Observational study comparing pharmacoinvasive strategy with primary percutaneous coronary intervention in patients presenting with ST elevation myocardial infarction to a tertiary care centre in India.

Objective: The objective was to study whether the incidence of composite end points (mortality, cardiogenic shock and re-myocardial infarction [re-MI]) in pharmacoinvasive strategy was noninferior to primary percutaneous coronary intervention (PCI) in patients with ST-elevation myocardial infarction (STEMI).
Methods: This was an observational study which included 138 patients. The study included patients admitted with a diagnosis of STEMI within 24 h of symptom onset, who underwent primary PCI or pharmacoinvasive therapy in a single center over a 9-month period. Primary end points (death within 30 days, re-MI within 30 days, and cardiogenic shock) and secondary end points (arrhythmias, bleeding manifestations, ischemic stroke, ejection fraction, mechanical complications, and duration of hospital stay) were compared between the two groups at 1 month after intervention.
Results: At one month follow-up, the incidence rate for primary end points was 5 events per 43 patients (11.6%) in pharmacoinvasive arm and 18 events per 95 patients (18.9%) in primary PCI arm, a difference of - 7.3% (95% confidence interval: 18.5, 7.1). This finding shows that pharmacoinvasive strategy as compared with primary PCI in the management of STEMI was equivalent in terms of composite primary outcome. There was no significant difference between the secondary outcomes between the two groups. Use of thrombus aspiration device and in turn the thrombus burden was significantly lower in the pharmacoinvasive arm.
Conclusion: This observational study showed that pharmacoinvasive strategy was as good as primary PCI in STEMI, in our setting, where primary PCI may be delayed or not possible at all due to financial and logistic constraints.

Introduction

ST-elevation myocardial infarction (STEMI), non-STEMI and unstable angina, forms the entire spectrum of acute coronary syndrome (ACS). One of the gravest complications of coronary artery disease is STEMI, which involves total occlusion of infarct-related artery. Timely and complete restoration of flow in infarct-related artery helps to reduce infarct size, preserve left ventricular function, and improve survival rates.

Coronary reperfusion in the setting of STEMI is established mainly by these two modalities:

Pharmacological - Fibrinolysis

Mechanical - Primary percutaneous coronary intervention (PCI).

The goal of treatment is to reduce the total ischemic time which refers to the period between the onset of symptoms and administration of reperfusion strategy which will result in restoration of coronary blood flow in the infarct-related artery. Various modalities used in the treatment of STEMI are discussed below.

Pharmacological strategy

Fibrinolytic therapy assumed significance in the setting of ACS given the central role of thrombus in the genesis of acute coronary occlusion. Agents for thrombolysis are streptokinase (STK) (first generation), alteplase (second generation), reteplase and tenecteplase (third generation). Fibrin-specific plasminogen activators (tenecteplase, reteplase) showed enhanced TIMI III flow rates and decreased reocclusion rates as compared to STK, which contributed to improved 30-day mortality rates.[1]

Fibrinolytic therapy should be started within 30 min after the diagnosis of STEMI is made, as its efficacy declines as the time from onset of coronary occlusion to therapy increases.

Despite the above-mentioned facts, thrombolysis has the following limitations:

Even after timely administration, thrombolysis may not occur in around 15% of patients

Among successfully thrombolysed patients, approximately one-fourth may have reocclusion of infarct-related artery resulting in re-myocardial infarction (MI)

Contraindications for thrombolysis limit its use in some patients

Increased risk of intracranial hemorrhage with fibrinolysis especially in elderly.

Prehospital fibrinolysis

A meta-analysis of six randomized trials (6434 patients) comparing prehospital to in-hospital fibrinolysis showed the following benefits:[2]

A shorter time to fibrinolysis (104 versus 162 min)

Reduced all-cause hospital mortality (odds ratio 0.83, 95% confidence interval [CI]: 0.70–0.98)

An absolute risk reduction of almost 2% that translated into one life saved for every 62 patients treated with prehospital fibrinolysis.

Primary percutaneous coronary intervention

Primary PCI is the treatment of choice in STEMI (American College of Cardiology/American Heart Association [ACC/AHA] Class IA recommendation)[3] as it establishes a higher percentage of complete and lasting reperfusion. Primary PCI restores angiographically normal flow in the previously occluded artery in more than 90% of patients,[45] whereas fibrinolytic therapy does so in only 50%–60% of such patients.

Current guidelines for the treatment of STEMI, recommend a door to balloon time of 90 min or less for patients undergoing primary PCI. However, in real world situations, especially in a developing country like ours, timely PCI remains a challenge due to the following factors.

