A growing number of countries and geographical regions are involved in major clinical trials. Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure is the largest trial in acutely decompensated heart failure (HF) with patients from 5 geographical regions: North America (NA), Latin America (LA), Western Europe (WE), Central Europe (CE), and Asia-Pacific (AP). Data from the 5 geographical areas were compared including baseline characteristics, medications, 30-day outcomes (mortality and mortality or HF hospitalization), and 180-day mortality. Of the 7,141 study patients, 3,243 (45.4%) were from NA (average of 15.2 patients/site), 1,762 (24.7%) from AP (28.4 patients/site), 967 (13.5%) from CE (20.2 patients/site), 665 (9.3%) from LA (17.1 patients/site), and 504 (7.1%) from WE (14.4 patients/site). There were marked differences in co-morbidities, clinical profile, medication use, length of stay, 30-day event rates, and 180-day mortality by region. Compared with NA, the adjusted risk for death or HF hospitalization at 30 days was significantly lower in CE (odds ratio [OR] 0.46, 95% CI 0.33 to 0.64), WE (OR 0.52 95% CI 0.35 to 0.75), and AP (OR 0.62 95% CI 0.48 to 0.79) and numerically lower in LA (OR 0.77, 95% CI 0.57 to 1.04) with similar results for 180-day mortality. In conclusion, in patients with acutely decompensated HF, major differences in baseline characteristics, treatments, length of the hospital stay, and 30-day HF rehospitalization rates, and 180-day mortality were found in patients enrolled from different geographical areas.
Cardiovascular clinical research, including research of new therapies for heart failure (HF), is undergoing progressive globalization. This is caused in part by the improvement in chronic HF treatment with a decrease in event rates and the need to detect smaller effects for new drugs (i.e., the requirement for large sample sizes), as well as by financial and recruitment challenges in regions such as North America (NA) and the desire to capitalize on emerging world markets. This shift in trial conduct is associated with a decreasing number of patients enrolled in NA and Western Europe (WE) and with increasing recruitment from Central Europe (CE), Latin America (LA), and, more recently, the Asia-Pacific (AP) region. Heterogeneity of geographical areas may, however, have a major impact on the results and interpretation of clinical trials. The Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial is the largest randomized controlled trial in patients with acute decompensated HF (ADHF). It was a global, clinical trial, which included patients from each of the 5 major geographical regions of the world. Importantly, it was the first large-scale acute HF trial to enroll patients from the AP region. Compared with previous analyses of geographical differences in HF trials, the fairly large sample sizes from each of the world regions allowed a robust analysis of the impact of geographical area on the clinical characteristics and outcomes of patients with acute HF.
Methods
The design and results of the ASCEND-HF trial have been reported previously. Briefly, the trial was an international, double-blind, placebo-controlled study evaluating the effectiveness and safety of nesiritide in addition to standard care versus standard care alone in 7,141 patients with ADHF. The trial was conducted from May 2007 to August 2010 at 398 centers in 30 countries throughout the world. Detailed inclusion and exclusion criteria have been described elsewhere. The 2 primary end points were a composite end point of all-cause mortality or HF readmission up to 30 days after randomization and the change in early dyspnea relief after study drug initiation.
Data on patient characteristics were collected during the baseline hospitalization. Rehospitalization and fatal events within 30 days after randomization were reviewed and categorized by an independent, blinded Clinical Events Committee. HF hospitalization was classified as previously described. In brief, HF hospitalization required typical clinical manifestations of worsening HF and the addition of or increase in treatment specifically for worsening HF. All-cause mortality was assessed through 180 days.
Enrollment took place in 30 countries in NA, LA, Europe, Asia, and Australia. For this analysis, countries were assigned to 1 of 5 geographical regions based on previous work : NA included the USA and Canada; LA included Argentina, Chile, Colombia, Brazil, and Mexico; WE included France, Germany, Greece, the Netherlands, Italy, Israel, Norway, Sweden, and the United Kingdom; CE included Bulgaria, Czech Republic, Lithuania, Poland, Romania, and Ukraine; and AP included Australia, India, China, Malaysia, New Zealand, Korea, Singapore, Taiwan, and Thailand.
