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Prevalence, management, and outcomes of familial hypercholesterolemia in patients with acute coronary syndromes in the Arabian Gulf
Journal of Clinical Lipidology (2018) -, -–-
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Original Article
Prevalence, management, and outcomes of familial hypercholesterolemia in patients with acute coronary syndromes in the Arabian Gulf Q4 Q1
Q2
Khalid Al-Rasadi*, Ibrahim Al-Zakwani, Alawi A. Alsheikh-Ali, Wael Almahmeed, Wafa Rashed, Mustafa Ridha, Raul D. Santos, Mohammad Zubaid Department of Biochemistry, Sultan Qaboos University Hospital, Muscat, Oman (Dr Al-Rasadi); Department of Pharmacology & Clinical Pharmacy, College of Medicine & Health Sciences, Sultan Qaboos University, Muscat, Oman (Dr Al-Zakwani); Gulf Health Research, Muscat, Oman (Dr Al-Zakwani); College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, UAE (Dr Alsheikh-Ali); Institute of Cardiac Sciences, Sheikh Khalifa Medical City, Abu Dhabi, UAE (Dr Alsheikh-Ali); Heart and Vascular Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, UAE (Dr Almahmeed); Department of Medicine, Mubarak Al–Kabeer Hospital, Ministry of Health, Kuwait (Dr Rashed); Department of Medicine, Al–Adan Hospital, Ministry of Health, Kuwait (Dr Ridha); Lipid Clinic Heart Institute (InCor), University of Sao Paulo Medical School Hospital, Sao Paulo, Brazil (Dr Santos); Preventive Medicine Center and Cardiology Program, Hospital Israelita Albert Einstein, Sao Paulo, Brazil (Dr Santos); and Department of Medicine, Faculty of Medicine, Kuwait University, Kuwait (Dr Zubaid) KEYWORDS: Acute coronary syndrome; Hypercholesterolemia; Cardiovascular abnormality; Diabetes; Middle East; Arabs
BACKGROUND: Information on the epidemiology of familial hypercholesterolemia (FH) in the Arabian Gulf region, which has an elevated rate of consanguinity and type II diabetes, is scarce. OBJECTIVES: To assess the prevalence of FH, its management, and impact on atherosclerotic cardiovascular disease (ASCVD) outcomes in a multicenter cohort of Arabian Gulf patients with acute coronary syndrome (ACS). METHODS: Patients (N 5 3224) hospitalized with ACS were studied. FH was diagnosed using the Dutch Lipid Clinic Network criteria. A composite endpoint of nonfatal myocardial infarction, stroke, transient ischemic attack, and mortality between the ‘‘probable/definite’’ and the ‘‘unlikely’’ FH patients was assessed after 1 year. Analyses were performed using univariate and multivariate statistical techniques. RESULTS: At admission, the proportion of ‘‘probable/definite’’, ‘‘possible’’, and ‘‘unlikely’’ FH in ACS patients was 3.7% (n 5 119), 28% (n 5 911), and 68% (n 5 2194), respectively. Overall, 54% (n 5 1730) of patients had diabetes, whereas 24% (n 5 783) were current smokers. The ‘‘probable/ definite’’ FH group was younger (50 vs 63 years; P , .001), had a greater prevalence of early coronary disease (38% vs 8.8%; P , .001), and previous statin use (87% vs 57%; P , .001) when compared with the ‘‘unlikely’’ FH group. After 1 year, the ‘‘probable/definite’’ FH cohort had worse lipid control (13% vs 23%; P , .001) and presented with a greater association with the composite ASCVD endpoint when
Funding: Gulf COAST is an investigator-initiated study that was supported by AstraZeneca and Kuwait University (project code XX02/11). Neither Kuwait University nor AstraZeneca had any role in the study design, data collection, data analysis, or writing the article.
* Corresponding author. Department of Biochemistry, Sultan Qaboos University Hospital, P.O. Box 38, Al-Khod, Muscat 123, Oman. E-mail address: [email protected] Submitted September 12, 2017. Accepted for publication February 8, 2018.
1933-2874/Ó2018 Published by Elsevier Inc. on behalf of National Lipid Association. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). https://doi.org/10.1016/j.jacl.2018.02.003 FLA 5.5.0 DTD JACL1257_proof 5 March 2018 11:56 am
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compared with the ‘‘unlikely’’ FH group (odds ratio: 1.85; 95% confidence interval: 1.01–3.38; P 5 .047) after multivariable adjustment. CONCLUSIONS: In Arabian Gulf citizens, FH was common in ACS patients, was undertreated, and was associated with a worse 1-year prognosis. Ó 2018 Published by Elsevier Inc. on behalf of National Lipid Association. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction Familial hypercholesterolemia (FH) is more frequently found in patients with acute coronary syndrome (ACS) as suggested by some cross-sectional studies1–5 and has been associated, in a prospective Swiss cohort, with worse inhospital prognosis and recurrent atherosclerotic cardiovascular disease (ASCVD) events.2,3 Nonetheless, FH remains largely underdiagnosed worldwide in the general population.6,7 Studies in Europe have shown that FH patients in the general population6–8 and specially after an ACS event2,3,9 are undertreated with lipid-lowering drugs (LLDs), and most patients fail to reach recommended low-density lipoprotein cholesterol (LDL-C) targets.10–13 There are currently no data available on the epidemiology of FH in ACS in the Arabian Gulf, a region where there is high prevalence of both consanguinity,14,15 which is an important risk factor for FH, and type II diabetes,16,17 a condition that severely aggravates the prognosis after an ACS event. Therefore, this study assessed the prevalence of FH, its management and ASCVD outcomes in a large multicenter cohort of Arabian Gulf patients who presented with ACS.
Methods Study population Details of the methods of the Gulf locals with ACS events (Gulf COAST) registry have been reported previously.18 Briefly, Gulf COAST registry is a prospective, multicenter, multinational, longitudinal, observational, cohort-based registry of consecutive citizens, from the Gulf region of the Middle East, (Bahrain, Kuwait, Oman, and United Arab Emirates) admitted from January 2012 to January 2013 to 29 hospitals with a diagnosis of ACS. The registry enrolled a total of 4061 patients who were citizens, 18 years of age or older with ACS diagnosed according to American College of Cardiology clinical data standards.19 Apart from excluding noncitizens and those who were not willing/able to sign an informed consent, there were no other exclusion criteria. An attempt was made to recruit all comers. This study was approved by the local institutional ethics committees of participating centers.
Diagnosis of FH The diagnosis of FH was based on the Dutch Lipid Clinic Network (DLCN) criteria,20 which consists of a
point score system and includes information about personal and first-degree relatives with high LDL-C, tendon xanthomas, and premature coronary heart disease (CHD). Tendon xanthomas and genetic mutations were scored zero in this study because of the unavailaibility of information about these parameters. Definitive FH score was defined as .8 points, probable 6–8, possible 3–5, and unlikely ,3. Owing to the small number of patients with definitive and probable FH, these 2 groups were combined as one ‘‘definitive/probable’’. The LDL-C on admission was corrected for prior statin use by multiplying a factor of 1.43 that considers an average 30% reduction in LDL-C by the use of average doses of statins as previously reported in similar studies.21,22
Data collection and clinical outcomes Data collected included patient demographics, previous ASCVD history and risk factors, prior medication use, laboratory data, clinical presentation and management during hospital stay including medications, reperfusion therapy and procedures, and discharge medications. Follow-up was performed at 1, 6, and 12 months from the date of enrollment and was carried out by clinic visits or telephone interviews. ASCVD events during follow-up were defined as the first occurrence of the composite endpoint of nonfatal myocardial infarction, atherothrombotic stroke, transient ischemic attack, or mortality after hospital discharge.
Statistical analysis For categorical variables, frequencies and percentages were reported. Differences among groups were analyzed using Pearson’s c2 tests (or Fisher’s exact tests for cells ,5). For continuous variables, mean and standard deviation were used to present the data while analyses were performed using univariate ordinary least squares regression. The association between ASCVD event and FH status was evaluated by multivariable logistic regression utilizing the simultaneous method and adjusting for age, sex, body mass index (BMI), smoking, hypertension, and diabetes mellitus.21–23 The goodness of fit of the multivariable logistic model was examined using the Hosmer & Lemeshow goodness-of-fit statistic24 as well as the C-index.25 An a priori 2-tailed level of significance was set at the 0.05 level. Statistical analyses were conducted using STATA version 13.1 (StataCorp, 2013, Stata Statistical Software, College Station, TX, USA).
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Epidemiology of FH in ACS patients in Arabs
Results Of the 4061 Arabian Gulf citizens recruited, baseline LDL-C was available for 3224 patients, which constituted the cohort for the present analysis. The overall mean age was 60 6 12 years (range 18–99), 67% (n 5 2175) were males, and 24% (n 5 783) were active/current smokers. Overall, the proportion of patients with premature CHD, family history of premature CHD, hypertension, and diabetes mellitus were 38% (n 5 1232), 15% (n 5 483), 64% (n 5 2077), and 54% (n 5 1730), respectively. Table 1 shows clinical and laboratory characteristics of studied patients according to DLCN criteria. Of 3224 patients, 3.4% (n 5 110) left the hospitals against medical advice. Among those that were discharged alive (N 5 2999), a further 3.1% (n 5 93) were lost to followup. The proportion of ‘‘probable/definite’’, ‘‘possible’’,
3 and ‘‘unlikely’’ FH in ACS patients was 3.7% (n 5 119), 28% (n 5 911), and 68% (n 5 2194), respectively. The ‘‘probable/definite’’ FH group was younger (P , .001), had a higher BMI (P 5 .004), a greater prevalence of smoking (P 5 .004), premature CHD (P , .001), family history of premature CHD (P , .001), higher baseline adjusted LDL-C (P , .001), and HbA1c (P , .001) levels but a lower GRACE risk score when compared with the ‘‘unlikely’’ FH cohort (P , .001). During admission, the ‘‘probable/definite’’ FH group was also less likely to be associated with unstable angina when compared with the ‘‘unlikely’’ FH cohort (P 5 .015). There was no difference in the proportion of ‘‘probable/definite’’ FH between those who remained in the study or were lost to follow-up after 1 year (3.7% vs 3.2%; P 5 1.000). Supplement Table 1 shows that there were no differences in demographic and clinical characteristics between the 2 groups.
