fifth of patients did not receive any reperfusion therapy. There was inappropriately long symptom-onset to hospital presentation as well as door-to-needle times. Use of newer thrombolytic agents in high risk patients was appropriate. Newer thrombolytic agents were associated with significantly lower mortality at 1-month and 1-year compared to the older agent, streptokinase.
Raeperfusion strategies such as primary percutaneous coronary intervention (PCI) and thrombolytic therapy (TT) are the most effective management techniques in patients with ST-elevation myocardial infarction (STEMI).[1,2] The preferred strategy, when it can be performed in a timely fashion, is primary PCI, which produces outcomes superior to those of TT. Unfortunately, in majority of countries including the United States about half of patients present to hospitals that do not have PCI capability. In an analysis, 91% of transferred patients had a door-to-balloon time greater than the recommended 90 minutes. In addition, as the time delay in door-to-balloon time increases, the mortality benefit of PCI over TT declines.[1,2] Furthermore, the guidelines do not state a preference between primary PCI and TT in STEMI patients presenting within the first 3 hours.[1,2] Hence, TT remains the default reperfusion strategy for STEMI patients in majority of the countries. Due to lack of hospitals with 24/7 catheterization laboratory facilities in the Middle East region, TT remains the major reperfusion strategy.[6,7]
Several thrombolytic agents currently being used differ with respect to fibrin affinity, fibrin specificity, method of administration (bolus vs. infusion), allergic reactions, and multiple other parameters.[8–10] Little is known about the use of various thrombolytic agents in the Middle East countries including the type of the agent used, whether they are appropriately used, as well as their impact on 30-day and 1-year mortality. The aim of the study was to evaluate the clinical characteristics and mortality of STEMI patients receiving TT in six Middle Eastern countries.
The Gulf Registry of Acute Coronary Events-II (Gulf RACE-II) is a large prospective, multinational, multicentre registry of acute coronary syndrome (ACS) patients in the Middle East during the period between October 2008 and June 2009. The study recruited 7,930 consecutive ACS patients above 18 years of age hospitalized with the final diagnosis of ACS from six adjacent Middle Eastern Gulf countries (Bahrain, Saudi Arabia, Qatar, Oman, United Arab Emirates, and Yemen). Patients were recruited from 65 hospitals with the final diagnoses of ACS including unstable angina and non-ST- and ST-elevation myocardial infarction (NSTEMI and STEMI, respectively). There were no exclusion criteria. Diagnosis of the different types of ACS and definitions of data variables were based on the American College of Cardiology clinical data standards. Demographic, clinical, and in-hospital treatment and outcome characteristics of the patients were also elicited. Patients were stratified into low-, medium-, and high-risk groups based on tertiles of the calculated baseline Global Registry of Acute Coronary Events (GRACE) risk score (variables: age, Killip class, systolic blood pressure, ST segment deviation, cardiac arrest on admission, serum creatinine, raised cardiac markers, heart rate).
Diabetes was defined as having a history of diabetes diagnosed and treated with medication and/or diet or fasting blood glucose 7.0 mmol/l (126 mg/dl) or greater. Hypertension was defined as having a history of hypertension diagnosed and treated with medication, diet, and/or exercise, blood pressure greater than 140 mmHg systolic or 90 mmHg diastolic on at least two occasions or as receiving any antihypertensive drug. Hyperlipidemia was defined as history of dyslipidemia diagnosed and/or treated by a physician or total cholesterol greater than 5.18 mmol/l (200 mg/dl), low-density lipoprotein greater than or equal to 3.37 mmol/l (130 mg/dl) or high-density lipoprotein less than 1.04 mmol/l (40 mg/dl). Current smoker was defined as smoking cigarettes or water-pipe (sheesha) or Khat chewer within 1 month of index admission. A positive family history for coronary artery disease was defined as evidence of coronary artery disease in a parent, sibling, or children before 55 years of age. Obesity was defined as body mass index (BMI) greater than 30 kg/m2. For each participating hospital, data were collected regarding site of thrombolysis, i.e., emergency room (ER) or coronary/intensive care unit (CCU/ICU), and whether thrombolysis was provided by cardiology service unit or ER physicians. Renal impairment in this study was defined as serum creatinine of >177 μmol/l (2 mg/dL). In-hospital medications recorded for the purpose of this study included aspirin, clopidogrel, statin, beta-blocker, angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), as well as the use of other dyslipidemic therapies. The study received ethical approval from the institutional ethical bodies in all participating countries.