Patients from different geographical areas were compared with respect to demographic, clinical, and laboratory data and clinical outcomes. All data are shown as median (interquartile range) or n (%) unless otherwise specified. Outcomes of interest included length of the initial hospital stay (LOS), and the 30-day postrandomization outcome of all-cause mortality or HF hospitalization, and all-cause mortality. In addition, we assessed 180-day mortality by world region. For mortality and rehospitalization events, odds ratios (30-day events) or hazard ratios (180-day mortality) and 95% CIs of the patients from different geographical areas, compared with those in NA, were calculated using Cox regression analysis with and without adjustment for baseline covariates. Adjustment covariates included clinically relevant variables that have been used in previous ASCEND-HF models . Kaplan–Meier plots were generated by region for clinical outcomes. A p value <0.05 was used to indicate statistical significance. There was no adjustment for multiple comparisons given the exploratory nature of this analysis. All statistical analyses were performed at Duke Clinical Research Institute (Durham, North Carolina) using SAS version 9.22 (SAS Institute, Cary, North Carolina).
| Asia / Pacific (n=1762) | Central Europe (n=967) | Latin America (n=665) | North America (n=3243) | Western Europe (n=504) | P value | |
|---|---|---|---|---|---|---|
| Demographics | ||||||
| Men | 1187 (67.1%) | 669 (69.2%) | 401 (60.3%) | 2109 (65.0%) | 336 (66.7%) | 0.003 |
| Age (years) | 62 (53,71) | 69 (59,75) | 70 (60,78) | 67 (56,78) | 74 (65,81) | < 0.001 NP |
| White | 46 (2.6%) | 966 (99.9%) | 390 (58.6%) | 2088 (64.4%) | 499 (99.0%) | < 0.001 |
| Black | 0 | 0 | 34 (5.1%) | 1040 (32.1%) | 3 (0.6%) | |
| Asian | 1712 (97.2%) | 1 (0.1%) | 0 | 52 (1.6%) | 2 (0.4%) | |
| Other | 3 (0.2%) | 0 | 241 (36.2%) | 63 (1.9%) | 0 | |
| Ethnicity Hispanic/Latino | 12 (0.7%) | 3 (0.3%) | 647 (97.3%) | 211 (6.5%) | 9 (1.8%) | < 0.001 |
| NYHA Class prior to decompensation | ||||||
| I | 29 (1.7%) | 10 (1.3%) | 96 (15.4%) | 88 (3.7%) | 32 (7.6%) | <0.001 |
| II | 176 (10.4%) | 189 (24.4%) | 181 (29.0%) | 443 (18.6%) | 109 (25.9%) | |
| III | 714 (42.1%) | 428 (55.2%) | 224 (35.9%) | 1314 (55.3%) | 173 (41.1%) | |
| IV | 775 (45.7%) | 149 (19.2%) | 123 (19.7%) | 533 (22.4%) | 107 (25.4%) | |
| Coronary artery disease | 838 (47.6%) | 644 (66.6%) | 213 (32.0%) | 1940 (59.9%) | 269 (53.4%) | <0.001 |
| Myocardial Infarction | 552 (31.3%) | 433 (44.8%) | 162 (24.4%) | 1142 (35.2%) | 201 (39.9%) | <0.001 |
| Previous PCI | 196 (11.1%) | 75 (7.8%) | 69 (10.4%) | 719 (22.2%) | 110 (21.9%) | <0.001 |
| Previous CABG | 146 (8.3%) | 99 (10.2%) | 44 (6.6%) | 914 (28.2%) | 113 (22.4%) | <0.001 |
| Atrial fibrillation | 301 (17.1%) | 552 (57.1%) | 214 (32.2%) | 1365 (42.1%) | 242 (48.0%) | <0.001 |
| Hypertension | 959 (54.4%) | 718 (74.3%) | 521 (78.3%) | 2625 (80.9%) | 327 (64.9%) | <0.001 |