Table 1 Baseline demographic, clinical and biochemical characteristics of the Gulf COAST cohort stratified by familial hypercholesterolemia (FH) status as defined by the Dutch Lipid Clinic Network criteria (N 5 3224) Dutch Lipid Clinic Network Characteristic, mean 6 SD unless specified otherwise Demographic Age, y Female sex, n (%) BMI, kg/m2 Smoking status, n (%) Current smoker Recent smoker (,1 mo) Past smoker (.1 y) Never smoked Comorbidities, n (%) Pre-existing CVD Premature CHD Family hx of premature CHD Hypertension Diabetes mellitus LDL-C*, mmol/L HbA1c Blood pressure (BP), mm Hg Systolic BP Diastolic BP GRACE risk score Discharged diagnosis†, n (%) LBBB MI NSTEMI STEMI Unstable angina
Probable/definite FH (n 5 119; 3.7%)
Possible FH (n 5 911; 28%)
Unlikely FH (n 5 2194; 68%)
P-value
50 6 10 45 (38%) 30.4 6 5.8
55 6 12 290 (32%) 29.1 6 5.9
63 6 12 714 (33%) 28.7 6 6.0
,.001 .234 .004
39 (33%) 2 (1.7%) 10 (8.4%) 68 (57%)
269 (30%) 16 (1.8%) 97 (11%) 529 (58%)
475 (22%) 47 (2.1%) 286 (13%) 1386 (63%)
.005 .734 .145 .186
102 (86%) 45 (38%) 47 (40%) 86 (72%) 71 (60%) 7.8 6 3.9 9.9 6 2.4%
603 (66%) 237 (26%) 238 (26%) 557 (61%) 466 (61%) 4.8 6 1.3 9.0 6 2.2%
527 (24%) 194 (8.8%) 198 (9.0%) 1434 (65%) 1193 (54%) 3.1 6 0.9 8.6 6 2.1%
,.001 ,.001 ,.001 .123 .260 ,.001 ,.001
145 6 30 85 6 17 109 6 33
142 6 28 82 6 17 119 6 41
141 6 28 79 6 16 133 6 41
.077 ,.001 ,.001
0 61 (55%) 31 (28%) 19 (17%)
5 (0.6%) 416 (49%) 248 (29%) 184 (22%)
14 (0.7%) 989 (49%) 464 (23%) 565 (28%)
1.000 .195 .214 .015
SD, standard deviation; BMI, Body mass index (n 5 3187); CVD, cardiovascular disease (myocardial infarction, stroke, transient ischemic attack, peripheral arterial disease); premature CHD, coronary heart disease (,55 y in males and ,60 y in females); Hx, history; LDL-C, low-density lipoprotein cholesterol; HbA1c, glycated hemoglobin A1c (n 5 1284), BP (n 5 3221), GRACE risk score (n 5 3209); LBBB MI, left bundle branch block myocardial infarction; NSTEMI, non-ST myocardial infarction; STEMI, ST myocardial infarction. Percentages may not add up to 100% because of rounding off. *Adjusted LDL-C (by a multiplication factor of 1.43 for those on prior statin use). †Analysis only included those that did not die in-hospital (n 5 115) as well as those that did not leave against medical advice (n 5 110) (3224–[115 1 110] 5 2999). Furthermore, 3 patients had missing discharged diagnosis. P-value represents the difference between the ‘‘probable/definite’’ and ‘‘unlikely’’ FH groups excluding the ‘‘possible’’ FH cohort.
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Table 2 shows medication use at baseline, at discharge, and at 1-year follow-up. At hospital discharge, there were generally no differences in medication use among the groups (P . .05 for all medications) except for the other LLDs, which were more likely to be prescribed to the ‘‘probable/definite’’ FH cohort compared with the ‘‘unlikely’’ FH group (P 5 .001). The proportion of patients that were on the 4 evidence-based medications (antiplatelet [aspirin], angiotensin converting enzyme inhibitors/angiotensin receptor blockers [angiotensin converting enzyme inhibitor/angiotensin receptor blocker], beta blockers, and statins) that reduce ASCVD morbidity and mortality concurrently at hospital discharge was 68% (n 5 2026) with no significant differences among the groups (P 5 .625). Overall, at 1-year follow-up, there were also no differences in medication use among the groups (P . .05 for all medications). The proportion of patients
that were on the 4 evidence-based medications concurrently at 1-year follow-up was similar between ‘‘probable/definite’’ and ‘‘unlikely’’ FH groups (at 71%). Figure 1 represents LDL-C goal attainment at 1-year follow-up of the ‘‘definite/probable’’, ‘‘possible’’, and ‘‘unlikely’’ FH cohorts, respectively. Most ACS patients did not reach their guideline-recommended LDL-C target, with the ‘‘definite/probable’’ FH group was more likely to achieve their LDL-C goals compared with the ‘‘unlikely’’ FH cohort (proportion at LDL-C goal: 13% vs 23%; P , .001). Table 3 shows in-hospital and 1-year cumulative procedures and outcomes. During hospitalization, the ‘‘probable/ definite’’ FH cohort was more likely to have recurrent angina when compared with the ‘‘unlikely’’ FH group (P , .001). There were no differences in hospital mortality among the groups. After 1-year follow-up, unadjusted rates Q3 of myocardial infarction, transient ischemic attack, and
Table 2 Medication characteristics of the Gulf COAST cohort stratified by familial hypercholesterolemia (FH) status as defined by the Dutch Lipid Clinic Network criteria (N 5 3224) Dutch Lipid Clinic Network Characteristic, n (%) unless specified otherwise Medication use before admission Aspirin Clopidogrel ACEI ARB Beta blocker Statin Other LLDs Medication use at discharge* Aspirin Clopidogrel ACEI ARB Beta blocker Statin Other LLDs EBM combination† Medication use at 1-y‡ Aspirin Clopidogrel ACEI ARB Beta blocker Statin Other LLDs EBM combination†
Probable/definite FH (n 5 119; 3.7%)
Possible FH (n 5 911; 28%)
Unlikely FH (n 5 2194; 68%)
P-value
87 28 50 19 61 104 1
(73%) (24%) (42%) (16%) (51%) (87%) (0.8%)
554 184 366 93 413 596 14
(61%) (20%) (40%) (10%) (45%) (65%) (1.5%)
1280 498 807 341 986 1247 28
(58%) (23%) (37%) (16%) (45%) (57%) (1.3%)
.002 .833 .250 .901 .178 ,.001 .680
110 86 71 18 94 109 8 72
(99%) (77%) (64%) (16%) (85%) (98%) (7.2%) (65%)
827 618 587 102 732 828 17 589
(97%) (72%) (69%) (12%) (86%) (97%) (2.0%) (69%)
1940 1555 1321 342 1706 1962 41 1365
(95%) (76%) (65%) (17%) (84%) (96%) (2.0%) (67%)
.098 .804 .833 .870 .821 .338 .001 .625
102 64 70 14 90 101 5 75
(97%) (61%) (67%) (13%) (86%) (96%) (4.8%) (71%)
768 531 566 131 709 764 21 615
(96%) (66%) (70%) (16%) (88%) (95%) (2.6%) (76%)
1708 1168 1204 360 1557 1730 53 1320
(92%) (63%) (65%) (19%) (83%) (93%) (2.8%) (71%)
.053 .735 .655 .133 .541 .185 .262 .880
ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; LLD, lipid-lowering drug; EBM, evidence-based medications. Percentages may not add up to 100% because of rounding off. P-value represents the difference between the ‘‘probable/definite’’ and ‘‘unlikely’’ FH groups excluding the ‘‘possible’’ FH cohort. *Medications at discharge excluded those that died in-hospital (n 5 115) as well as those that left against medical advice (n 5 110) (3224–[115 1 110] 5 2999). †EBM combination consisted of (antiplatelet [aspirin], ACEI/ARB, beta blocker, and statin). ‡Medication use at 1-y excluded those that died in-hospital (n 5 115), those that left against medical advice (n 5 110), those that died at 1-mo follow-up (n 5 34), 6-mo follow-up (n 5 102), and 12-mo follow-up (n 5 88) (3224–[115 1 110134 1 102188] 5 2775).
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Percent attaining LDL-C goal (< 1.8 mmol/L)
25%
web 4C=FPO
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Epidemiology of FH in ACS patients in Arabs 23%
20% P < .001* 15%
13%
12%
10%
5%
0% LDL-C Probable/de inite FH (9/69)
LDL-C Possible FH (68/549)
LDL-C Unlikely FH (334/1456)
Figure 1 LDL-C goal attainments at 1-year follow-up stratified by familial hypercholesterolemia (FH) status of the Gulf COAST as per the Dutch Lipid Clinic Network criteria (N 5 2074). LDLC, low-density lipoprotein cholesterol. * denotes an overall significant P-value in goal attainment among the 3 FH cohorts.
stroke. There was a significant unadjusted higher rate of percutaneous coronary interventions in ‘‘probable/definite’’ FH patients (P , .001) during follow-up. However, this
5 difference disappeared once adjusted for age, sex, BMI, smoking, hypertension, diabetes mellitus, GRACE risk score, pre-existing CVD, and adjusted LDL-C (adjusted odds ratio 1.72; 95% confidence interval: 0.93–3.18). There were no significant differences in unadjusted cumulative mortality between the ‘‘probable/definite’’ and the ‘‘unlikely’’ FH groups either at 6-month (P 5 .050) or at 12-month (P 5 .081). Table 4 shows that after multivariate adjustment (age, sex, BMI, smoking, hypertension, and diabetes mellitus), the ‘‘probable/definite’’ FH cohort was more likely to be associated with the composite ASCVD endpoint when compared with the ‘‘unlikely’’ FH group (adjusted odds ratio: 1.85; 95% confidence interval: 1.01–3.38; P 5 .047).
