CE: Satish ED: Maitreyee Op: Sampath MCA 11568: LWW_MCA_11568

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1 CE: Satish ED: Maitreyee Op: Sampath MCA 11568: LWW_MCA_11568 Pathophysiology and natural history 1 AQ1 Prevalence and prognosis of congestive heart failure in Saudi patients admitted with acute coronary syndrome (from SPACE registry) Hanan B. Albackr a, Khalid F. AlHabib a, Anhar Ullah b, Hussam Alfaleh a, Ahmad Hersi a, Fayez Alshaer a, Khalid AlNemer b, Shukri Al Saif d, Amir Taraben e and Tarek Kashour c Objectives The aim of this study was to assess the prevalence, clinical features, and in-hospital outcomes of heart failure in patients with acute coronary syndrome (ACS). Materials and methods The Saudi Project for Assessment of Coronary Events recruited patients admitted with ACS from 17 hospitals in Saudi Arabia from 2005 to The outcomes of ACS patients with congestive heart failure (CHF) compared with those without CHF were analyzed. Results A total of 4523 patients with ACS were identified, of whom 905 (20%) had CHF. Compared with no CHF, patients with CHF were older (62±13.1 vs. 57±12.9 years; P = 0.001), less likely to be men (70 vs. 79%; P = 0.001), likely to present with non-st-segment elevation myocardial infarction (48 vs. 36%; P = 0.001), likely to have diabetes (71 vs. 54%; P = 0.001), hypertension (64 vs. 54%; P = 0.001), previous history of coronary artery disease (53 vs. 43%; P = 0.001), and likely to have significant left ventricular systolic dysfunction (left ventricular ejection fraction <35%) (56 vs. 30%; P = 0.001). Patients with CHF were less likely to receive in-hospital b-blockers (74 vs. 86%; P = 0.001) and a percutaneous coronary intervention (19 vs. 50%; P = 0.001). Adjusted in-hospital mortality and cardiogenic shock were higher in the CHF group (odds ratio 4.43, 95% confidence interval ; and odds ratio 3.51, 95% confidence interval ), respectively. Conclusion ACS patients with CHF in the Saudi Project for Assessment of Coronary Events were older, more likely to have more cardiac risk factors, and less likely to be treated with optimum medical treatment on admission. These findings were associated with higher incidence of their in-hospital adverse outcomes. More aggressive treatment is warranted to improve prognosis. Coron Artery Dis 00: c 2013 Wolters Kluwer Health Lippincott Williams & Wilkins. Coronary Artery Disease 2013, 00: Keywords: acute coronary syndrome, heart failure, mortality, SPACE registry a King Fahad Cardiac Center, College of Medicine, King Saud University, b Security Forces Hospital, c Department of Medicine, Prince Salman Heart Center, King Fahad Medical City, Riyadh, d Saud Al-Babtain Cardiac Center, Dammam and e King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia Correspondence to Hanan B. Albackr, MD, MBBS, FRCPC, King Fahad Cardiac Center, College of Medicine, King Saud University, PO Box 7805, Riyadh 11472, Saudi Arabia Tel: ¾ 1854; fax: ; s: halbackr@ksu.edu.sa; halbackr@gmail.com Received 14 April 2013 Revised 4 July 2013 Accepted 4 July 2013 Introduction Coronary artery disease (CAD), including the acute coronary syndromes (ACSs), is the most common cause of heart failure (HF). However, HF is a frequent complication of ACS, and this has been shown to be associated with increased mortality [1 3]. In a prospective, multinational study of ACS patients hospitalized in 65 centers in six Arab Gulf countries, 25% had HF on presentation or during the hospital stay [3]. HF was associated with higher in-hospital mortality that persisted after adjusting for age, sex, and presentation and treatment characteristics. Patients with HF were older, more likely to have comorbid conditions, and were less often treated with evidence-based therapies [2,3]. Owing to the strong association between ACS and HF, it is important to understand the determinants of HF in patients hospitalized with ACS and the impact of HF on their outcomes. The prevalence and the outcomes of congestive heart failure (CHF) in the Saudi population hospitalized with ACS are not known. Thus, the aim of this study was to describe the prevalence, patient characteristics, treatment patterns, and in-hospital outcomes of CHF complicating ACS in patients who were enrolled in the Saudi Project for Assessment of Coronary Events (SPACE) registry. Materials and methods Study population The SPACE study is a prospective, multicenter, observational study of all consecutive ACS patients who were admitted to 17 participating hospitals between December 2005 and December The details of the study design have been outlined previously [4]. The study included hospitalized patients with ST-segment elevation c 2013 Wolters Kluwer Health Lippincott Williams & Wilkins DOI: /MCA.0b013e328364d98f