| Peripheral arterial disease | 43 (2.4%) | 94 (9.7%) | 37 (5.6%) | 493 (15.2%) | 73 (14.5%) | <0.001 |
| Cerebrovascular disease | 98 (5.6%) | 121 (12.5%) | 38 (5.7%) | 512 (15.8%) | 73 (14.5%) | <0.001 |
| Diabetes mellitus | 732 (41.5%) | 281 (29.1%) | 228 (34.3%) | 1585 (48.9%) | 220 (43.7%) | <0.001 |
| Chronic respiratory disease | 105 (6.0%) | 110 (11.4%) | 62 (9.3%) | 802 (24.7%) | 99 (19.6%) | <0.001 |
| Depression treated with medications | 29 (1.6%) | 10 (1.0%) | 27 (4.1%) | 449 (13.8%) | 47 (9.3%) | <0.001 |
| Cancer in last 5 years | 14 (0.8%) | 15 (1.6%) | 11 (1.7%) | 187 (5.8%) | 45 (8.9%) | <0.001 |
| Symptoms and physical examination | ||||||
| Dyspnea | ||||||
| At rest | 1103 (62.6%) | 711 (73.5%) | 429 (64.5%) | 1824 (56.3%) | 348 (69.0%) | <0.001 |
| With minimal activity | 659 (37.4%) | 256 (26.5%) | 236 (35.5%) | 1418 (43.7%) | 156 (31.0%) | |
| Nocturnal dyspnea | 1117 (63.6%) | 625 (64.6%) | 473 (71.2%) | 1962 (60.6%) | 272 (54.2%) | <0.001 |
| Orthopnea | 1169 (66.6%) | 728 (75.3%) | 573 (86.2%) | 2620 (80.9%) | 395 (78.4%) | <0.001 |
| Peripheral Edema | 971 (55.1%) | 783 (81.0%) | 540 (81.2%) | 2674 (82.5%) | 362 (71.8%) | <0.001 |
| Weight Gain | 804 (45.8%) | 642 (66.7%) | 455 (68.4%) | 2444 (75.5%) | 328 (65.6%) | <0.001 |
| Pulmonary congestion | 1527 (86.7%) | 901 (93.2%) | 638 (95.9%) | 2669/3240 (82.4%) | 466 (92.6%) | <0.001 |
| Pulmonary rales | 1527 | 901 | 638 | 2669 | 466 | <0.001 |
| ≥ 1/3 lung fields | 516 (33.8%) | 404 (44.8%) | 233 (36.5%) | 1130 (42.3%) | 184 (39.5%) | |
| < 1/3 lung fields | 1011 (66.2%) | 497 (55.2%) | 405 (63.5%) | 1539 (57.7%) | 282 (60.5%) | |
| Systolic blood pressure (mmHg) | 120 (110, 134) | 130 (116, 140) | 120 (110, 140) | 124 (110, 140) | 124 (110, 140) | < 0.001 NP |
| Diastolic blood pressure (mmHg) | 76 (70, 84) | 80 (70, 86) | 79 (70, 84) | 72 (64, 83) | 70 (60, 80) | < 0.001 NP |
| Respiration rate (breaths/min) | 24 (22, 26) | 24 (22, 26) | 24 (22, 26) | 22 (20, 24) | 23 (20, 26) | < 0.001 NP |
| Heart rate (beats/min) | 88 (78, 99) | 84 (72, 98) | 80 (70, 94) | 80 (70, 91) | 80 (69, 92) | < 0.001 NP |
| Weight (kg) | 62.5 (54.0, 72.0) | 83.9 (73.0, 97.3) | 73.0 (62.0, 84.0) | 87.4 (73.0, 106) | 80.0 (68.8, 92.0) | < 0.001 NP |
| BMI (kg/m 2 ) | 23.7 (21.0, 26.7) | 28.9 (25.6, 33.3) | 27.0 (23.9, 31.1) | 29.9 (25.5, 35.5) | 27.7 (24.2, 31.9) | < 0.001 NP |
| Baseline laboratories and diagnostic evaluations | ||||||
| Sodium (mmol/L) | 137 (134, 140) | 141 (138, 143) | 138 (135, 141) | 139 (137, 141) | 140 (137, 142) | <0.001 NP |
| Creatinine (mg/dL) | 1.2 (1.0, 1.5) | 1.2 (1.0, 1.4) | 1.2 (1.0, 1.5) | 1.3 (1.0, 1.7) | 1.3 (1.0, 1.6) | <0.001 NP |
| BUN (mg/dL) | 24.8 (18.0, 37.2) | 24.1 (18.0, 36.1) | 39.1 (23.1, 55.1) | 24.1 (17.0, 34.1) | 34.1 (21.8, 52.8) | <0.001 NP |
| Hemoglobin (g/dL) | 12.6 (11.3, 14.0) | 13.6 (12.4, 14.8) | 13.2 (11.8, 14.5) | 12.4 (11.0, 13.7) | 12.7 (11.4, 14.0) | <0.001 NP |