Discussion Few studies have reported the prevalence of FH in patients hospitalized for ACS,1–5 and to the best of our knowledge, this is the first large study examining the prevalence of FH and its impact on clinical outcomes after a 1-year follow-up in ACS patients in the Middle East. FH was relatively frequent, affected younger individuals, was associated with early CHD onset, and was poorly controlled
Table 3 In-hospital and cumulative 1-y procedures and outcomes including mortality of the Gulf COAST cohort stratified by familial hypercholesterolemia (FH) status as defined by the Dutch Lipid Clinic Network criteria (N 5 3224) Dutch Lipid Clinic Network Characteristic, n (%) unless specified otherwise In-hospital outcomes Recurrent angina Cardiogenic shock Re-infarction Repeat lysis Heart failure Ventilation Inotropes Cardiac arrhythmias Stroke 1-y clinical outcomes* Myocardial infarction TIA Stroke 1-y revascularization procedures* PCI CABG Mortality In-hospital 1-mo, cumulative 6-mo, cumulative 12-mo, cumulative
Probable/definite FH (n 5 111)
Possible FH (n 5 842)
Unlikely FH (n 5 2012)
P-value
30 3 3 2 11 2 4 3 0
147 46 16 4 102 40 64 25 7
288 107 31 7 303 125 153 121 18
(13%) (4.9%) (1.4%) (0.3%) (14%) (5.7%) (7.0%) (5.5%) (0.8%)
,.001 .249 .399 .038 .167 .079 .136 .169 1.000
(25%) (2.5%) (2.5%) (1.7%) (9.2%) (1.7%) (3.4%) (2.5%)
(16%) (5.1%) (1.8%) (0.4%) (11%) (4.4%) (7.0%) (2.7%) (0.8%)
6 (5.4%) 2 (1.8%) 0
28 (3.3%) 7 (0.8%) 6 (0.7%)
78 (3.9%) 33 (1.6%) 39 (1.9%)
.423 .896 .264
55 (50%) 7 (6.3%)
341 (41%) 50 (5.9%)
674 (34%) 96 (4.8%)
,.001 .465
1 1 4 8
(0.8%) (0.8%) (3.4%) (6.7%)
27 39 64 80
(3.0%) (4.3%) (7.0%) (8.8%)
87 111 191 266
(4.0%) (5.1%) (8.7%) (12%)
.117 .068 .050 .081
TIA, transient ischemic attack; PCI, percutaneous coronary interventions; CABG, coronary artery bypass graft. Percentages may not add up to 100% because of rounding off. *One-year outcomes and procedures excluded those that died in-hospital (n 5 115), those that left against medical advice (n 5 110) and those that died at 1-mo follow-up (n 5 34) (3224–[115 1 110 1 34] 5 2965). P-value represents the difference between the ‘‘probable/definite’’ and ‘‘unlikely’’ FH groups excluding the ‘‘possible’’ FH cohort.
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Table 4 Association between 1-year follow-up atherosclerotic cardiovascular (ASCVD) event and familial hypercholesterolemia (FH) using the Dutch Lipid Clinic Network criteria in acute coronary syndrome patients in the Middle East (N 5 2999)* Dutch Lipid Clinic Network ASCVD event Events/participants, n (%) Unadjusted odds ratio (OR) (95% CI) Age/sex adjusted OR (95% CI) Adjusted OR (95% CI) (adjusted for age, sex, body mass index smoking, hypertension, and diabetes mellitus)
Unlikely FH (n 5 2034; 68%)
Possible FH (n 5 854; 28%)
Probable/definite FH (n 5 111; 3.7%)
286/2034 (14%) 1.00 Referent 1.00 Referent 1.00 Referent
88/854 (10%) 0.70 (0.54–0.90)† 1.13 (0.86–1.48) 1.13 (0.87–1.47)
14/111 (13%) 0.88 (0.50–1.57) 2.01 (1.10–3.69)† 1.85 (1.01–3.38)†
CI, confidence interval; BMI, body mass index; cardiovascular (myocardial infarction, transient ischemic attack, stroke, and peripheral arterial disease). Adjusted analyses were performed using multivariable logistic regression. *The analysis of ASCVD events excluded those that had died in-hospital (n 5 115) as well as those that left against medical advice during admission (n 5 110) (3224–[115 1 110] 5 2999). An ASCVD event included follow-up (after discharge to 1-y) transient ischemic attack, stroke, myocardial infarction, and mortality. †P , .05.
during follow-up. Most importantly, those with ‘‘probable/ definite’’ FH diagnosis were more likely to be associated with adverse ASCVD outcomes after a 1-year follow-up, even after adjusting for baseline demographic and clinical characteristics. The impact of FH diagnosis on outcomes was striking even considering the elevated rates of type II diabetes (60%) and current smoking (33%), conditions associated with a worse prognosis after ACS.26,27 In the present study, the prevalence of ‘‘probable/ definite’’ FH using the DLCN criteria was 3.7% (1 in 27), which is 7 times higher than the estimated prevalence of FH in the general population (0.5% based on the 1/200 prevalence).28 In addition, patients with ‘‘probable/ definite’’ FH were approximately 10 years younger than the ‘‘unlikely’’ FH, developed CHD earlier, and had a high prevalence of multiple ASCVD risk factors such as smoking (1 in 3), hypertension (7 in 10), and diabetes (6 in 10). The real prevalence of FH in Arabian Gulf countries is unknown.15,29,30 However, one striking finding of our study was that the prevalence of ‘‘probable/definite’’ FH was more than double of a similar Swiss ACS cohort where a 1.6% (vs 3.7%) prevalence was reported using the same DLCN criteria without notation of ‘‘tendon xanthomas’’ or the same DLCN criteria without notation of ‘‘tissue cholesterol deposits’’.1,2 One possible explanation for this finding is the elevated rate of consanguinity among Gulf citizens,14,15 which could inflate the prevalence of genetically determined conditions such as FH. Despite of the lack of information on statin dose in the study, overall patients were undertreated because LDL-C levels ,1.8 mmol/L (70 mg/dL) were attained roughly in 1 in 10 and 1 in 4 of the ‘‘probable/definite’’ FH and ‘‘unlikely’’ FH groups, respectively. This indicates a serious gap in treatment of these very high ASCVD risk groups and the possible nonoptimal use of high-intensity statin and other LLDs in the region. These findings were similar to the
ones from the Centralized Pan-Middle East Survey on the Undertreatment of Hypercholesterolemia study. The LDL-C goal achievements in patients with very high ASCVD risk was 32% and most patients were on moderate intensity statins.31 Our study shows that this gap is even greater for putative FH patients. Indeed, many studies confirm the undertreatment of FH in patients with or without evidence of ASCVD.6,8,9 Early diagnosis and treatment of FH can decrease the risk for CHD development. In the present study, we observed that patients with ‘‘probable/definite’’ FH had a greater recurrence of ischemia during in-hospital admission and after a 1-year follow-up they presented a 2.15-fold greater adjusted risk of ASCVD recurrence than the ‘‘unlikely’’ FH. The higher recurrent ASCVD event rates in the FH patients could be explained by factors such as long-term elevated cholesterol burden exposure, delay in initiating LLDs, possible use of low-intensity LLDs, and the presence of other uncontrolled ASCVD risk factors. The increased number of recurrent ASCVD events has occurred despite the fact that a high proportion (71%) of patients were still on the 4 evidence-based medications concurrently at 1-year follow-up. The utilization of evidence-based medications in ACS patients in the present study was significantly higher compared with a similar ACS cohort in the Gulf RACE study published in 2011 (71% vs 49%).32 One important characteristic of the studied population is the extremely elevated prevalence of type II diabetes in both ‘‘probable/definite’’ and the ‘‘unlikely’’ FH groups (60% and 54%, respectively). In a cross-sectional study in the Netherlands, the prevalence of diabetes was lower in FH patients compared with their nonaffected relatives and was the lowest in patients carrying receptor-negative mutations in the LDL receptor gene.33 The differences between this and the Dutch study may be related to the pre-existing
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Epidemiology of FH in ACS patients in Arabs
very high prevalence of obesity, metabolic syndrome, and type II diabetes in the general population of the Arabian Gulf region.16,17 However, it is crucial to emphasize the importance of FH diagnosis in the occurrence of ASCVD in the follow-up even considering the previously described deleterious role played by diabetes after an ACS event. Our study has several limitations. There are missing data regarding the presence of tendon xanthomas, high cholesterol levels in the first-degree family members and the genetic analysis, which could affect the true estimation of FH prevalence in this population. However, the presence of high levels of plasma cholesterol or tendon xanthomas may be difficult to demonstrate specially in patients or relatives with FH who receive previous statin treatment. The statin doses were not reported in the present study, and we had to adjust LDL-C levels, for an average LDL-C reduction in those receiving previous statin use. Nevertheless, this procedure has been done previously in similar studies.22,23 Furthermore, the information of whether these FH patients are not being optimally treated or if there is treatment resistance due to high baseline LDL-C levels is difficult to conclude. Finally, there are missing patients’ data during the 1-year follow-up, which can limit the conclusion about the percentage of undertreatment and the true rate of recurrent ASCVD events. However, the number of losses to follow-up was relatively small; there were no differences in the proportion of ‘‘probable/definite’’ FH and in clinical characteristics between those remained in the study and those that were lost to follow-up (Supplement Table 1).
Conclusion Clinical diagnosis of FH is common in patients hospitalized with ACS and is associated with a worse 1-year clinical outcome in the Arabian Gulf region. The rates seem to be higher than those in Western countries and reflect underdiagnosis of such high ASCVD risk cases. Strategies to optimize the management of FH patients and their family members are highly required to prevent residual and future ASCVD events in the region.
Acknowledgments Authors’ contributions: Mohammad Zubaid, Wael Almahmeed, and Alawi A. Alsheikh-Ali designed and coordinated the study. Khalid Al-Rasadi, Raul D. Santos, and Ibrahim Al-Zakwani wrote the draft of the article. All authors critically reviewed and approved the present article.