2 2 Coronary Artery Disease 2013, Vol 00 No 00 myocardial infarction (STEMI), non-st-segment elevation myocardial infarction (NSTEMI), and unstable angina. Ethics approval was obtained from the institutional review board of individual hospitals. Diagnosis of the different types of ACS and definitions of data variables were based on the data elements and definitions for measuring the clinical management and outcomes of patients with ACS that were developed by the American College of Cardiology [5]. For NSTEMI, STEMI, or left bundle branch block myocardial infarction, the definition required the typical rise and fall of biochemical markers of myocardial necrosis (troponin or creatine kinase-mb) with at least one of the following: ischemic symptoms, pathological Q waves on an ECG, ECG changes indicative of ischemia, or coronary artery intervention. For unstable angina, the definition required biochemical cardiac markers to be within normal range, along with ischemic symptoms that were prolonged, of new onset, or accelerating, and ECG changes indicative of ischemia. The data collected included patient s demographics, previous medical history, provisional diagnosis on admission and final discharge diagnosis, ECG findings, laboratory investigations, medical therapies, use of cardiac procedures and interventions, in-hospital outcomes, and overall mortality. In this substudy of SPACE, patients were divided into two groups: those who had ACS complicated by CHF and those who did not have CHF. The ACS with HF cohort included patients with HF at the time of hospital presentation according to the Killip classification class II [findings consistent with mild-to-moderate HF including a third heart sound (S3), lung rales less than one-half way up the posterior lung fields, or jugular venous distension] or class III (overt pulmonary edema) or HF that developed in-hospital during the hospital stay, as coded by the site investigator. We excluded patients with cardiogenic shock because of their unique clinical presentation and prognosis. Cardiogenic shock was confirmed by both clinical and hemodynamic criteria. The clinical criteria were hypotension (a systolic blood pressure of <90 mmhg for at least 30 min or the need for supportive measures to maintain a systolic blood pressure of >> 90 mmhg) and an end-organ hypoperfusion (cool extremities or a urine output of <30 ml/h). The hemodynamic criteria were a cardiac index of no more than 2.2 l/min/m 2 of the body surface area and a pulmonary capillary wedge pressure of at least 15 mmhg. Statistical analysis Categorical data were summarized as absolute numbers and percentages. Continuous data were summarized as mean and SD or median and interquartile range. Comparisons between groups for categorical data were performed using the w 2 -test or Fisher s exact test; comparisons between groups for continuous variables were performed using Student s t-test or the Mann Whitney U-test. Multiple logistic regression models were used to estimate the adjusted odds ratio (OR). Adjustments were made for age, sex, BMI, smoking, hyperlipidemia, diabetes, history of hypertension, past CAD, peripheral arterial disease, diagnostic coronary angiography, percutaneous coronary intervention (PCI), coronary artery bypass graft surgery (CABG), and pharmacological therapies including acetylsalicylic acid, clopidogrel, b-blockers, angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB), statin, heparin, and glycoprotein IIb/IIIa inhibitors. Stepwise, multivariable logistic regression was used to identify independent predictors of in-hospital HF adjusted for the following baseline covariates: age, sex, heart rate, systolic