Outcomes of Primary Percutaneous Coronary Intervention at
a Joint Commission International Accredited Hospital in a
Developing

Percutaneous coronary intervention (PCI) is an established therapy for patients with symptomatic coronary artery disease including acute coronary syndromes. In patients presenting with ST-elevation myocardial infarction (STEMI), a considerable body of evidence now suggests that reperfusion with primary PCI provides better short- and long-term outcomes compared to fibrinolytic therapy.^1-3 Although widely adopted as the default strategy for patients presenting with STEMI in developed nations, there are virtually no data on the applicability, success and outcomes of primary PCI in third-world nations, particularly the Indo-Pakistan subcontinent. A few small studies from India have suggested the potential feasibility of primary PCI,^4,5 but had limited follow up and did not have the power to determine predictors of mortality. As developing countries brace themselves for a cardiovascular epidemic, the question arises: Is primary PCI a viable therapeutic option in these countries?

In recent years, well-equipped hospitals with Joint Commission International Accreditation (JCIA) and staffed by physicians highly trained from centers of excellence in the West have taken root in developing nations.⁶ This accreditation recognizes the hospital’s performance in complying with international healthcare quality standards. The key question, however, is whether such hospitals, albeit JCIA-certified (and therefore carrying the unbiased third-party validation), can truly offer healthcare outcomes that are on a par with hospitals in developed nations. The primary aim of our study was to determine the patient characteristics, short- and intermediateterm outcomes and predictors of mortality in patients undergoing primary PCI for STEMI in a JCIA-certified hospital in Pakistan. Our secondary aim was to compare our results with the published literature from developed countries.

Materials and Methods

Patient population. We reviewed the charts of 277 consecutive patients undergoing primary PCI for STEMI at the Aga Khan University Hospital (AKUH) in Karachi, Pakistan, between January 2001 and December 2005. The AKUH is a JCIA-certified tertiary care hospital located in the metropolitan city of Karachi that receives a mixture of affluent as well as low- and middle-income patients and serves the entire city as a referral center for patients requiring high-intensity tertiary care. The hospital has had a primary PCI program in place since 1999 and performs approximately 500 PCI procedures annually. The laboratory is staffed by interventional cardiologists with accredited training in either North America or the United Kingdom. The cardiac catheterization laboratory maintains a prospective PCI database that is maintained andupdated regularly. The database was queried for patients meeting the following inclusion criteria for our study: (1) chest pain lasting > 30 minutes associated with an ST-elevation of ≥ 1 mm in ≥ 2 contiguous leads; plus (2) time from symptom-onset to presentation ≤ 24 hours; and (3) primary PCI as the reperfusion strategy. Patients receiving fibrinolytic therapy, undergoing primary PCI for stent thrombosis and non-ST-elevation myocardial infarction (NSTEMI), and those presenting beyond 24 hours following the onset of symptoms were excluded from this analysis. At our institution patients presenting with acute STEMI are offered primary PCI as the preferred method of reperfusion. Based on a variety of considerations, primarily financial, patients opt for either PCI or fibrinolytic therapy. This incorporation of costs into the “equation” of decision making is a distinctly unusual operational detail that is widespread in the Indo-Pakistan subcontinent, where state funding for such procedures is negligible and patients are required to bear most (if not all) expenses. Needless to say, this contributes to delays in definitive therapy.

Procedure. Primary PCI of the infarct-related artery was performed in standard fashion using a variety of guiding catheters, guidewires and low-profile balloons. The vast majority of interventions were performed via the femoral route. All patients received 5000–10,000 units of intravenous heparin, aspirin 300 mg and clopidogrel (loaded with 300–600 mg at the operator’s discretion, followed by 75 mg per day). Coronary stenting, glycoprotein (GP) IIb/IIIa inhibitor and intracoronary nitroprusside and adenosine use were at the discretion of the operators. Stent size selection was primarily based on visual assessment of vessel size and lesion length. All patients received aspirin indefinitely and clopidogrel 75 mg daily for a minimum of 1 or 6 months for bare-metal and drug-eluting stents, respectively.