Financial disclosures Khalid Al-Rasadi received research grant from Sanofi, served on the speaker’s bureau and as an advisory board member for Sanofi, AstraZeneca, and Pfizer. Mohammad Zubaid and Wael Almahmeed received speakers’ bureau
7 from Sanofi, Boehringer Ingelheim, Amgen, and AstraZeneca. Alawi A. Alsheikh-Ali has received honoraria related to consulting and speaker’s activities from Boehringer Ingelheim, Bayer, and Pfizer. Raul D. Santos has received honoraria related to consulting and speaker’s activities from Amgen, AstraZeneca, BioLab, Boehringer Ingelheim, Eli Lilly, Genzyme, Kowa, Merck, Sanofi/Regeneron, Pfizer, ProCaps, Torrent, and Unilever. Ibrahim Al-Zakwani, Wafa Rashed, and Mustafa Ridha have nothing to disclose.
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25. Hanley JA, McNeil BJ. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology. 1982;143: 29–36. 26. Lettino M, Andell P, Zeymer U, et al. Diabetic patients with acute coronary syndromes in contemporary European registries: characteristics and outcomes. Eur Heart J Cardiovasc Pharmacother. 2017;3: 198–213. 27. Robertson JO, Ebrahimi R, Lansky AJ, Mehran R, Stone GW, Lincoff AM. Impact of cigarette smoking on extent of coronary artery disease and prognosis of patients with non-ST-segment elevation acute coronary syndromes: an analysis from the ACUITY Trial (Acute Catheterization and Urgent Intervention Triage Strategy). JACC Cardiovasc Interv. 2014;7:372–379. 28. Hovingh GK, Davidson MH, Kastelein JJ, O’Connor AM. Diagnosis and treatment of familial hypercholesterolaemia. Eur Heart J. 2013; 34:962–971. 29. Al Rasadi K, Almahmeed W, AlHabib KF, et al. Dyslipidaemia in the Middle East: Current status and a call for action. Atherosclerosis. 2016;252:182–187. 30. Al-Ashwal A, Alnouri F, Sabbour H, et al. Identification and Treatment of Patients with Homozygous Familial Hypercholesterolaemia: information and Recommendations from a Middle East Advisory Panel. Curr Vasc Pharmacol. 2015;13:759–770. 31. Arafah M, Al-Hinai AT, Al Mahmeed W, et al. Centralized panMiddle East Survey on the undertreatment of hypercholesterolemia: results from the CEPHEUS study in Arabian Gulf countries. Angiology. 2014;65:919–926. 32. Al-Zakwani I, Zubaid M, Panduranga P, et al. Medication use patterns and predictors of optimal therapy at discharge in 8176 patients with acute coronary syndrome from 6 Middle Eastern countries: data from the gulf registry of acute coronary events. Angiology. 2001;62: 447–454. 33. Besseling J, Kastelein JJ, Defesche JC, Hutten BA, Hovingh GK. Association between familial hypercholesterolemia and prevalence of type 2 diabetes mellitus. JAMA. 2015;313:1029–1036.
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Appendix: Gulf Organization
COAST
Administrative
Steering Committee: Mohammad Zubaid (Principal Investigator, steering committee chairman, Kuwait), Wafa Rashed (Registry manager, National Coordinator, Kuwait), Mustafa Ridha (Kuwait), Fahad Alenezi (Kuwait), Rashid Alhamdan (Kuwait), Mousa Akbar (Kuwait), Najib Alrawahi (National Coordinator, Oman), Haitham Amin (National Coordinator, Bahrain), Wael Almahmeed (UAE), Alawi Alsheikh-Ali (Registry statistician, UAE), Abdullah Shehab (National Coordinator, UAE), Husam Ouda (UAE), Abdullah Alnuaimi (UAE), Fahad Baslaib (UAE), Arif AlMulla (UAE) and Harlan Krumholz (USA).
Investigators Bahrain Bahrain Defense Hospital: Leena Sulaibikh*, Babu Thevan, Dev Sheel, Fahimuddin Sayed, Fawaz Bardooli, Hugmi Jain, Jasim Mohammed, Manal Matar, Rajesh Jayakumar, Sanjeev Kumar Jaiswal, S Mushtaq Sayed, Vinayak Vadgaonkar. Salmaniya Medical Complex: Taysir Garadah*, Khalid Bin Thani*, Aisha Al-Moosa, Alaa
8.e1 Al-Zamrooni, Mohamed E. Alalawi, Eman Murad, Fajer AlMoosa, Aziza Matooq.
Kuwait Adan Hospital: Sadiq Abdul*, Abdel aleem Rabie, Ahmed Nabil Hassan, Ahmed El Mugharbil, Sherif Arafat. Ahmadi (Kuwait Oil Company) Hospital: Shahid Zubair* Chest Hospital: Medhat Soliman*, Mohamed Farouk Elkhalifa, Mohamed Ali Sallam, Viji Koshy George. Farwaniya Hospital: Amr Elguindy*, Ahmed Amin, Ayman Abdel Mawgoud, Emad Nashaat, Mahmoud Abdel Tawab, MiladRafla, Mohamed Okba, Mousa Arafat. Jahra Hospital: Mohammad El Gindy*, Melek Atta, Mustafa Alshaikha, Rim Ahmed. Mubarak Hospital: Ibrahim Farrag*, Abdulmonem Mohamad, Ashraf Hammad, Fawzy Maqlad, Gladis Hefny, Hani Bassiouny, Ihab Awwad, Maged Youssef, Motaz Elarini, Nabil Ragab, SamehElmasry, Samir Mohamad. Sabah Hospital: Islam Elsisy*, Mahmoud Korashy, Simon George.
Oman Armed Forces Hospital: BR Kamath*, Bichu Ruchir Kumar. Bahla Hospital: Kurian Mathew*. Burami Hospital:
Supplement Table 1 Demographic and clinical characteristics between the Gulf COAST group remaining at the end of the year and the cohort that was lost to follow-up (LTF) Characteristic, mean 6 SD unless specified otherwise
LTF (n 5 93; 3.1%)
Remaining (n 5 2,906; 96.9%)
P-value
Probable/definite FH, n (%) Demographic Age, y Female sex, n (%) BMI, kg/m2 Comorbidities, n (%) Pre-existing CVD Premature CHD Family hx of premature CHD Hypertension Diabetes mellitus LDL-C*, mmol/L HbA1c GRACE risk score Discharged diagnosis†, n (%) LBBB MI NSTEMI STEMI Unstable angina
3 (3.2%)
108 (3.7%)
1.000
61 6 13 29 (31%) 29.6 6 6.0
60 6 12 949 (33%) 28.9 6 6.0
.544 .765 .311
29 (31%) 13 (14%) 13 (14%) 54 (58%) 52 (56%) 3.5 6 1.3 9.0 6 2.0% 129 6 39
1,135 (39%) 448 (15%) 455 (16%) 1,876 (65%) 1,548 (53%) 3.8 6 1.7 8.8 6 2.2% 126 6 39
.125 .705 .661 .198 .615 .172 .458 .426
2 (2.2%) 44 (47%) 25 (27%) 22 (24%)
17 (0.6%) 1,422 (49%) 718 (25%) 746 (26%)
.413
SD, standard deviation; BMI, Body mass index; CVD, cardiovascular disease (myocardial infarction, stroke, transient ischemic attack, peripheral arterial disease); CHD, coronary heart disease (,55 years in males and ,60 years in females); Hx, history; LDL-C, low-density lipoprotein cholesterol; HbA1c, glycated hemoglobin A1c, GRACE risk score; LBBB MI, left bundle branch block myocardial infarction; NSTEMI, non-ST myocardial infarction; STEMI, ST myocardial infarction. Percentages may not add up to 100% because of rounding off. *Adjusted LDL-C (by a multiplication factor of 1.43 for those on prior statin use). †Analysis only included those that did not die in-hospital as well as those that did not leave against medical advice. Furthermore, 3 patients had missing discharged diagnosis.
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Naguib Asham Zaki*. Ibri Hospital: BimalChakroborty*, Abdalla Abdalla, Ayman Aziz, Nipa Saha, Yaseer Khan. Nizwa Hospital: Mourad Al Sharkawy*, Abdel-Salam Gamil, Abubaker Ahmed, Ahmed Abdulla Elamin, Ahmed Nidham Nidham, Amjad Saeed Merghani Hammour, Azhar Alshaibany, Bahaa Eldin Mohamed, Fahmy Hilal, Imadeldin Mohammed Alhaj, Mahmud Hassan, Mohamed Ebrahime, Sabah Al Saeedi, Emad Salah Fathy, Ahmed Hegazy. Royal Hospital: Mohamed AlRiyami*, Amir Al-Amri*, Wadhha Alsiyabi, Hany Samir. Royal Police Hospital: Abdul Malik*, Renchi Mathew. Rustaq Hospital: Osama Alkadi*, AlaaElmeligy, Mian Nasirud Din. Sohar Hospital: Aouf Mohamad Alazzawi *, Ali Al-Khafaji, Hamada Mohamed Amin, Hatim Issa, Jan Gorgy, Mohamed Abdulraheem, Salma Jabeen, Sameh Girgis, Sheshadri Pasupathy. Sur Hospital: Qassim Shimal*, Ganesh Vimal. Sumail Hospital: Safwat Abdel
Wahab*, Ahmed Mosad Ibrahim, Manal Sabry Mohamed. Sultan Qaboos Salalah Hospital: Prit pal Singh*.
United Arab Emirates Dubai Hospital: Nooshin Bazargani*, Arif Abdullatif AlMulla*, Sadek Ali. Fujairah Hospital: Amrish Agrawal* Khorfakan Hospital: Magda Helal*. Qasimi Hospital: Wael Al Abbasi*, Loai Abu Mousa*, Ruwaida Najeeb. Ras Al Khaima Hospital: Adel Wassef* Rashid Hospital: Khalifa Omar Muhammed*, Amr Moustafa*, Ali Raza Rajani, Khalifa Muhammed, Mohamed Al-Raqabani, Shibu Bahuleyan. Sheikh Khalifa Medical City (SKMC): Masood Ghori*, Amer Sana, Hamdy Mohamed. Tawam Hospital: Sadek El Mokahal*, Amany Hillis, Mohammed Nour Mustafa, Teena Abdalla. Zayed Military Hospital: Zubair Memon* *Chief site officer.