Low levels of literacy, has resulted in decreased awareness about the disease and its early signs and symptoms resulting in delayed initiation of treatment

Dearth of center's performing primary PCI

Timely transfer to such centers also remains a huge challenge considering the lack of emergency ambulance services and the state of our road infrastructure

Delays within a tertiary care center contributed by multiple factors such as arranging finances, obtaining consent, availability of PCI laboratory during busy hours, availability of round the clock workforce.

Inadequate private and public health insurance programs have resulted in very low disposable incomes for most of the families towards. “towards their health expenses”. Hence, arranging finances on an emergency basis for a relatively costly intervention like primary PCI is a “luxury” that very few people in a developing country like ours is endowed with.

Pharmacoinvasive strategy assumes significance in such a scenario.

Pharmacoinvasive strategy

Fibrinolytic therapy and primary PCI are two commonly used reperfusion strategies which are conventionally viewed as mutually exclusive alternative therapeutic modalities. However, a great deal of recently acquired clinical evidence supports the view that the two in combination are synergistic. The practical difficulties in implementing primary PCI in routine practice along with the evidence of the benefit of prehospital fibrinolysis (especially if administered early) and the overarching importance of time to reperfusion, regardless of the strategy used, serve as the foundation for the development of a unified approach for the management of patients with STEMI.

This synergistic or unified approach is referred to as pharmacoinvasive therapy.[678] Pharmacoinvasive strategy refers to routine angiography with a view to revascularise the infarct-related artery 3–24 h after fibrinolysis.

Time is a crucial factor in STEMI care. The risk of 1-year mortality was increased by 7.5% for each 30 min delay in treatment,[910] confirming to the age old adage of time is muscle.

Delay in undergoing primary PCI results in reduced benefit of the invasive procedure. Nallamothu et al. in his published studies, highlighted the fact that mortality benefit associated with primary PCI was lost if PCI-related delay exceeded 60 min pointing to the theoretical assumption of early fibrinolytic therapy compensating for PCI-related delay.[8]

Create and Kerala ACS Registry shows that there is a significant delay in patient presentation, and initiation of timely reperfusion in India.[1112] Pharmacoinvasive approach helps to shorten the time to reperfusion of infarct-related artery by initiation of lysis. PCI in 3-24 h helps to consolidate the initial reperfusion process and prevent reocclusion of the infarct-related artery. Several trials (CARESS-in-AMI, TRANSFER-AMI, WEST study, STREAM, STEP AMI) have addressed the potential benefit of pharmacoinvasive strategy.[913141516]

Methods

Study design

This was an observational cohort study with a 1 month follow-up.

Setting

The study was conducted in the Department of Cardiology at Christian Medical College (CMC), Vellore. This is a tertiary care hospital in South India with a dedicated 24 h emergency chest pain unit and cardiac catheterization laboratory service.

Study population

Patients admitted with a diagnosis of STEMI in the cardiac Intensive Care Unit, over a period of 9 months were recruited. Informed consent was obtained before recruitment. Data were obtained by history and clinical examination, electrocardiogram, echocardiography (ECHO), and routine blood investigations. Protocol was approved by the IRB (Institutional Review Board) of the institution.

Sample size

The sample size was calculated based on average mortality and composite outcome (Cardiogenic shock, Re-MI) rate of around 15% in CMC in the year 2012.

Inclusion criteria

STEMI patients within a window period of 24 h of symptom onset

Patients who underwent PCI or pharmacoinvasive therapy for treatment of STEMI.

Exclusion criteria

Previous coronary artery bypass grafting/PCI

Contraindication for lysis

Severe renal impairment (estimated glomerular filtration rate <30 ml/min)

Patients lysed with tenecteplase

Consent not given by patient/relatives.

Primary percutaneous coronary intervention arm

All patients willing for primary PCI who could arrange finances for the same on an urgent basis was included in the primary PCI arm.

Pharmacoinvasive arm

All patients either referred from an outside center after thrombolysis or who were initially thrombolysed in our center, and who subsequently underwent coronary angiogram in our center with intent to undergo revascularization of infarct-related artery were included in the pharmacoinvasive therapy arm.

Outcomes

The primary end points included:

Death within 30 days

Re-MI within 30 days, and

Cardiogenic shock.

The secondary end points were:

Arrhythmias

Bleeding manifestations (intracranial hemorrhage, gastrointestinal bleeding, mucosal bleeding)

Ischemic stroke

Ejection fraction (measured by ECHO)

Mechanical complications (mitral regurgitation, ventricular septal rupture, ventricular free wall rupture)

Duration of hospital stay.