Descriptive statistics were used to describe the data. For categorical variables, frequencies and percentages were reported. Differences between groups were analyzed using Pearson's chi-square test (or Fisher's exact test for cells <5). For continuous variables, median and interquartile range (25th and 75th percentiles) were used to present the data while analysis was performed using the Kruskal Wallis test. An a priori two-tailed level of significance was set at the 0.05 level. Statistical analyses were conducted using STATA version 12.0 (STATA Corporation, College Station, TX).
Among 2,465 STEMI patients who presented to the hospital within 12 hours of symptoms onset, 66.0% (n = 1,586) were thrombolysed while 7.6% (n = 183) had primary PCI. The rest of the STEMI population included those that were contraindicated to thrombolysis (3.7%; n = 88), while the remaining was the shortfall to reperfusion (22.7%; n = 544). Out of the cohort that was thrombolysed, 43% (n = 674) were treated with streptokinase, 44% (n = 700) with reteplase, 10% (n = 164) with tenecteplase, while the rest, 3% (n = 48) were given alteplase. For the purpose of this study and due to the small sample size of alteplase patients, only those that were treated with streptokinase, reteplase, and tenecteplase were included in this study (n = 1,538).
Demographic, clinical, and hospital/physician characteristics are outlined in Table 1. The overall median age of the cohort was 50 (45-59) years with majority being males (91%). The overall median symptom onset-to-presentation was 165 (95-272) minutes with those treated with streptokinase presenting significantly late after symptom onset than those administered either reteplase or tenecteplase (190 vs. 137 vs. 170 minutes, respectively; P < 0.001). The overall median door-to-needle time was 38 (24–60) minutes with those treated with streptokinase having slight delay in door-to-needle times than those administered reteplase or tenecteplase (40 vs. 35 vs. 34 minutes, respectively; P < 0.001). There were also significantly fewer patients in the streptokinase group who had their door-to-needle times of <30 minutes than those on reteplase or tenecteplase cohorts (27% vs. 39% vs. 38%; P < 0.001).
There were no significant differences in the majority of risk factors and clinical presentation among the three TT groups. Compared to the streptokinase group, the reteplase and tenecteplase cohorts were younger, more likely to have hyperlipidemia with a higher proportion of patients with higher GRACE risk scores. Thrombolytic agents were more likely to be administered by a cardio service unit than an ER physician. Streptokinase patients were more likely to be administered the thrombolytic agent in an ICU/CCU setting; however, the newer thrombolytic agents were more likely to be administered in an ER environment.
Table 2 presents medications use among STEMI patients in six Middle Eastern countries pre-admission, during in-hospital, and at discharge. There was a prominent use of aspirin (93%), while clopidogrel was prescribed in only 71% of the patients at discharge. Seventy percent of the patients (n = 1073) were on both aspirin and clopidogrel concurrently during admission. The other most commonly prescribed medication at discharge was statin (93%) followed by beta-blockers (82%). ACEIs were prescribed in 76% of the subjects while ARBs (4.3%) were infrequently used. There was clearly a marked increase in evidence-based cardiac medications use between pre-admission and in-hospital. Compared to the streptokinase group, the newer thrombolytic agents were associated with the increased use of clopidogrel, beta-blocker, and ACEI.
The overall 30-day and 1-year mortalities were 2.68% and 2.21%, respectively. The effect of thrombolytic agents on 1-month and 1-year mortality is also shown in Table 3. Tenecteplase and reteplase patients were associated with a significantly lower mortality at 1-month compared to streptokinase patients (0.8% vs. 1.7% vs. 4.2%; P = 0.014). Furthermore, this reduction in mortality was also seen at 1-year, where tenecteplase and reteplase patients had lower mortalities when compared to the patients on streptokinase (0% vs. 1.7% vs. 3.4%; P = 0.044).
The present study is the first to compare clinical characteristics among STEMI patients from the Middle East treated with three commonly used thrombolytic agents. The main findings from this study are: STEMI patients from the Middle East are predominantly male, young and are thrombolysed with streptokinase and reteplase in equal numbers; nearly one-fifth of eligible STEMI patient did not receive any reperfusion therapy; there was inappropriately long symptom-onset to hospital presentation time as well as door-to-needle time; use of newer thrombolytic agents in high risk patients was appropriate; and newer thrombolytic agents were associated with significant reduction in mortality at both 1-month and 1-year compared to the older agent, streptokinase.