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Original Article
Prevalence, management, and outcomes of familial hypercholesterolemia in patients with acute coronary syndromes in the Arabian Gulf Q4 Q1
Q2
Khalid Al-Rasadi*, Ibrahim Al-Zakwani, Alawi A. Alsheikh-Ali, Wael Almahmeed, Wafa Rashed, Mustafa Ridha, Raul D. Santos, Mohammad Zubaid Department of Biochemistry, Sultan Qaboos University Hospital, Muscat, Oman (Dr Al-Rasadi); Department of Pharmacology & Clinical Pharmacy, College of Medicine & Health Sciences, Sultan Qaboos University, Muscat, Oman (Dr Al-Zakwani); Gulf Health Research, Muscat, Oman (Dr Al-Zakwani); College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, UAE (Dr Alsheikh-Ali); Institute of Cardiac Sciences, Sheikh Khalifa Medical City, Abu Dhabi, UAE (Dr Alsheikh-Ali); Heart and Vascular Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, UAE (Dr Almahmeed); Department of Medicine, Mubarak Al–Kabeer Hospital, Ministry of Health, Kuwait (Dr Rashed); Department of Medicine, Al–Adan Hospital, Ministry of Health, Kuwait (Dr Ridha); Lipid Clinic Heart Institute (InCor), University of Sao Paulo Medical School Hospital, Sao Paulo, Brazil (Dr Santos); Preventive Medicine Center and Cardiology Program, Hospital Israelita Albert Einstein, Sao Paulo, Brazil (Dr Santos); and Department of Medicine, Faculty of Medicine, Kuwait University, Kuwait (Dr Zubaid) KEYWORDS: Acute coronary syndrome; Hypercholesterolemia; Cardiovascular abnormality; Diabetes; Middle East; Arabs
BACKGROUND: Information on the epidemiology of familial hypercholesterolemia (FH) in the Arabian Gulf region, which has an elevated rate of consanguinity and type II diabetes, is scarce. OBJECTIVES: To assess the prevalence of FH, its management, and impact on atherosclerotic cardiovascular disease (ASCVD) outcomes in a multicenter cohort of Arabian Gulf patients with acute coronary syndrome (ACS). METHODS: Patients (N 5 3224) hospitalized with ACS were studied. FH was diagnosed using the Dutch Lipid Clinic Network criteria. A composite endpoint of nonfatal myocardial infarction, stroke, transient ischemic attack, and mortality between the ‘‘probable/definite’’ and the ‘‘unlikely’’ FH patients was assessed after 1 year. Analyses were performed using univariate and multivariate statistical techniques. RESULTS: At admission, the proportion of ‘‘probable/definite’’, ‘‘possible’’, and ‘‘unlikely’’ FH in ACS patients was 3.7% (n 5 119), 28% (n 5 911), and 68% (n 5 2194), respectively. Overall, 54% (n 5 1730) of patients had diabetes, whereas 24% (n 5 783) were current smokers. The ‘‘probable/ definite’’ FH group was younger (50 vs 63 years; P , .001), had a greater prevalence of early coronary disease (38% vs 8.8%; P , .001), and previous statin use (87% vs 57%; P , .001) when compared with the ‘‘unlikely’’ FH group. After 1 year, the ‘‘probable/definite’’ FH cohort had worse lipid control (13% vs 23%; P , .001) and presented with a greater association with the composite ASCVD endpoint when
Funding: Gulf COAST is an investigator-initiated study that was supported by AstraZeneca and Kuwait University (project code XX02/11). Neither Kuwait University nor AstraZeneca had any role in the study design, data collection, data analysis, or writing the article.
* Corresponding author. Department of Biochemistry, Sultan Qaboos University Hospital, P.O. Box 38, Al-Khod, Muscat 123, Oman. E-mail address: [email protected] Submitted September 12, 2017. Accepted for publication February 8, 2018.
1933-2874/Ó2018 Published by Elsevier Inc. on behalf of National Lipid Association. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). https://doi.org/10.1016/j.jacl.2018.02.003 FLA 5.5.0 DTD JACL1257_proof 5 March 2018 11:56 am
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compared with the ‘‘unlikely’’ FH group (odds ratio: 1.85; 95% confidence interval: 1.01–3.38; P 5 .047) after multivariable adjustment. CONCLUSIONS: In Arabian Gulf citizens, FH was common in ACS patients, was undertreated, and was associated with a worse 1-year prognosis. Ó 2018 Published by Elsevier Inc. on behalf of National Lipid Association. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction Familial hypercholesterolemia (FH) is more frequently found in patients with acute coronary syndrome (ACS) as suggested by some cross-sectional studies1–5 and has been associated, in a prospective Swiss cohort, with worse inhospital prognosis and recurrent atherosclerotic cardiovascular disease (ASCVD) events.2,3 Nonetheless, FH remains largely underdiagnosed worldwide in the general population.6,7 Studies in Europe have shown that FH patients in the general population6–8 and specially after an ACS event2,3,9 are undertreated with lipid-lowering drugs (LLDs), and most patients fail to reach recommended low-density lipoprotein cholesterol (LDL-C) targets.10–13 There are currently no data available on the epidemiology of FH in ACS in the Arabian Gulf, a region where there is high prevalence of both consanguinity,14,15 which is an important risk factor for FH, and type II diabetes,16,17 a condition that severely aggravates the prognosis after an ACS event. Therefore, this study assessed the prevalence of FH, its management and ASCVD outcomes in a large multicenter cohort of Arabian Gulf patients who presented with ACS.
Methods Study population Details of the methods of the Gulf locals with ACS events (Gulf COAST) registry have been reported previously.18 Briefly, Gulf COAST registry is a prospective, multicenter, multinational, longitudinal, observational, cohort-based registry of consecutive citizens, from the Gulf region of the Middle East, (Bahrain, Kuwait, Oman, and United Arab Emirates) admitted from January 2012 to January 2013 to 29 hospitals with a diagnosis of ACS. The registry enrolled a total of 4061 patients who were citizens, 18 years of age or older with ACS diagnosed according to American College of Cardiology clinical data standards.19 Apart from excluding noncitizens and those who were not willing/able to sign an informed consent, there were no other exclusion criteria. An attempt was made to recruit all comers. This study was approved by the local institutional ethics committees of participating centers.
Diagnosis of FH The diagnosis of FH was based on the Dutch Lipid Clinic Network (DLCN) criteria,20 which consists of a
point score system and includes information about personal and first-degree relatives with high LDL-C, tendon xanthomas, and premature coronary heart disease (CHD). Tendon xanthomas and genetic mutations were scored zero in this study because of the unavailaibility of information about these parameters. Definitive FH score was defined as .8 points, probable 6–8, possible 3–5, and unlikely ,3. Owing to the small number of patients with definitive and probable FH, these 2 groups were combined as one ‘‘definitive/probable’’. The LDL-C on admission was corrected for prior statin use by multiplying a factor of 1.43 that considers an average 30% reduction in LDL-C by the use of average doses of statins as previously reported in similar studies.21,22
Data collection and clinical outcomes Data collected included patient demographics, previous ASCVD history and risk factors, prior medication use, laboratory data, clinical presentation and management during hospital stay including medications, reperfusion therapy and procedures, and discharge medications. Follow-up was performed at 1, 6, and 12 months from the date of enrollment and was carried out by clinic visits or telephone interviews. ASCVD events during follow-up were defined as the first occurrence of the composite endpoint of nonfatal myocardial infarction, atherothrombotic stroke, transient ischemic attack, or mortality after hospital discharge.
Statistical analysis For categorical variables, frequencies and percentages were reported. Differences among groups were analyzed using Pearson’s c2 tests (or Fisher’s exact tests for cells ,5). For continuous variables, mean and standard deviation were used to present the data while analyses were performed using univariate ordinary least squares regression. The association between ASCVD event and FH status was evaluated by multivariable logistic regression utilizing the simultaneous method and adjusting for age, sex, body mass index (BMI), smoking, hypertension, and diabetes mellitus.21–23 The goodness of fit of the multivariable logistic model was examined using the Hosmer & Lemeshow goodness-of-fit statistic24 as well as the C-index.25 An a priori 2-tailed level of significance was set at the 0.05 level. Statistical analyses were conducted using STATA version 13.1 (StataCorp, 2013, Stata Statistical Software, College Station, TX, USA).
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Results Of the 4061 Arabian Gulf citizens recruited, baseline LDL-C was available for 3224 patients, which constituted the cohort for the present analysis. The overall mean age was 60 6 12 years (range 18–99), 67% (n 5 2175) were males, and 24% (n 5 783) were active/current smokers. Overall, the proportion of patients with premature CHD, family history of premature CHD, hypertension, and diabetes mellitus were 38% (n 5 1232), 15% (n 5 483), 64% (n 5 2077), and 54% (n 5 1730), respectively. Table 1 shows clinical and laboratory characteristics of studied patients according to DLCN criteria. Of 3224 patients, 3.4% (n 5 110) left the hospitals against medical advice. Among those that were discharged alive (N 5 2999), a further 3.1% (n 5 93) were lost to followup. The proportion of ‘‘probable/definite’’, ‘‘possible’’,
3 and ‘‘unlikely’’ FH in ACS patients was 3.7% (n 5 119), 28% (n 5 911), and 68% (n 5 2194), respectively. The ‘‘probable/definite’’ FH group was younger (P , .001), had a higher BMI (P 5 .004), a greater prevalence of smoking (P 5 .004), premature CHD (P , .001), family history of premature CHD (P , .001), higher baseline adjusted LDL-C (P , .001), and HbA1c (P , .001) levels but a lower GRACE risk score when compared with the ‘‘unlikely’’ FH cohort (P , .001). During admission, the ‘‘probable/definite’’ FH group was also less likely to be associated with unstable angina when compared with the ‘‘unlikely’’ FH cohort (P 5 .015). There was no difference in the proportion of ‘‘probable/definite’’ FH between those who remained in the study or were lost to follow-up after 1 year (3.7% vs 3.2%; P 5 1.000). Supplement Table 1 shows that there were no differences in demographic and clinical characteristics between the 2 groups.