blood pressure on presentation, diabetes mellitus, hypertension, previous history of CAD, previous revascularization (CABG or PCI), and serum creatinine. All tests were two-sided, with a 5% level of significance. All analyses were carried out using the SAS/STAT software (SAS Institute Inc., Cary, North Carolina, USA). Results Baseline features of the study population SPACE enrolled 5055 consecutive patients with ACS; the data of this analysis were available for 4524 patients. The baseline characteristics are summarized in Table 1. CHF complicated ACS in 905 (20%) patients. CHF patients were older (62±13.1 vs. 57±12.9 years; P =0.001) and less likely to be men (70 vs. 79%; P = 0.001) than patients without CHF. Risk factors for CAD were more prevalent in patients with CHF, including a larger proportion with diabetes mellitus (71 vs. 54%; P =0.001) and hypertension (64 vs. 54%; P = 0.001). Similarly, history of documented CAD was more common in patients with CHF, including a higher proportion of patients with a previous history of CAD (53 vs. 43%; P =0.001), stroke (9.5 vs. 5.5%; P = 0.001), peripheral arterial disease (25 vs. 10%; P = 0.001), and previous history of CABG (9 vs. 5%; P =0.001). Presentation characteristics At presentation, patients with CHF were more likely to have NSTEMI (48 vs. 36%; P = 0.001), to be hypotensive (4.2 vs. 2.7%; P = 0.016), and tachycardic (28 vs. 11%; P = 0.001) but were less likely to present with typical ischemic chest pain as their primary symptom (72 vs. 92%; P = 0.001) (Table 1). CHF patients were more likely to have lower hemoglobin level (13.3 vs. 14%; P = 0.001) and higher serum creatinine level upon admission (99.5 vs. 89%; P =0.001). Patients with CHF and STEMI were found to present late to hospital after the onset of symptoms compared with

3 Congestive heart failure in Saudi patients Albackr et al. 3 Table 1 Baseline characteristics and laboratory investigations in acute coronary syndrome patients with and without heart failure ACS with HF [N (%)] = 905 (20%) ACS without HF [N (%)] = 3619 (80%) P-value Variables Age [mean (SD)] 62.2 (13.06) 57.1 (12.89) Male [n (%)] 637 (70) 2865 (79) Saudi [n (%)] 748 (83) 2936 (81) Past medical history [n (%)] Diabetes mellitus 639 (71) 1963 (54) Hypertension 575 (64) 1946 (54) Hyperlipidemia 393 (44) 1502 (42) Smoker 227 (25) 1230 (34) Peripheral arterial disease 128 (14) 219 (6) Stroke 84 (9) 197 (5) CABG 80 (9) 196 (5) History of CAD 484 (54) 1522 (42) Clinical presentation [n (%)] Heart rate > (28) 406 (11) SBP <90 38 (4) 97 (3) Ischemic chest pain 544 (72) 2513 (92) Investigations Peak CPK 278 (949) 235 (919) Peak CK-MB 23 (103) 20 (90) Positive serum troponin [n (%)] 678 (72) 2223 (61) Total cholesterol (mean±sd) 4.5± ± Low-density lipoprotein 2.6 (1.33) 2.7 (1.31) Fasting blood glucose 7.2 (4.0) 6.5 (3.3) First hemoglobin 13.3 (2.8) 14.0 (2.3) [median(iqr)] White cell count 10.1 (5.7) 8.9 (4.5) First serum creatinine 99.5 (43.5) 89.0 (29) ACS diagnosis [n (%)] STEMI 322 (36) 1455 (40) 0.01 NSTEMI 430 (48) 1291 (36) < Unstable angina 153 (17) 873 (24) < Table 2 In-hospital treatments and procedures for acute coronary syndrome patients with and without congestive heart failure Variables ACS with CHF (n = 905) n (%) ACS without CHF (n = 3619) n (%) P-value Aspirin 738 (97.6) 2771 (97.9) Clopidogrel 642 (85) 2501 (88) b-blocker 556 (74) 2430 (86) < Statin 714 (94) 2726 (96) ACEI/ARB 634 (84) 2104 (74) < Heparin 752 (90) 2848 (84) < GP IIb/IIIa inhibitors 173 (21) 1029 (31) < Coronary angiogram 476 (53) 2482 (69) < TVD/LM 226 (47) 849 (34) < PCI 192 (21) 1322 (37) < CABG 71 (8) 313 (9) LVEF r 5% 478 (56) 994 (30) ACEI, angiotensin-converting enzyme inhibitor; ACS, acute coronary syndrome; ARB, angiotensin receptor blocker; CABG, coronary artery bypass graft surgery; CHF, congestive heart failure; GP, glycoprotein; LM, left main; LVEF, left ventricular ejection fraction; PCI, percutaneous coronary intervention; TVD, triplevessel disease. Fig In-hospital meds Discharge meds Data presented as n (%), unless otherwise specified. Units for lab investigations are U/l for CPK and CK-MB, mmol/l for serum creatinine, g/l for serum hemoglobin, 10e9/l for white cell count, and mmol/l for