Statistical analysis

Data were entered into EpiData software and analyzed using (The EpiData Association, Odense, Denmark) SAS version 9.3 for windows (SAS Institute Inc., Cary, North Carolina, USA) for windows. Descriptive statistics were provided for continuous variables and frequency with a percentage for categorical variables. Comparison of baseline differences between primary and pharmacoinvasive arms was done using Chi-square test or Fisher's exact test for categorical variables and using independent sample t-test or Wilcoxon rank sum test for continuous variables, depending on the distribution of data. Normality of the study data was accessed using Shapiro–Wilk test and histogram. We aimed to show that the difference between primary outcome in pharmacoinvasive and primary PCI arm was not more than 7.5%. For noninferiority to be shown with the use of CI approach for bad outcome, the upper limit of the two-sided 95% CI for the difference (pharmacoinvasive minus primary) had to be lower than 7.5%. We used the Wilson score method to estimate 95% CIs. For secondary endpoints, we used proportion test and t-test for comparison.

Results

Patient characteristics

A total of 138 patients were analyzed out of which 95 were in the primary PCI arm, and 43 were in the pharmacoinvasive arm. It was observed that all the demographic and clinical variables were nearly equal between the two groups [Table 1].

Table 1

Baseline characteristics, coronary risk factors, and angiographic profile comparing primary percutaneous coronary intervention and pharmacoinvasive arm

Variables	Primary arm (n=95) (%)	Pharmacoinvasive arm (n=43) (%)	P*
Age	57.6 (12.2)	52.7 (14.3)	0.041†
Gender (male)	89 (93.7)	36 (83.7)	0.111
Hypertension	34 (35.8)	13 (30.2)	0.523#
Diabetes	38 (40.0)	13 (30.2)	0.271#
Dyslipidemia	19 (20.0)	7 (16.3)	0.605#
Smoking	33 (34.7)	18 (42.9)	0.365#
Family history of CAD	36 (37.9)	9 (20.9)	0.049#
Diagnosis
Anterior	51 (53.7)	32 (74.4)	0.060
Inferior	41 (43.2)	11 (25.6)
Others	3 (3.2)	0
Access site
Radial	92 (96.8)	41 (95.3)	0.647
Femoral	3 (3.2)	2 (4.7)
Infarct-related artery
LAD	52 (54.7)	31 (73.8)	0.112
LCX	6 (6.3)	1 (2.4)
RCA	37 (38.9)	10 (23.8)
Use of thrombus aspiration	70 (73.7)	9 (21.4)	<0.001

*Significance based on Fisher’s exact test, #Based on Chi-square test, test of significance: †Independent sample t-test. LAD: Left anterior descending, LCX: Left circumflex, RCA: Right coronary artery, CAD: Coronary artery disease

The majority of patients (29%) who presented with STEMI hired a taxi to reach our hospital. About 23% of patients were transported in an ambulance while 16% of patients reached our center in an auto rickshaw and 7% in a two wheeler! 53.7% of patients in primary PCI arm and 74.4% of patients in pharmacoinvasive arm presented with anterior wall MI. Among the various risk factors for CAD, cohort of patients with family history of CAD was significantly more in the primary PCI arm (38% vs. 21%, P = 0.049). There was a significant reduction in the need for thrombus aspiration catheter in the pharmacoinvasive arm (21% vs. 74%, P < 0.001).

The median time delay from onset of symptoms to first medical contact was similar in the two study groups [Table 2]. The door to balloon time in our center (80 min) was within the specified limit as recommended by the ACC/AHA (90 min). The mean duration between lysis and CAG was 10 h.

Table 2

Comparison of time intervals between the primary percutaneous coronary intervention and pharmacoinvasive treatment arms

Variable	Primary PCI (n=94)	Pharmacoinvasive (n=43)	P
Pain to door time (h)	4.0 (3.0-7.0)	4.0 (3.0-8.0)	0.784§
Door to balloon time (min)*	80 (75-90)	-	-
Lysis to CAG (h)*	-	10 (5-13)	-

Median (IQR) all others are mean (SD). §Test of significance - Wilcoxon rank sum test. SD: Standard deviation, PCI: Percutaneous coronary intervention, CAG: Coronary angiography, IQR: Interquartile range

Outcome - primary and secondary end point

Table 3 shows the primary and the secondary endpoint analysis in primary and pharmacoinvasive arms. Mortality percentages among pharmacoinvasive and primary PCI arms were 11.6% and 18.9%, respectively. Among the composite outcomes, a difference of-7.3% (95% CI: 18.5, 7.1) was observed [Figure 1]. The results based on the CI show noninferiority of pharmacoinvasive to primary at the 7.5% margin. Hence, pharmacoinvasive as compared with primary PCI was statistically equivalent (as good as) in terms of combined primary outcome (mortality and composite outcomes). That is since the upper CI still lie below 7.5%, and also the lower CI lie below -7.5%, the pharmacoinvasive arm is considered to be equivalent to the primary arm. When comparing each component of the primary endpoint, the proportion of patients who had mortality, cardiogenic shock, and re-MI was relatively lower in pharmacoinvasive arm. There was no significant difference in secondary outcomes between the two groups.