Table 1 Baseline demographic, clinical and biochemical characteristics of the Gulf COAST cohort stratified by familial hypercholesterolemia (FH) status as defined by the Dutch Lipid Clinic Network criteria (N 5 3224) Dutch Lipid Clinic Network Characteristic, mean 6 SD unless specified otherwise Demographic Age, y Female sex, n (%) BMI, kg/m2 Smoking status, n (%) Current smoker Recent smoker (,1 mo) Past smoker (.1 y) Never smoked Comorbidities, n (%) Pre-existing CVD Premature CHD Family hx of premature CHD Hypertension Diabetes mellitus LDL-C*, mmol/L HbA1c Blood pressure (BP), mm Hg Systolic BP Diastolic BP GRACE risk score Discharged diagnosis†, n (%) LBBB MI NSTEMI STEMI Unstable angina
Probable/definite FH (n 5 119; 3.7%)
Possible FH (n 5 911; 28%)
Unlikely FH (n 5 2194; 68%)
P-value
50 6 10 45 (38%) 30.4 6 5.8
55 6 12 290 (32%) 29.1 6 5.9
63 6 12 714 (33%) 28.7 6 6.0
,.001 .234 .004
39 (33%) 2 (1.7%) 10 (8.4%) 68 (57%)
269 (30%) 16 (1.8%) 97 (11%) 529 (58%)
475 (22%) 47 (2.1%) 286 (13%) 1386 (63%)
.005 .734 .145 .186
102 (86%) 45 (38%) 47 (40%) 86 (72%) 71 (60%) 7.8 6 3.9 9.9 6 2.4%
603 (66%) 237 (26%) 238 (26%) 557 (61%) 466 (61%) 4.8 6 1.3 9.0 6 2.2%
527 (24%) 194 (8.8%) 198 (9.0%) 1434 (65%) 1193 (54%) 3.1 6 0.9 8.6 6 2.1%
,.001 ,.001 ,.001 .123 .260 ,.001 ,.001
145 6 30 85 6 17 109 6 33
142 6 28 82 6 17 119 6 41
141 6 28 79 6 16 133 6 41
.077 ,.001 ,.001
0 61 (55%) 31 (28%) 19 (17%)
5 (0.6%) 416 (49%) 248 (29%) 184 (22%)
14 (0.7%) 989 (49%) 464 (23%) 565 (28%)
1.000 .195 .214 .015
SD, standard deviation; BMI, Body mass index (n 5 3187); CVD, cardiovascular disease (myocardial infarction, stroke, transient ischemic attack, peripheral arterial disease); premature CHD, coronary heart disease (,55 y in males and ,60 y in females); Hx, history; LDL-C, low-density lipoprotein cholesterol; HbA1c, glycated hemoglobin A1c (n 5 1284), BP (n 5 3221), GRACE risk score (n 5 3209); LBBB MI, left bundle branch block myocardial infarction; NSTEMI, non-ST myocardial infarction; STEMI, ST myocardial infarction. Percentages may not add up to 100% because of rounding off. *Adjusted LDL-C (by a multiplication factor of 1.43 for those on prior statin use). †Analysis only included those that did not die in-hospital (n 5 115) as well as those that did not leave against medical advice (n 5 110) (3224–[115 1 110] 5 2999). Furthermore, 3 patients had missing discharged diagnosis. P-value represents the difference between the ‘‘probable/definite’’ and ‘‘unlikely’’ FH groups excluding the ‘‘possible’’ FH cohort.
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Table 2 shows medication use at baseline, at discharge, and at 1-year follow-up. At hospital discharge, there were generally no differences in medication use among the groups (P . .05 for all medications) except for the other LLDs, which were more likely to be prescribed to the ‘‘probable/definite’’ FH cohort compared with the ‘‘unlikely’’ FH group (P 5 .001). The proportion of patients that were on the 4 evidence-based medications (antiplatelet [aspirin], angiotensin converting enzyme inhibitors/angiotensin receptor blockers [angiotensin converting enzyme inhibitor/angiotensin receptor blocker], beta blockers, and statins) that reduce ASCVD morbidity and mortality concurrently at hospital discharge was 68% (n 5 2026) with no significant differences among the groups (P 5 .625). Overall, at 1-year follow-up, there were also no differences in medication use among the groups (P . .05 for all medications). The proportion of patients
that were on the 4 evidence-based medications concurrently at 1-year follow-up was similar between ‘‘probable/definite’’ and ‘‘unlikely’’ FH groups (at 71%). Figure 1 represents LDL-C goal attainment at 1-year follow-up of the ‘‘definite/probable’’, ‘‘possible’’, and ‘‘unlikely’’ FH cohorts, respectively. Most ACS patients did not reach their guideline-recommended LDL-C target, with the ‘‘definite/probable’’ FH group was more likely to achieve their LDL-C goals compared with the ‘‘unlikely’’ FH cohort (proportion at LDL-C goal: 13% vs 23%; P , .001). Table 3 shows in-hospital and 1-year cumulative procedures and outcomes. During hospitalization, the ‘‘probable/ definite’’ FH cohort was more likely to have recurrent angina when compared with the ‘‘unlikely’’ FH group (P , .001). There were no differences in hospital mortality among the groups. After 1-year follow-up, unadjusted rates Q3 of myocardial infarction, transient ischemic attack, and
Table 2 Medication characteristics of the Gulf COAST cohort stratified by familial hypercholesterolemia (FH) status as defined by the Dutch Lipid Clinic Network criteria (N 5 3224) Dutch Lipid Clinic Network Characteristic, n (%) unless specified otherwise Medication use before admission Aspirin Clopidogrel ACEI ARB Beta blocker Statin Other LLDs Medication use at discharge* Aspirin Clopidogrel ACEI ARB Beta blocker Statin Other LLDs EBM combination† Medication use at 1-y‡ Aspirin Clopidogrel ACEI ARB Beta blocker Statin Other LLDs EBM combination†
Probable/definite FH (n 5 119; 3.7%)
Possible FH (n 5 911; 28%)
Unlikely FH (n 5 2194; 68%)
P-value
87 28 50 19 61 104 1
(73%) (24%) (42%) (16%) (51%) (87%) (0.8%)
554 184 366 93 413 596 14
(61%) (20%) (40%) (10%) (45%) (65%) (1.5%)
1280 498 807 341 986 1247 28
(58%) (23%) (37%) (16%) (45%) (57%) (1.3%)
.002 .833 .250 .901 .178 ,.001 .680
110 86 71 18 94 109 8 72
(99%) (77%) (64%) (16%) (85%) (98%) (7.2%) (65%)
827 618 587 102 732 828 17 589
(97%) (72%) (69%) (12%) (86%) (97%) (2.0%) (69%)
1940 1555 1321 342 1706 1962 41 1365
(95%) (76%) (65%) (17%) (84%) (96%) (2.0%) (67%)
.098 .804 .833 .870 .821 .338 .001 .625
102 64 70 14 90 101 5 75
(97%) (61%) (67%) (13%) (86%) (96%) (4.8%) (71%)
768 531 566 131 709 764 21 615
(96%) (66%) (70%) (16%) (88%) (95%) (2.6%) (76%)
1708 1168 1204 360 1557 1730 53 1320
(92%) (63%) (65%) (19%) (83%) (93%) (2.8%) (71%)
.053 .735 .655 .133 .541 .185 .262 .880
ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; LLD, lipid-lowering drug; EBM, evidence-based medications. Percentages may not add up to 100% because of rounding off. P-value represents the difference between the ‘‘probable/definite’’ and ‘‘unlikely’’ FH groups excluding the ‘‘possible’’ FH cohort. *Medications at discharge excluded those that died in-hospital (n 5 115) as well as those that left against medical advice (n 5 110) (3224–[115 1 110] 5 2999). †EBM combination consisted of (antiplatelet [aspirin], ACEI/ARB, beta blocker, and statin). ‡Medication use at 1-y excluded those that died in-hospital (n 5 115), those that left against medical advice (n 5 110), those that died at 1-mo follow-up (n 5 34), 6-mo follow-up (n 5 102), and 12-mo follow-up (n 5 88) (3224–[115 1 110134 1 102188] 5 2775).
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Percent attaining LDL-C goal (< 1.8 mmol/L)
25%
web 4C=FPO
449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504
Epidemiology of FH in ACS patients in Arabs 23%
20% P < .001* 15%
13%
12%
10%
5%
0% LDL-C Probable/de inite FH (9/69)
LDL-C Possible FH (68/549)
LDL-C Unlikely FH (334/1456)
Figure 1 LDL-C goal attainments at 1-year follow-up stratified by familial hypercholesterolemia (FH) status of the Gulf COAST as per the Dutch Lipid Clinic Network criteria (N 5 2074). LDLC, low-density lipoprotein cholesterol. * denotes an overall significant P-value in goal attainment among the 3 FH cohorts.
stroke. There was a significant unadjusted higher rate of percutaneous coronary interventions in ‘‘probable/definite’’ FH patients (P , .001) during follow-up. However, this
5 difference disappeared once adjusted for age, sex, BMI, smoking, hypertension, diabetes mellitus, GRACE risk score, pre-existing CVD, and adjusted LDL-C (adjusted odds ratio 1.72; 95% confidence interval: 0.93–3.18). There were no significant differences in unadjusted cumulative mortality between the ‘‘probable/definite’’ and the ‘‘unlikely’’ FH groups either at 6-month (P 5 .050) or at 12-month (P 5 .081). Table 4 shows that after multivariate adjustment (age, sex, BMI, smoking, hypertension, and diabetes mellitus), the ‘‘probable/definite’’ FH cohort was more likely to be associated with the composite ASCVD endpoint when compared with the ‘‘unlikely’’ FH group (adjusted odds ratio: 1.85; 95% confidence interval: 1.01–3.38; P 5 .047).