other values. ACS, acute coronary syndrome; CABG, coronary artery bypass graft surgery; CAD, coronary artery disease; CK-MB, creatine kinase-mb; CPK, creatinine phosphokinase; HF, heart failure; IQR, interquartile range; NSTEMI, non-stsegment elevation myocardial infarction; SBP, systolic blood pressure; STEMI, ST-segment elevation myocardial infarction ASA Clopidogrel β-blockers ACEI/ARB Statin non-chf patients with STEMI (177 vs. 135 min; P < 0.001), with no difference in the median door to needle time (48 vs. 52 min; P = 0.824), respectively. The cohort with ACS and HF was more likely to have worse left ventricular systolic function in the range of moderately severe left ventricular systolic dysfunction (ejection fraction = 30 35%) compared with the non-hf group (56 vs. 30%; P =0.001) (Table 2). Medical therapy for acute coronary syndrome patients with congestive heart failure in the first 24 h of hospitalization and on hospital discharge. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ASA, acetylsalicyclic acid. without CHF (Table 2). However, upon discharge, the use of b-blockers increased in CHF patients but did not differ with ACEI/ARB and statins (Table 2; Fig. 1). Medical therapies Patients with ACS and CHF were less likely to receive inhospital b-blockers (74 vs. 86%; P = 0.001), statins (94 vs. 96%; P = 0.020), clopidogrel (85 vs. 88%; P = 0.01), and glycoprotein IIb/IIIa inhibitors (21 vs. 31%; P = 0.001), but more likely to receive ACEI or ARB (84 vs. 74%; P = 0.001) and unfractionated or low-molecular-weight heparin (90 vs. 84%; P = 0.001) compared with those In-hospital procedures CHF patients were less likely to undergo coronary angiography (53 vs. 69%; P = 0.001) and PCI (21 vs. 37%; P = 0.001) but had similar CABG (8 vs. 9%; P = 0.423) compared with non-chf patients. In addition, patients with CHF were more likely to have a history of triple vessel or left main CAD on coronary angiography (47 vs. 34%; P = 0.001) (Table 2).

4 4 Coronary Artery Disease 2013, Vol 00 No 00 In-hospital outcomes In-hospital mortality and cardiogenic shock were significantly higher in the CHF patients. Adjusted inhospital mortality and cardiogenic shock were several folds higher in the CHF group (OR 4.43, 95% confidence interval ; and OR 3.51, 95% confidence interval , respectively). HF was also associated with an adverse effect on in-hospital recurrent ischemia, stroke, and major bleeding (Tables 3 and 4). Several presentation characteristics were independently associated with an increased risk of HF including older age, higher heart rate, lower systolic blood pressure on presentation, history of diabetes mellitus, hypertension, or CAD, and higher serum creatinine (Table 5). Discussion In this substudy, we have observed that one in every five patients with ACS had HF during admission. In both men and women, the prevalence of HF complicating ACS increased considerably with age, and it was also found that women were more likely to present with HF and ACS. Several of our findings are consistent with previous reports characterizing HF in patients with ACS. In the global registry of acute coronary syndrome (GRACE) HF determinants substudy, it was found that HF on hospital admission was associated with an B3 4-fold increase in hospital and 6-month death rates. There was also reduced frequency of PCI and lower b-blocker usage among patients with HF on admission [1,6]. Similar findings were obtained in nonclinical trial settings in NRMI-2, the Canadian ACS registries, and the European Heart Survey of ACS (Euro Heart Survey ACS), where HF was one of the strongest predictors of in-hospital death in patients with ACS [7,8]. Our observation was also similar to what was found in the international data in GRACE (19%) [1,6] and the national data of the Gulf Registry of Acute Coronary Events (Gulf RACE) (25%), a prospective, multinational study of all consecutive patients hospitalized with a diagnosis of ACS in 65 centers in six Arab countries [2,3]. The higher rate of HF in patients with ACS in SPACE may be because of a higher prevalence of diabetes mellitus in the Saudi population [4,9], multivessel disease, previous history of coronary events, and late presentation of ACS