Data collection. The prospective database contains information on variables including age, gender, history of diabetes (defined as a fasting glucose ≥ 126 mg/dl or on treatment), hyperlipidemia (fasting cholesterol ≥ 200 mg/dl or on treatment), hypertension (systolic blood pressure ≥ 140/90 mmHg or on treatment), smoking (ever vs. never), prior PCI or coronary bypass grafting (CABG), left ventricular function (visually estimated ejection fraction [EF] using either echocardiography or left ventriculography), presence of cardiogenic shock (defined as a systolic blood pressure [SBP] of < 90 mmHg for at least 30 minutes, or requirement of inotropes to maintain a SBP > 90 mmHg), angiographic and procedural details (culprit vessel, number of diseased vessels, use of stents, GP IIb/IIIa inhibitors and Thrombolysis in Myocardial Infarction [TIMI] flow). Hospital charts of individual patients were reviewed for further information including need of intubation, electrocardiogram (ECG) ST-segment analysis, admission laboratory data including hemoglobin, serum creatine (estimated glomerular filtration rate was computed using the MDRD equation⁷) and white blood cell count. Timing variables were computed as follows: chest pain-to-emergency room (ER) was defined as the time difference between the time of onset, as obtained from the history, and the time of presentation to the ER; door-to-catheterization laboratory time was defined as the time taken for the patient to reach the latter from the point of entry to the ER. Our database was not routinely recording the exact time of first balloon inflation during the earlier years of our program, thus the door-to-balloon times (time taken from presentation to the ER to first balloon inflation) are not available. TIMI flow rates were visually determined and documented by the individual operator both before and after the PCI. PCI success was defined as achievement of vessel patency to a residual ≤ 30%. Hospital charts were reviewed for the patient’s last known follow up and status. Patients were then contacted via telephone and, with informed verbal consent, further follow up was documented (5 patients refused to respond). Major bleeding was defined as a hematoma > 10 cm in diameter or bleeding requiring transfusion, vascular surgery or resulting in major morbidity. The primary outcome was all-cause mortality studied from the time of the intervention out to the maximum time of follow up.

Statistical methods. All variables were entered into the Statistical Package for Social Sciences, version 14 (SPSS Inc., Chicago, Illinois). Means and standard deviations were calculated for continuous variables and frequencies for categorical variables. Univariate survival analysis was performed according to the Kaplan–Meier method and differences in survival curves were assessed with the log-rank test. Patients lost at follow up were censored at the time of the last visit or contact. Potential survival correlates were further scrutinized with univariate and multivariate Cox proportional hazards models, with calculated risk ratios (hazard ratios [HR] for independent variables reported with 95% confidence intervals [CI]). Variables with a p-value ≤ 0.2 were entered into the multivariable model. The number of variables considered was intentionally limited because of the limited number of events. In a visual evaluation of log(–log(survival)) plots, no violation of the proportional hazards assumption became apparent. P-values < 0.05 were considered significant. Censored individuals were compared with respect to baseline characteristics to the remaining cohort at time intervals of 1 and 2 years, and no significant differences were apparent, thus no violation of the censoring assumptions was noted. The corresponding author had full access to the data and had final responsibility for its integrity as well as the decision to submit the study for publication. All authors have read and agree to the manuscript as written.

Results

A total of 277 subjects were included in this study. The median duration of follow up was 546 days (interquartile range [IQR] 211; 892 days). Table 1 shows the baseline demographic and clinical characteristics as well as outcomes of the studied cohort. The mean age was just under 55 years. Approximately one-third were diabetic and 15% presented with cardiogenic shock or required intubation during theirhospital stay. The mean left ventricular ejection fraction (LVEF) was 45%. The median timefrom- onset of symptoms to presentation was 160 minutes, and the median door-to-laboratory time was 90 minutes. Twenty-three subjects died in the hospital (8.3%), and another 11 subjects died during follow up. Major bleeding occurred in 4.3% of patients.

Table 2 shows the angiographic and procedural details of the patients undergoing primary PCI. Multivessel disease (defined as > 50% stenosis in ≥ 2 epicardial vessels) was present in 56% of patients. Procedural success was extremely high (97%), as was the use of stents (96%) and GP IIb/IIIa inhibitors (~90%).

Figure 1 shows the in-hospital and 30-day mortality rates of the study cohort and compares these outcomes with published data from developed nations. Figure 2 shows the Kaplan-Meier curve for the overall survival experience of the cohort as well as subjects presenting with and without cardiogenic shock. As is evident, the intermediate-term prognosis is excellent.

Table 3 summarizes the reported mortality rates for acute STEMI treated by primary PCI in major contemporary Western trials and registries.