| BNP (pg/mL) | 494 (370, 1513) | 1130 (737, 2984) | 2068 (1144, 3422) | 1031 (602, 1892) | 889 (507, 1737) | <0.001 NP |
| NT-proBNP (pg/mL) | 4658 (2206, 9679) | 3861(1879, 7783) | 5031 (2200, 11000) | 4799 (2413, 9247) | 4000 (1487, 9140) | <0.001 NP |
| QRS duration (msec) | 100 (84, 120) | 100 (80, 122) | 100 (80, 120) | 112 (94, 148) | 120 (95, 149) | <0.001 NP |
| Ejection fraction (%) | 28 (20, 35) | 32 (25, 38) | 30 (24, 37) | 27 (20, 40) | 30 (23, 45) | <0.001 NP |
| X-Ray indicating pulmonary congestion | 1259 (82.9%) | 709 (87.1%) | 582 (97.3%) | 2251 (74.4%) | 405 (87.1%) | <0.001 |
| Asia / Pacific (n=1762) | Central Europe (n=967) | Latin America (n=665) | North America (n=3243) | Western Europe (n=504) | P value | |
|---|---|---|---|---|---|---|
| Pre-randomization medical treatment | ||||||
| Chronic use of loop Diuretics | 822 (46.7%) | 608 (62.9%) | 350 (52.6%) | 2426 (74.9%) | 333 (66.2) | <0.001 |
| Total daily loop diuretic dose, mg ∗ | 40 (20, 80) | 40 (20, 40) | 40 (40, 80) | 80 (40, 120) | 80 (40, 125) | <0.001 NP |
| ACE Inhibitor/ARB | 911 (51.7%) | 622 (64.3%) | 462 (69.5%) | 2039 (62.9%) | 306 (60.7%) | <0.001 |
| Aldosterone antagonist | 453 (25.7%) | 425 (44.0%) | 228 (34.3%) | 749 (23.1%) | 137 (27.2%) | <0.001 |
| Beta blocker | 608 (34.5%) | 564 (58.3%) | 298 (44.8%) | 2386 (73.6%) | 302 (59.9%) | <0.001 |
| Digoxin | 571 (32.4%) | 288 (29.8%) | 192 (28.9%) | 763 (23.5%) | 81 (16.1%) | <0.001 |
| Hydralazine | 22 (1.2%) | 4 (0.4%) | 32 (4.8%) | 472 (14.6%) | 2 (0.4%) | <0.001 |
| Oral/Topical Nitrates | 513 (29.1%) | 179 (18.5%) | 82 (12.3%) | 802 (24.7%) | 105 (20.8%) | <0.001 |
| Anticoagulant | 113 (6.4%) | 237 (24.5%) | 98 (14.7%) | 1084 (33.4%) | 190 (37.7%) | <0.001 |
| Inotropes | 181 (10.3%) | 27 (2.8%) | 27 (4.1%) | 56 (1.7%) | 22 (4.4%) | <0.001 |
| Vasodilators | 395 (22.4%) | 243 (25.1%) | 179 (26.9%) | 147 (4.5%) | 95 (18.8%) | <0.001 |
| Device therapy | ||||||
| Pacemaker | 28 (1.6) | 48 (5.0) | 49 (7.4) | 269 (8.3) | 46 (9.1) | <0.001 |
| ICD | 8 (0.5) | 35 (3.6) | 7 (1.1) | 536 (16.5) | 26 (5.2) | <0.001 |
| CRT (with or without ICD) | 10 (0.6) | 14 (1.4) | 13 (2.0) | 547 (16.9) | 56 (11.1) | <0.001 |
| Discharge Medications | 1761 | 967 | 665 | 504 | ||
| ACE Inhibitor/ARB | 1188 (67.5%) | 742 (76.7%) | 471 (70.8%) | 1949/3242 (60.1%) | 350 (69.4%) | <0.001 |
| Aldosterone antagonists | 792 (45.0%) | 644 (66.6%) | 380 (57.1%) | 929/3243 (28.6%) | 205 (40.7%) | <0.001 |
| Beta blockers | 909 (51.6%) | 705 (72.9%) | 378 (56.8%) | 2258/3242 (69.6%) | 329 (65.3%) | <0.001 |
| Digoxin | 787 (44.7%) | 347 (35.9%) | 210 (31.6%) | 744/3242 (22.9%) | 97 (19.2%) | <0.001 |
| Hydralazine | 35 (2.0%) | 4 (0.4%) | 33 (5.0%) | 473/3243 (14.6%) | 1 (0.2%) | <0.001 |
| Anticoagulant | 168 (9.5%) | 331 (34.2%) | 128 (19.2%) | 993/3243 (30.6%) | 211 (41.9%) | <0.001 |
| Oral/Topical Nitrates | 544 (30.9%) | 132 (13.7%) | 66 (9.9%) | 714/3243 (22.0%) | 80 (15.9%) | <0.001 |
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