in our population; other potential explanations include differences in genetic predisposition, environmental factors, and severity of CAD in the Saudi population [4]. Our cohort was found to have higher incidence of diabetes, which is twice the rate in Europe and North America (Table 1). It is a very important finding, confirming the report from the Gulf RACE registry, and represents a major public health problem in Arab countries. They are more likely to have a previous history of cardiac intervention such as PCI or bypass surgery as well as worse left ventricular systolic function (Table 2). HF patients have higher incidence of cardiogenic shock and, therefore, were more likely to be treated with vasopressors and inotropes [10]. Furthermore, inotropes are usually used in patients with severe HF. In these two situations, many physicians will withhold b-blockers until Table 3 In-hospital complications in acute coronary syndrome patients with and without congestive heart failure Variables ACS with CHF (n = 905) n (%) ACS without CHF (n = 3619) n (%) P-value Death 70 (7.7) 59 (1.6) < Recurrent ischemia 122 (13.5) 437 (12) 0.25 Recurrent myocardial 12 (1.33) 46 (1.3) infarction Cardiogenic shock 88 (9.7) 92 (2.5) < Stroke 13 (1.4) 27 (0.75) Major bleeding 13 (1.4) 48 (1.3) ACS, acute coronary syndrome; CHF, congestive heart failure. Table 5 Presentation characteristics associated with in-hospital heart failure in patients with acute coronary syndromes Wald w 2 Odds ratio 95% confidence interval P-value Age (10-year increase) < Male Diabetes mellitus < IHD Creatinine (10 U increase) IHD, ischemic heart disease. Table 4 Crude and adjusted odds ratios for in-hospital outcomes in patients with congestive heart failure Outcomes Crude OR (95% CI) P-value Adjusted OR (95% CI) P-value Death 5.06 ( ) < ( ) < Recurrent ischemia 1.13 ( ) ( ) Recurrent myocardial infarction 1.04 ( ) ( ) Cardiogenic shock 4.12 ( ) < ( ) < Stroke 1.94 ( ) ( ) Major bleeding 1.08 ( ) ( ) CI, confidence interval; OR, odds ratio.

5 Congestive heart failure in Saudi patients Albackr et al. 5 the patient is stabilized so as not to suppress the useful catecholamine response to acute HF [6,10]. However, afterload reduction is usually established earlier in the management course and this might explain the higher ACEI and lower b-blocker use in this patient population. Nonetheless, the delivery of guideline-based therapy was excellent (Table 2). Given the higher mortality rate in patients with ACS and HF, it has been shown that those are the subsets that drive greater benefit from revascularization [11]. However, our study shows that cardiac catheterization and revascularization are underused in patients with HF, probably because of the predicted risk of renal failure with contrast injection in those hypotensive patients. Nonetheless, we still believe that ACS and HF should undergo invasive investigation to determine whether they can benefit in revascularization. It was found that both ACS patients with or without HF have lower rates of both coronary angiogram and coronary intervention and this could be related to the higher rate of diabetes and renal impairment in our population as well as late presentation of the STEMI population in which they present with signs of HF and so they may not be able to tolerate the contrast load. Another interesting observation that we have made is that the patients with ACS and HF were more likely to present with NSTEMI. This may be because of the fact that these patients are mostly diabetic and have multivessel disease rather than single-vessel disease. This was different from what was found in the Gulf RACE HF substudy that found patients with HF were significantly more likely to have anterior ST-segment elevation on their presenting ECG compared with those without HF [3]. It is also possible that some patients may have been admitted with a primary exacerbation of HF but were misclassified as ACS (NSTEMI) because of a slight elevation in biochemical markers of myocardial necrosis. Patients with ACS complicated by HF were much more likely to die in the hospital or experience other inhospital complications such as recurrent ischemia, stroke, cardiogenic shock, or major