Table 3

Distribution of primary and secondary end points among the primary percutaneous coronary intervention and pharmacoinvasive arms

Variable	Primary PCI arm (n=95) (%)	Pharmacoinvasive arm (n=43) (%)	Difference (%) (95% CI)*
Primary end point
Overall	18 (18.9)	5 (11.6)	−7.3 (−18.5-7.1)
Mortality	5 (5.3)	2 (4.7)	−0.6 (−7.9-10.6)
Cardiogenic shock	12 (12.6)	3 (7.0)	−5.7 (−15.0-7.1)
re-MI	1 (1.1)	0	−1.1 (−5.7-7.2)
Secondary end point
Ejection fraction mean (SD)	44.3 (7.5)	42.4 (7.7)	−1.9 (−4.6-0.9)$
Bleeding manifestations	1 (1.1)	0	−1.1 (−5.7-7.2)
Ischemic stroke	0	1 (2.3)	2.3 (−2.0-12.1)
Arrhythmias	3 (3.2)	1 (2.3)	−0.8 (−6.9-9.1)
Duration of hospital stay median (minimum-maximum)	3 (2-20)	3 (1-7)	0.048@

$Independent sample t-test, *CI was calculated based on Wilson score method. CI: Confidence interval, SD: Standard deviation, PCI: Percutaneous coronary intervention, re-MI: re-Myocardial infarction

Figure 1

Difference between pharmacoinvasive and primary percutaneous coronary intervention arm with respect to the primary outcomes (95% confidence interval) , re-MI: re-Myocardial infarction, Cardio.Shock: Cardiogenic shock

Discussion

Pharmacoinvasive strategy is an alternative to primary PCI in patients presenting with STEMI in whom primary PCI cannot be done with a door to balloon time of 90 min or first medical contact to device time ≤120 min.

In our study, pharmacoinvasive strategy as compared with primary PCI was statistically equivalent in terms of combined primary outcome. The distribution of secondary end points was similar between the two study arms [Table 3]. In the STREAM study, where a similar comparison was attempted in patients arriving within 3 h, there was a significant increase in intracranial hemorrhage in pharmacoinvasive group which became nonsignificant after 50% reduction in the dose of tenecteplase among patients 75 years or older.[14]

It should be borne in mind that pharmacoinvasive arm had a larger number of patients with anterior wall MI and the mean troponin values in pharmacoinvasive arm were also higher. Yet the results point toward no significant difference in clinical outcome at 1 month. There was a significant reduction in the need for thrombus aspiration catheter in the pharmacoinvasive arm (21% vs. 74%, P < 0.001) suggesting a decrease in the thrombus burden in patients who were subjected to thrombolysis with STK. To quote the figures from STEPP AMI, thrombus was present in 26.7% in pharmacoinvasive group versus 63.2% in primary PCI group.[9] Mode of transport is an important cog in the full wheel of effective and timely reperfusion therapy. In many cases, the delay in reaching the hospital can be the difference between life and death. Hence, its important to understand the fact that only 23% of patients with STEMI was transferred to our hospital in an ambulance.

Till date, very few studies have compared pharmacoinvasive strategy with primary angioplasty in India. A unique feature of this study was that STK was used as the fibrinolytic agent among all our patients, due to the prohibitive cost of using tenecteplase. Pharmacoinvasive strategy using STK proved to be relatively safe and was associated with comparable outcomes as primary PCI which assumes importance in a country like ours where execution of primary PCI within the guideline recommended time period still remains a huge challenge due to paucity of funds, lack of universal insurance cover, dearth of ambulance services, poor road infrastructure, and limited centers with primary PCI facility.

Conclusion

The following conclusions can be drawn from this study:

Pharmacoinvasive as compared with primary PCI was statistically equivalent in terms of composite primary outcome

There was no significant difference between the secondary outcomes between the two groups

Use of thrombus aspiration device and in turn the thrombus burden was significantly lower in the pharmacoinvasive group than in primary PCI arm.

Limitations

This was an observational study with all its associated drawbacks such as the potential for the presence of unknown confounders or biases that may have influenced the results.

A larger sample size may be required to conclusively prove the hypothesis. Furthermore, a longer observation period may be useful to assess whether there is any difference in long-term outcome between the two groups.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.