Tables 4 and 5, respectively, show the univariate and multivariate predictors (by Cox proportional hazards analysis) of death in patients undergoing primary PCI in our institution with the associated hazards ratios and corresponding 95% confidence intervals. Independent predictors of mortality included age, cardiogenic shock at presentation, requirement for intubation, prior CABG and LVEF.

Discussion

This is the first sizeable report on outcomes for primary PCI in acute STEMI from the Indo- Pakistan subcontinent with robust follow-up data. We show in an unselected “real-world” population, a high success rate (> 95%) of the index procedure and an excellent overall in-hospital survival rate (91.7%), particularly in the absence of cardiogenic shock (almost 98%). As shown in Table 2, our outcomes compare extremely favorably with those reported in studies from developed nations. Thus, we suggest that outcomes in a JCIA-certified hospital in a third-world country may be at par with those in developed countries — not only in low-risk (non-cardiogenic shock) subjects, but in those presenting with cardiogenic shock for whom the prognosis is much worse. These favorable results are maintained over longer-term follow up (Figure 2). The rates of initial success as wellas TIMI 3 flow were also comparable to Western data.^8-10 There are a number of findings in our study that merit further discussion. The mean age in our study group was < 55 years, lower than that seen in studies from the developed world (Table 3).

Age is, in general, a strong prognostic indicator and one may argue that we selected out a lower-risk cohort not generalizable to other patients in the region. However, this lower age at presentation is consistent with other studies on acute MI in broader, more representative populations in Pakistan not necessarily undergoing primary PCI,¹¹ and probably reflects premature atherosclerosis that is commonly seen in the Indo-Pakistan subcontinent. We found no relationship on multivariate analysis between chest pain-to-presentation time and outcomes. Although intuitively surprising, this has been seen in the second National Registry of Myocardial Infarction (NRMI-2)¹² and may reflect the inherent difficulties in accurately timing the onset of coronary occlusion (when infarction begins as opposed to the preinfarct anginal phase) as well as, perhaps, a survivor cohort effect. We also found no significant association between door-to-laboratory time (a surrogate for door-to-balloon time), unlike other studies, and this may reflect the fact that the arrival-tolaboratory time was high — around 90 minutes (with actual door-to-balloon times approaching at least 120 minutes if we assume a minimum of 30 minutes for patient preparation, diagnostic angiography and subsequent PCI). It has been suggested that once door-to-balloon times exceed 90 minutes, the benefits begin to decline.¹³ Furthermore, as the time-to-PCI increases, so does mortality.¹⁴ It is possible that we did not see such a relationship because of smaller numbers of patients with longer times (86.3% subjects had a door-to-laboratory time of ≤ 120 minutes).

What are the implications of our study? Widespread availability of primary PCI, although vigorously promoted,¹⁵ has yet to become a reality, even in the developed world. We have shown in the first sizeable report from the Indo-Pakistan subcontinent that primary PCI is a viable therapeutic option and can be performed with excellent immediate-, short- and long-term results despite relatively longer chest pain-to-presentation and door-to-laboratory (surrogate for door-to-balloon) times. As Pakistan (and India) brace themselves for a cardiovascular epidemic, it is clear that acute STEMI will continue to occur, leading to a loss in productivity. The mean age in our study was just under 55 years — an age group that comprises the workforce of any nation. Although fibrinolytic therapy (almost exclusively streptokinase) is widely available, at least in urban Pakistan, the efficacy of the latter in attaining patency with TIMI 3 flow is, at best, around 50%.¹⁶ Thus, paradoxically, developing countries like Pakistan need widespread, expensive primary PCI services because such nations cannot afford the burden of lost productivity due to inadequate myocardial salvage. The key question, of course, is whether such programs can be funded by the state on a widespread scale. Formal economic analyses aside, the intuitive answer is that there is no choice. Preservation of the workforce must be a state priority. Drastic cost-cutting measures including the use of cheap bare-metal stents, resterilized equipment including guiding catheters, wires and balloons,¹⁷ and the involvement of tertiary care university hospitals in training operators to perform primary PCI in community hospitals will be essential components of such a program, coupled with close surveillance. One may argue that primary PCI involves the highest-risk patients and should remain in the domain of the most experienced operators, that is, at major tertiary hospitals. However, only 15% of patients present with cardiogenic shock and are at greatest risk for intraprocedural complications — a subset that may be referred to a tertiary care facility. What is eminently clear is that the current lack of services (Karachi, for example, home to 15 million people, has only 2 centers offering primary PCI around-the-clock) is unacceptable. Widespread state-funded primary PCI programs commencing from the urban areas and then extending to rural communities, coupled with funded educational campaigns to get patients to present earlier following onset of pain, as well as programs facilitating access to primary and secondary preventive measures, are essential for this region.