Discussion Few studies have reported the prevalence of FH in patients hospitalized for ACS,1–5 and to the best of our knowledge, this is the first large study examining the prevalence of FH and its impact on clinical outcomes after a 1-year follow-up in ACS patients in the Middle East. FH was relatively frequent, affected younger individuals, was associated with early CHD onset, and was poorly controlled
Table 3 In-hospital and cumulative 1-y procedures and outcomes including mortality of the Gulf COAST cohort stratified by familial hypercholesterolemia (FH) status as defined by the Dutch Lipid Clinic Network criteria (N 5 3224) Dutch Lipid Clinic Network Characteristic, n (%) unless specified otherwise In-hospital outcomes Recurrent angina Cardiogenic shock Re-infarction Repeat lysis Heart failure Ventilation Inotropes Cardiac arrhythmias Stroke 1-y clinical outcomes* Myocardial infarction TIA Stroke 1-y revascularization procedures* PCI CABG Mortality In-hospital 1-mo, cumulative 6-mo, cumulative 12-mo, cumulative
Probable/definite FH (n 5 111)
Possible FH (n 5 842)
Unlikely FH (n 5 2012)
P-value
30 3 3 2 11 2 4 3 0
147 46 16 4 102 40 64 25 7
288 107 31 7 303 125 153 121 18
(13%) (4.9%) (1.4%) (0.3%) (14%) (5.7%) (7.0%) (5.5%) (0.8%)
,.001 .249 .399 .038 .167 .079 .136 .169 1.000
(25%) (2.5%) (2.5%) (1.7%) (9.2%) (1.7%) (3.4%) (2.5%)
(16%) (5.1%) (1.8%) (0.4%) (11%) (4.4%) (7.0%) (2.7%) (0.8%)
6 (5.4%) 2 (1.8%) 0
28 (3.3%) 7 (0.8%) 6 (0.7%)
78 (3.9%) 33 (1.6%) 39 (1.9%)
.423 .896 .264
55 (50%) 7 (6.3%)
341 (41%) 50 (5.9%)
674 (34%) 96 (4.8%)
,.001 .465
1 1 4 8
(0.8%) (0.8%) (3.4%) (6.7%)
27 39 64 80
(3.0%) (4.3%) (7.0%) (8.8%)
87 111 191 266
(4.0%) (5.1%) (8.7%) (12%)
.117 .068 .050 .081
TIA, transient ischemic attack; PCI, percutaneous coronary interventions; CABG, coronary artery bypass graft. Percentages may not add up to 100% because of rounding off. *One-year outcomes and procedures excluded those that died in-hospital (n 5 115), those that left against medical advice (n 5 110) and those that died at 1-mo follow-up (n 5 34) (3224–[115 1 110 1 34] 5 2965). P-value represents the difference between the ‘‘probable/definite’’ and ‘‘unlikely’’ FH groups excluding the ‘‘possible’’ FH cohort.
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Table 4 Association between 1-year follow-up atherosclerotic cardiovascular (ASCVD) event and familial hypercholesterolemia (FH) using the Dutch Lipid Clinic Network criteria in acute coronary syndrome patients in the Middle East (N 5 2999)* Dutch Lipid Clinic Network ASCVD event Events/participants, n (%) Unadjusted odds ratio (OR) (95% CI) Age/sex adjusted OR (95% CI) Adjusted OR (95% CI) (adjusted for age, sex, body mass index smoking, hypertension, and diabetes mellitus)
Unlikely FH (n 5 2034; 68%)
Possible FH (n 5 854; 28%)
Probable/definite FH (n 5 111; 3.7%)
286/2034 (14%) 1.00 Referent 1.00 Referent 1.00 Referent
88/854 (10%) 0.70 (0.54–0.90)† 1.13 (0.86–1.48) 1.13 (0.87–1.47)
14/111 (13%) 0.88 (0.50–1.57) 2.01 (1.10–3.69)† 1.85 (1.01–3.38)†
CI, confidence interval; BMI, body mass index; cardiovascular (myocardial infarction, transient ischemic attack, stroke, and peripheral arterial disease). Adjusted analyses were performed using multivariable logistic regression. *The analysis of ASCVD events excluded those that had died in-hospital (n 5 115) as well as those that left against medical advice during admission (n 5 110) (3224–[115 1 110] 5 2999). An ASCVD event included follow-up (after discharge to 1-y) transient ischemic attack, stroke, myocardial infarction, and mortality. †P , .05.
during follow-up. Most importantly, those with ‘‘probable/ definite’’ FH diagnosis were more likely to be associated with adverse ASCVD outcomes after a 1-year follow-up, even after adjusting for baseline demographic and clinical characteristics. The impact of FH diagnosis on outcomes was striking even considering the elevated rates of type II diabetes (60%) and current smoking (33%), conditions associated with a worse prognosis after ACS.26,27 In the present study, the prevalence of ‘‘probable/ definite’’ FH using the DLCN criteria was 3.7% (1 in 27), which is 7 times higher than the estimated prevalence of FH in the general population (0.5% based on the 1/200 prevalence).28 In addition, patients with ‘‘probable/ definite’’ FH were approximately 10 years younger than the ‘‘unlikely’’ FH, developed CHD earlier, and had a high prevalence of multiple ASCVD risk factors such as smoking (1 in 3), hypertension (7 in 10), and diabetes (6 in 10). The real prevalence of FH in Arabian Gulf countries is unknown.15,29,30 However, one striking finding of our study was that the prevalence of ‘‘probable/definite’’ FH was more than double of a similar Swiss ACS cohort where a 1.6% (vs 3.7%) prevalence was reported using the same DLCN criteria without notation of ‘‘tendon xanthomas’’ or the same DLCN criteria without notation of ‘‘tissue cholesterol deposits’’.1,2 One possible explanation for this finding is the elevated rate of consanguinity among Gulf citizens,14,15 which could inflate the prevalence of genetically determined conditions such as FH. Despite of the lack of information on statin dose in the study, overall patients were undertreated because LDL-C levels ,1.8 mmol/L (70 mg/dL) were attained roughly in 1 in 10 and 1 in 4 of the ‘‘probable/definite’’ FH and ‘‘unlikely’’ FH groups, respectively. This indicates a serious gap in treatment of these very high ASCVD risk groups and the possible nonoptimal use of high-intensity statin and other LLDs in the region. These findings were similar to the
ones from the Centralized Pan-Middle East Survey on the Undertreatment of Hypercholesterolemia study. The LDL-C goal achievements in patients with very high ASCVD risk was 32% and most patients were on moderate intensity statins.31 Our study shows that this gap is even greater for putative FH patients. Indeed, many studies confirm the undertreatment of FH in patients with or without evidence of ASCVD.6,8,9 Early diagnosis and treatment of FH can decrease the risk for CHD development. In the present study, we observed that patients with ‘‘probable/definite’’ FH had a greater recurrence of ischemia during in-hospital admission and after a 1-year follow-up they presented a 2.15-fold greater adjusted risk of ASCVD recurrence than the ‘‘unlikely’’ FH. The higher recurrent ASCVD event rates in the FH patients could be explained by factors such as long-term elevated cholesterol burden exposure, delay in initiating LLDs, possible use of low-intensity LLDs, and the presence of other uncontrolled ASCVD risk factors. The increased number of recurrent ASCVD events has occurred despite the fact that a high proportion (71%) of patients were still on the 4 evidence-based medications concurrently at 1-year follow-up. The utilization of evidence-based medications in ACS patients in the present study was significantly higher compared with a similar ACS cohort in the Gulf RACE study published in 2011 (71% vs 49%).32 One important characteristic of the studied population is the extremely elevated prevalence of type II diabetes in both ‘‘probable/definite’’ and the ‘‘unlikely’’ FH groups (60% and 54%, respectively). In a cross-sectional study in the Netherlands, the prevalence of diabetes was lower in FH patients compared with their nonaffected relatives and was the lowest in patients carrying receptor-negative mutations in the LDL receptor gene.33 The differences between this and the Dutch study may be related to the pre-existing
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Epidemiology of FH in ACS patients in Arabs
very high prevalence of obesity, metabolic syndrome, and type II diabetes in the general population of the Arabian Gulf region.16,17 However, it is crucial to emphasize the importance of FH diagnosis in the occurrence of ASCVD in the follow-up even considering the previously described deleterious role played by diabetes after an ACS event. Our study has several limitations. There are missing data regarding the presence of tendon xanthomas, high cholesterol levels in the first-degree family members and the genetic analysis, which could affect the true estimation of FH prevalence in this population. However, the presence of high levels of plasma cholesterol or tendon xanthomas may be difficult to demonstrate specially in patients or relatives with FH who receive previous statin treatment. The statin doses were not reported in the present study, and we had to adjust LDL-C levels, for an average LDL-C reduction in those receiving previous statin use. Nevertheless, this procedure has been done previously in similar studies.22,23 Furthermore, the information of whether these FH patients are not being optimally treated or if there is treatment resistance due to high baseline LDL-C levels is difficult to conclude. Finally, there are missing patients’ data during the 1-year follow-up, which can limit the conclusion about the percentage of undertreatment and the true rate of recurrent ASCVD events. However, the number of losses to follow-up was relatively small; there were no differences in the proportion of ‘‘probable/definite’’ FH and in clinical characteristics between those remained in the study and those that were lost to follow-up (Supplement Table 1).
Conclusion Clinical diagnosis of FH is common in patients hospitalized with ACS and is associated with a worse 1-year clinical outcome in the Arabian Gulf region. The rates seem to be higher than those in Western countries and reflect underdiagnosis of such high ASCVD risk cases. Strategies to optimize the management of FH patients and their family members are highly required to prevent residual and future ASCVD events in the region.
Acknowledgments Authors’ contributions: Mohammad Zubaid, Wael Almahmeed, and Alawi A. Alsheikh-Ali designed and coordinated the study. Khalid Al-Rasadi, Raul D. Santos, and Ibrahim Al-Zakwani wrote the draft of the article. All authors critically reviewed and approved the present article.