In this registry, among 2,465 STEMI patients who presented to the hospital within 12 hours of symptoms onset, the majority were male and young. Nearly 66% of the total STEMI patients received thrombolysis, indicating that thrombolysis is the major form of reperfusion strategy in the Middle East countries. However, nearly 23% of the patients with STEMI who present within 12 hours and are candidates for TT according to current guidelines, did in fact receive no such therapy. This is not different from the situation in other countries, since this reperfusion therapy shortfall is already known from multinational registries in Europe and other countries, and remains an issue.[13,14]
The overall median symptom-onset to hospital presentation was 165 minutes, which is inappropriately- long compared to 89 minutes and 120 minutes in Emergency Medical Services (EMS)-transported and self-transported patients, respectively, in the NCDR registry. One of the main possible reason for this long delay is underutilization of EMS services in the Middle Eastern countries (only 17% vs. 60% in NCDR registry). Increased delay times to restoration of coronary flow are associated with increased infarction size, increased risk of subsequent congestive heart failure, and higher mortality. Furthermore, those patients who presented late were more likely to be treated with streptokinase than with either reteplase or tenecteplase (190 vs. 137 vs. 170 minutes, respectively). This is in contrast to guideline recommendations which advocate fibrin-specific newer thrombolytic agent for patients presenting more than 4 hours after the onset of symptoms. This is attributed to the drug's fibrin specificity leading to better dissolution of older coronary clots.[1,2] The overall median door-to-needle time in this study was 38 minutes which is longer compared to 29 and 30 minutes seen in the NCDR and GRACE registry, respectively.[15,17] The predominant cause for this delay observed in this registry was the administration of TT by the cardiology service unit and in CCU/ICU rather than in the ER room by the ER physicians thus leading to a delay in transport and subsequent administration of TT. The guideline recommended optimal door-to-needle time of <30 minutes was achieved in only 34% of the patients, which is low compared to 45%, 64% and 67% in the GRACE, Euro Heart Survey ACS-III and the UK MINAP registry, respectively.[17–19]
Out of the cohort that was thrombolysed; equal numbers of patients were treated with reteplase and streptokinase, even though guidelines recommend newer thrombolytic agents such as reteplase and tenecteplase which have the potential advantages of prolonged half-life (less re-occlusion rates), increased fibrin specificity (more potent and lower non-cerebral bleeding risk) and increased resistance to inhibition by plasminogen activators as well as increased 90-minute coronary patency rates (60-75% vs. 50% with streptokinase) and TIMI (Thrombolysis in Myocardial Infarction) grade 3 flow ( 60% vs. 32% with streptokinase).[1,2] The majority of patients in the higher GRACE risk score were treated with newer thrombolytic agents. This is in accordance with the guideline recommendations. One other observation from our data relates to the increased use of evidence based secondary prevention drug therapies in patients treated with newer TT when compared to streptokinase.
Apart from the GUSTO-I trial that demonstrated the superiority of alteplase over streptokinase, no other trial has demonstrated a reduced mortality with one thrombolytic agent in comparison with another.[9,10,20–23] In two large meta-analysis comparing the efficacy of thrombolytics in acute myocardial infarction, Dundar et al., and Giraldz et al., reported that there was no significant differences in 30-35 days mortality among these three thrombolytic agents. In this registry, on univariate analysis, the use of newer thrombolytic agents was associated with significantly lower mortalities at both 1-month and 1-year. The mortality benefits of the newer thrombolytic agents in this registry may be related to more use of other evidence based medications with newer thrombolytic agents as demonstrated in this study as well as in CLARITY-TIMI-28 (Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis in Myocardial Infarction) and COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial) trials. This study has clinical implications. The mortality benefit seen from newer thrombolytic agents suggests that there should be a change in the pattern of use of thrombolytic agents in the Middle East countries. The use of streptokinase needs to be discouraged. The cost consideration does not seem to be a factor in this population as treatment in the Middle Eastern countries is provided freely to their citizens.
As with any registry study, confounding or unknown variables could have influenced the results especially with the fact that multivariable techniques were not employed due to low study power. Furthermore, losses to follow-up at both, 1-month and 1-year, could have biased the results either way. Although Gulf RACE included a broad representation of hospital types, there is a probability that some of the participating centres may not be fully representative of their countries with respect to STEMI management. However, registry data does provide crucial complementary evidence and hence the results are more likely to reflect clinical practice.
The majority of STEMI patients from the Middle East were thrombolysed with streptokinase and reteplase in equal numbers. Nearly one-fifth of patients did not receive any reperfusion therapy. There was inappropriately long symptom-onset to hospital presentation as well as door-to-needle times. Use of newer thrombolytic agents in high risk patients was appropriate. Newer thrombolytic agents were associated with significantly lower mortality at both 1-month and 1-year compared to the older agent, streptokinase.
Gulf RACE-2 is a Gulf Heart Association project supported by Sanofi-Aventis, Paris, Qatar. The sponsors had no involvement in the study conception or design; data collection, analysis, or interpretation of data; writing, review, or approval of the manuscript; or the decision to submit the manuscript for publication.
Source of Support: Nil
Conflict of Interest: None declared.