Study Limitations

Our study is not without limitations. First, the sample size is relatively small, and larger studies are needed to validate these results. Second, although these are consecutive patients undergoing primary PCI, they do not represent all-comers who presented with acute STEMI. As described in the Methods section, many such patients opt for fibrinolysis. Therefore, there would be a potential bias towards either affluent or sicker patients undergoing primary PCI. That said, the presumedlower mortality rate of affluent patients and the higher mortality rate of the sicker patients may balance each other out. Third, as mentioned earlier, door-to-balloon times were not directly estimated, thus the association between this variable and outcomes is poorly defined by our study. Furthermore, a significant proportion of this delay-to-PCI comprises the time taken by patients to decide whether they can proceed with the procedure, based on financial constraints. We did not have the data to determine the intricacies of this delay. Fourth, our data represent a single-center experience where the operators are fairly experienced and the hospital was state-of-the-art. Whether these results can be generalized to other hospitals in developing countries is unclear. Fifth, we did not make a distinction between in-hospital and follow-up mortality. Taking mortality as a whole may fail to provide a complete understanding of whether the correlates of mortality differ in the acute and chronic phases of acute STEMI. We did not feel that our sample size was large enough to justify such an analysis. Finally, our use of historical data to compare our experience with Western outcomes carries obvious limitations and is by no means definitive. There are many differences both in patient characteristics (age in our study was lower than in the studies listed in Table 3; on the other hand, door-to-balloon times were higher) and selection methods. Nevertheless, we feel that our data do enable us to make the point that outcomes similar to the West may be possible in developing countries, and further study, perhaps with a real-time Western comparator group, would be in order.

Conclusion

In conclusion, this is the first report from the Indo-Pakistan subcontinent to provide a comprehensive review of patient characteristics and outcomes of primary PCI for acute STEMI. We report a high initial success rate and excellent short- and intermediate-term survival, particularly in the subset presenting without cardiogenic shock. Our results compare favorably to Western data despite longer door-to-balloon times. Furthermore, our data suggest that Western quality of care for a critical illness like STEMI may be duplicated in a third-world country in a JCIA-certified hospital with skilled operators on staff. There is a strong need to make the practice of primary PCI more widespread in developing nations, a task that will require serious commitment at the state level if this is to be realized. More outcomes data are needed from similar hospitals in the region to determine whether our results are generalizable.

Acknowledgements. The authors wish to acknowledge colleagues involved in taking care of the patients reported on in this study. These include Drs. Sajid H. Dhakam, S.M. Najaf Nadeem, Khawar A. Kazmi, Aamir Hameed, Sohail Khan, Fateh Ali Tipoo and Javed M. Tai.

References

1. Grines CL, Browne KF, Marco J, et al. A comparison of immediate angioplasty with thrombolytic therapy for acute myocardial infarction. The Primary Angioplasty in Myocardial Infarction Study Group. N Engl J Med 1993;328:673–679.

2. Zijlstra F, Hoorntje JC, de Boer MJ, et al. Long-term benefit of primary angioplasty as compared with thrombolytic therapy for acute myocardial infarction. N Engl J Med 1999;341:1413–1419.

3. Andersen HR, Nielsen TT, Rasmussen K, et al. A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction. N Engl J Med 2003;349:733–742.

4. Reddy NK, Raju PR, Kapoor S, et al. Prospective observational study of primary angioplasty of the infarct-related artery for acute myocardial infarction. Indian Heart J 1999;51:167–172.

5. Ranjan, A, Patel, TM, Shah, SC, et al. Transradial primary angioplasty and stenting in Indian patients with acute myocardial infarction: Acute results and 6-month follow-up. Indian Heart J 2005;57:681– 687.

6. Milstein, A, Smith, M. America’s new refugees—Seeking affordable surgery offshore. N Engl J Med 2006;355:1637–1640.

7. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;130:461–470.