Financial disclosures Khalid Al-Rasadi received research grant from Sanofi, served on the speaker’s bureau and as an advisory board member for Sanofi, AstraZeneca, and Pfizer. Mohammad Zubaid and Wael Almahmeed received speakers’ bureau
7 from Sanofi, Boehringer Ingelheim, Amgen, and AstraZeneca. Alawi A. Alsheikh-Ali has received honoraria related to consulting and speaker’s activities from Boehringer Ingelheim, Bayer, and Pfizer. Raul D. Santos has received honoraria related to consulting and speaker’s activities from Amgen, AstraZeneca, BioLab, Boehringer Ingelheim, Eli Lilly, Genzyme, Kowa, Merck, Sanofi/Regeneron, Pfizer, ProCaps, Torrent, and Unilever. Ibrahim Al-Zakwani, Wafa Rashed, and Mustafa Ridha have nothing to disclose.
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16. Alhyas L, McKay A, Balasanthiran A, Majeed A. Prevalences of overweight, obesity, hyperglycaemia, hypertension and dyslipidaemia in the Gulf: systematic review. JRSM Short Rep. 2011;2:55. 17. Aljefree N, Ahmed F. Prevalence of cardiovascular disease and associated risk factors among adult population in the Gulf region: a systematic review. Adv Public Health. 2015;2015:23. 18. Zubaid M, Thani KB, Rashed W, et al, Gulf COAST investigators. Design and Rationale of Gulf locals with Acute Coronary Syndrome Events (Gulf Coast) Registry. Open Cardiovasc Med J. 2014;8:88–93. 19. Weintraub WS, Karlsberg RP, Tcheng JE, et al. ACCF/AHA 2011 key data elements and definitions of a base cardiovascular vocabulary for electronic health records: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Clinical Data Standards. J Am Coll Cardiol. 2011;58:202–222. 20. European Association for Cardiovascular Prevention & Rehabilitation, Reiner Z, Catapano AL, De Backer G, et al. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J. 2011;32:1769–1818. 21. Jones PH, Davidson MH, Stein EA, et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial). Am J Cardiol. 2003;92: 152–160. 22. Langsted A, Kamstrup PR, Benn M, Tybjærg-Hansen A, Nordestgaard BG. High lipoprotein(a) as a possible cause of clinical familial hypercholesterolaemia: a prospective cohort study. Lancet Diabetes Endocrinol. 2016;4:577–587. 23. Steg PG, Goldberg RJ, Gore JM, et al. 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;90:358–363. 24. Lemeshow S, Hosmer DW Jr. A review of goodness of fit statistics for use in the development of logistic regression models. Am J Epidemiol. 1982;115:92–106.
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Epidemiology of FH in ACS patients in Arabs
Appendix: Gulf Organization
COAST
Administrative
Steering Committee: Mohammad Zubaid (Principal Investigator, steering committee chairman, Kuwait), Wafa Rashed (Registry manager, National Coordinator, Kuwait), Mustafa Ridha (Kuwait), Fahad Alenezi (Kuwait), Rashid Alhamdan (Kuwait), Mousa Akbar (Kuwait), Najib Alrawahi (National Coordinator, Oman), Haitham Amin (National Coordinator, Bahrain), Wael Almahmeed (UAE), Alawi Alsheikh-Ali (Registry statistician, UAE), Abdullah Shehab (National Coordinator, UAE), Husam Ouda (UAE), Abdullah Alnuaimi (UAE), Fahad Baslaib (UAE), Arif AlMulla (UAE) and Harlan Krumholz (USA).
Investigators Bahrain Bahrain Defense Hospital: Leena Sulaibikh*, Babu Thevan, Dev Sheel, Fahimuddin Sayed, Fawaz Bardooli, Hugmi Jain, Jasim Mohammed, Manal Matar, Rajesh Jayakumar, Sanjeev Kumar Jaiswal, S Mushtaq Sayed, Vinayak Vadgaonkar. Salmaniya Medical Complex: Taysir Garadah*, Khalid Bin Thani*, Aisha Al-Moosa, Alaa
8.e1 Al-Zamrooni, Mohamed E. Alalawi, Eman Murad, Fajer AlMoosa, Aziza Matooq.
Kuwait Adan Hospital: Sadiq Abdul*, Abdel aleem Rabie, Ahmed Nabil Hassan, Ahmed El Mugharbil, Sherif Arafat. Ahmadi (Kuwait Oil Company) Hospital: Shahid Zubair* Chest Hospital: Medhat Soliman*, Mohamed Farouk Elkhalifa, Mohamed Ali Sallam, Viji Koshy George. Farwaniya Hospital: Amr Elguindy*, Ahmed Amin, Ayman Abdel Mawgoud, Emad Nashaat, Mahmoud Abdel Tawab, MiladRafla, Mohamed Okba, Mousa Arafat. Jahra Hospital: Mohammad El Gindy*, Melek Atta, Mustafa Alshaikha, Rim Ahmed. Mubarak Hospital: Ibrahim Farrag*, Abdulmonem Mohamad, Ashraf Hammad, Fawzy Maqlad, Gladis Hefny, Hani Bassiouny, Ihab Awwad, Maged Youssef, Motaz Elarini, Nabil Ragab, SamehElmasry, Samir Mohamad. Sabah Hospital: Islam Elsisy*, Mahmoud Korashy, Simon George.
Oman Armed Forces Hospital: BR Kamath*, Bichu Ruchir Kumar. Bahla Hospital: Kurian Mathew*. Burami Hospital:
Supplement Table 1 Demographic and clinical characteristics between the Gulf COAST group remaining at the end of the year and the cohort that was lost to follow-up (LTF) Characteristic, mean 6 SD unless specified otherwise
LTF (n 5 93; 3.1%)
Remaining (n 5 2,906; 96.9%)
P-value
Probable/definite FH, n (%) Demographic Age, y Female sex, n (%) BMI, kg/m2 Comorbidities, n (%) Pre-existing CVD Premature CHD Family hx of premature CHD Hypertension Diabetes mellitus LDL-C*, mmol/L HbA1c GRACE risk score Discharged diagnosis†, n (%) LBBB MI NSTEMI STEMI Unstable angina
3 (3.2%)
108 (3.7%)
1.000
61 6 13 29 (31%) 29.6 6 6.0
60 6 12 949 (33%) 28.9 6 6.0
.544 .765 .311
29 (31%) 13 (14%) 13 (14%) 54 (58%) 52 (56%) 3.5 6 1.3 9.0 6 2.0% 129 6 39
1,135 (39%) 448 (15%) 455 (16%) 1,876 (65%) 1,548 (53%) 3.8 6 1.7 8.8 6 2.2% 126 6 39
.125 .705 .661 .198 .615 .172 .458 .426
2 (2.2%) 44 (47%) 25 (27%) 22 (24%)
17 (0.6%) 1,422 (49%) 718 (25%) 746 (26%)
.413
SD, standard deviation; BMI, Body mass index; CVD, cardiovascular disease (myocardial infarction, stroke, transient ischemic attack, peripheral arterial disease); CHD, coronary heart disease (,55 years in males and ,60 years in females); Hx, history; LDL-C, low-density lipoprotein cholesterol; HbA1c, glycated hemoglobin A1c, GRACE risk score; LBBB MI, left bundle branch block myocardial infarction; NSTEMI, non-ST myocardial infarction; STEMI, ST myocardial infarction. Percentages may not add up to 100% because of rounding off. *Adjusted LDL-C (by a multiplication factor of 1.43 for those on prior statin use). †Analysis only included those that did not die in-hospital as well as those that did not leave against medical advice. Furthermore, 3 patients had missing discharged diagnosis.
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Naguib Asham Zaki*. Ibri Hospital: BimalChakroborty*, Abdalla Abdalla, Ayman Aziz, Nipa Saha, Yaseer Khan. Nizwa Hospital: Mourad Al Sharkawy*, Abdel-Salam Gamil, Abubaker Ahmed, Ahmed Abdulla Elamin, Ahmed Nidham Nidham, Amjad Saeed Merghani Hammour, Azhar Alshaibany, Bahaa Eldin Mohamed, Fahmy Hilal, Imadeldin Mohammed Alhaj, Mahmud Hassan, Mohamed Ebrahime, Sabah Al Saeedi, Emad Salah Fathy, Ahmed Hegazy. Royal Hospital: Mohamed AlRiyami*, Amir Al-Amri*, Wadhha Alsiyabi, Hany Samir. Royal Police Hospital: Abdul Malik*, Renchi Mathew. Rustaq Hospital: Osama Alkadi*, AlaaElmeligy, Mian Nasirud Din. Sohar Hospital: Aouf Mohamad Alazzawi *, Ali Al-Khafaji, Hamada Mohamed Amin, Hatim Issa, Jan Gorgy, Mohamed Abdulraheem, Salma Jabeen, Sameh Girgis, Sheshadri Pasupathy. Sur Hospital: Qassim Shimal*, Ganesh Vimal. Sumail Hospital: Safwat Abdel
Wahab*, Ahmed Mosad Ibrahim, Manal Sabry Mohamed. Sultan Qaboos Salalah Hospital: Prit pal Singh*.
United Arab Emirates Dubai Hospital: Nooshin Bazargani*, Arif Abdullatif AlMulla*, Sadek Ali. Fujairah Hospital: Amrish Agrawal* Khorfakan Hospital: Magda Helal*. Qasimi Hospital: Wael Al Abbasi*, Loai Abu Mousa*, Ruwaida Najeeb. Ras Al Khaima Hospital: Adel Wassef* Rashid Hospital: Khalifa Omar Muhammed*, Amr Moustafa*, Ali Raza Rajani, Khalifa Muhammed, Mohamed Al-Raqabani, Shibu Bahuleyan. Sheikh Khalifa Medical City (SKMC): Masood Ghori*, Amer Sana, Hamdy Mohamed. Tawam Hospital: Sadek El Mokahal*, Amany Hillis, Mohammed Nour Mustafa, Teena Abdalla. Zayed Military Hospital: Zubair Memon* *Chief site officer.
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