bleeding. Study limitations All the centers participating in this registry are tertiary care centers and hence there may be a selection bias. Our analysis may also be limited by the absence of information on previous history of HF and outcomes after hospital discharge. It is also possible that some patients may have been admitted with a primary exacerbation of HF but were misclassified as ACS because of a slight elevation in biochemical markers of myocardial necrosis. Finally, the observational nature of the study precludes us from inferring cause-and-effect associations between treatment patterns and in-hospital outcomes. Conclusion In this observational study from the SPACE registry, we aimed to characterize the Saudi population presenting with ACS and HF, which has not been investigated before, and also to monitor the quality of care and assess the degree of adherence to international guidelines. It was found that ACS patients with CHF were older, more likely to have diabetes, hypertension, history of multivessel disease, lower left ventricular ejection fraction, and hemodynamically unstable than those without CHF. These findings potentially explain the higher incidence of in-hospital adverse outcomes in ACS patients with CHF. More aggressive treatment of these patients is warranted to improve prognosis. Acknowledgements Conflicts of interest There are no conflicts of interest. References 1 Steg PG, Dabbous OH, Feldman LJ, Cohen-Solal A, Aumont MC, López- Sendón J, et al. Determinants and prognostic impact of heart failure complicating acute coronary syndromes: observations from the Global Registry of Acute Coronary Events (GRACE). Circulation 2004; 109: Zubaid M, Rashed WA, Al-Khaja N, Almahmeed W, Al-Lawati J, Sulaiman K, et al. Clinical presentation and outcomes of acute coronary syndromes in the Gulf Registry of Acute Coronary Events (Gulf RACE). Saudi Med J 2008; 29: Alsheikh-Ali AA, Al-Mallah MH, Al-Mahmeed W, Albustani N, Al Suwaidi J, Sulaiman K, et al. Heart failure in patients hospitalized with acute coronary syndromes: observations from the Gulf Registry of Acute Coronary Events (Gulf RACE). Eur J Heart Fail 2009; 11: AlHabib KF, Hersi A, AlFaleh H, Kurdi M, Arafah M, Youssef M, et al. The Saudi project for assessment of coronary events (SPACE) registry: design and results of a phase I pilot study. Can J Cardiol 2009; 25:e255 e Cannon CP, Battler A, Brindis RG, Cox JL, Ellis SG, Every NR, et al. American College of Cardiology key data elements and definitions for measuring the clinical management and outcomes of patients with acute coronary syndromes. A report of the American College of Cardiology Task Force on Clinical Data Standards (Acute Coronary Syndromes Writing Committee). J Am Coll Cardiol 2001; 38: Steg PG, Goldberg RJ, Gore JM, Fox KA, Eagle KA, Flather MD, et al. GRACE Investigators. Baseline characteristics, management practices, and in-hospital outcomes of patients hospitalized with acute coronary syndromes in the Global Registry of Acute Coronary Events (GRACE). Am J Cardiol 2002; 90: Segev A, Strauss BH, Tan M, Mendelsohn AA, Lai K, Ashton T, et al. Prognostic significance of admission heart failure in patients with non-stelevation acute coronary syndromes (from the Canadian Acute Coronary Syndrome Registries). Am J Cardiol 2006; 98: Haim M, Battler A, Behar S, Fioretti PM, Boyko V, Simoons ML, Hasdai D. Acute coronary syndromes complicated by symptomatic and asymptomatic heart failure: does current treatment comply with guidelines? Am Heart J 2004; 147: Al-Nozha MM, Arafah MR, Al-Mazrou YY, Al-Maatouq MA, Khan NB, Khalil MZ, et al. Coronary artery disease in Saudi Arabia. Saudi Med J 2004; 25: Rosengren A, Wallentin L, Simoons M, Gitt AK, Behar S, Battler A, et al. Age, clinical presentation, and outcome of acute coronary syndromes in the Euroheart acute coronary syndrome survey. Eur Heart J 2006; 27: Wiviott SD, Morrow DA, Frederick PD, Antman EM, Braunwald E. Application of the Thrombolysis in Myocardial Infarction risk index in non-stsegment elevation myocardial infarction: evaluation of patients in the National Registry of Myocardial Infarction. J Am Coll Cardiol 2006; 47: AQ2

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