8. Ellis K, Boccalandro F, Burjonroppa S, et al. Risk of bleeding complications is not increased in patients undergoing rescue versus primary percutaneous coronary intervention for acute myocardial infarction. J Interv Cardiol 2005;18:361–365.

9. Grines CL, Cox DA, Stone GW, et al. Coronary angioplasty with or without stent implantation for acute myocardial infarction. Stent Primary Angioplasty in Myocardial Infarction Study Group. N Engl J Med 1999;341:1949–1956.

10. Stone GW, Grines CL, Cox DA, et al. Comparison of angioplasty with stenting, with or without abciximab, in acute myocardial infarction. N Engl J Med 2002;346:957–966.

11. Khan MS, Jafary FH, Jafar TH, et al. Knowledge of modifiable risk factors of heart disease among patients with acute myocardial infarction in Karachi, Pakistan: A cross sectional study. BMC Cardiovasc Disord 2006;6:18.

12. Cannon CP, Gibson,CM, Lambrew CT, et al. Relationship of symptom-onset-toballoon time and door-to-balloon time with mortality in patients undergoing angioplasty for acute myocardial infarction. JAMA 2000;283:2941–2947.

13. 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). Circulation 2004;110:588–636.

14. De Luca G, Suryapranata H, Zijlstra F, et al. Symptom-onset-to-balloon time and mortality in patients with acute myocardial infarction treated by primary angioplasty. J Am Coll Cardiol 2003;42:991–997.

15. de Belder A. Should primary angioplasty be available for all patients with an ST elevation myocardial infarction? Heart 2005;91:1509–1511.

16. Lincoff AM, Topol EJ. Illusion of reperfusion. Does anyone achieve optimal reperfusion during acute myocardial infarction? Circulation 1993;88:1361–1374.

17. Vaitkus PT. The reuse of single-use cardiac catheters: Safety, economical, ethical and legal issues. Conseil d'evaluation des technologies de la sante du Quebec. Can J Cardiol 1994;10:413–421.

18. Tiefenbrunn AJ, Chandra NC, French WJ, et al. Clinical experience with primary percutaneous transluminal coronary angioplasty compared with alteplase (recombinant tissue-type plasminogen activator) in patients with acute myocardial infarction: A report from the Second National Registry of Myocardial Infarction (NRMI-2). J Am Coll Cardiol 1998;31:1240–1245.

19. Hochman JS, Sleeper LA, Webb JG, et al. Early revascularization in acute myocardial infarction complicated by cardiogenic shock. SHOCK Investigators. Should we emergently revascularize occluded coronaries for cardiogenic shock. N Engl J Med 1999;341:625–634.

20. Webb JG, Lowe AM, Sanborn TA, et al. Percutaneous coronary intervention for cardiogenic shock in the SHOCK trial. J Am Coll Cardiol 2003;42:1380–1386.

21. Webb JG, Sanborn TA, Sleeper LA, et al. Percutaneous coronary intervention for cardiogenic shock in the SHOCK Trial Registry. Am Heart J 2001;141:964–970.

22. Bonnefoy E, Lapostolle F, Leizorovicz A, et al. Primary angioplasty versus prehospital fibrinolysis in acute myocardial infarction: A randomised study. Lancet 2002;360:825–829.

23. Widimsky P, Budesinsky T, Vorac, D, et al. Long distance transport for primary angioplasty vs immediate thrombolysis in acute myocardial infarction. Final results of the randomized national multicentre trial — PRAGUE-2. Eur Heart J 2003;24:94–104.

24. Fernandez-Aviles F. Gracia II Trial. In: European Society of Cardiology, Vienna, Austria 2003.

25. Klein LW, Shaw RE, Krone RJ, et al. Mortality after emergent percutaneous coronary intervention in cardiogenic shock secondary to acute myocardial infarction and usefulness of a mortality prediction model. Am J Cardiol 2005;96:35–41.

26. Abbas AE, Brodie B, Dixon S, et al. Primary versus tenecteplase-facilitated percutaneous coronary intervention in patients with ST-segment elevation acute myocardial infarction (ASSENT-4 PCI): Randomised trial. Lancet 2006;367:569–578.

27. Armstrong PW, Granger,CB, Adams PX, et al. Pexelizumab for acute ST-elevation myocardial infarction in patients undergoing primary percutaneous coronary intervention: A randomized controlled trial. JAMA 2007;297:43–51.