TABLE 1.
Report of CVD in Follow-Up, by Cancer Trial Characteristic
| Trials | Patients | CVD Not Reported* | p Value† | ||
|---|---|---|---|---|---|
| Overall | 189 | 97,566 | 71 (37.6) | Univariate | Multivariable |
| Cancer type | |||||
| Breast | 22 (11.3) | 16,536 | 10 (45.4) | 0.078 | 0.070 |
| Colorectal/GI | 24 (12.7) | 13,441 | 6 (25.0) | ||
| Genitourinary | 33 (17.5) | 27,461 | 14 (42.4) | ||
| Leukemia | 24 (11.8) | 8,469 | 7 (29.2) | ||
| Lung | 19 (10.1) | 9,666 | 7 (36.8) | ||
| Lymphoma | 25 (12.8) | 4,402 | 5 (20.0) | ||
| Skin | 11 (5.8) | 7,048 | 6 (54.5) | ||
| Other | 31 (15.9) | 10,543 | 17 (54.8) | ||
| Therapeutic class | |||||
| Chemotherapy | 31 (16.4) | 14,014 | 19 (61.3) | <0.001 | 0.157 |
| Biologic or immunotherapy | 67 (35.5) | 33,747 | 25 (37.3) | ||
| Hormonal | 14 (7.4) | 17,845 | 7 (50.0) | ||
| Targeted | 70 (37.0) | 30,111 | 17 (24.3) | ||
| Other therapies | 7 (3.7) | 1,849 | 3 (42.9) | ||
| Trial size | |||||
| <100 | 21 (11.3) | 1,257 | 9 (42.9) | 0.889 | - |
| 100–499 | 97 (51.3) | 26,853 | 37 (38.1) | ||
| 500–999 | 54 (28.6) | 37,051 | 20 (37.0) | ||
| >1,000 | 17 (9.0) | 32,405 | 5 (29.4) | ||
| Trial phase‡ | |||||
| Phase 2 | 52 (27.5) | 7,569 | 17 (32.7) | 0.394 | - |
| Phase 3 | 137 (72.5) | 89,997 | 54 (39.4) | ||
| Funding source | |||||
| Industry 160 (84.7) | 87,469 | 59 (36.9) | 0.975 | - | |
| Government/nonprofit | 4 (2.1) | 1,325 | 2 (50.0) | ||
| Both | 25 (13.2) | 8,772 | 9 (36.0) | ||
| Start of enrollment | |||||
| Before 1998 | 18 (9.5) | 14,083 | 7 (43.7) | <0.001 | 0.003 |
| 1998–2002 | 30 (15.9) | 15,039 | 9 (28.1) | ||
| 2003–2007 | 39 (20.6) | 20,567 | 15 (38.5) | ||
| 2008–2012 | 67 (35.5) | 34,164 | 27 (40.3) | ||
| 2013–2018 | 35 (18.5) | 13,713 | 6 (17.1) | ||
| Year of approval | |||||
| 1998–2002 | 28 (14.4) | 10,732 | 14 (50.0) | 0.178 | 0.199 |
| 2003–2007 | 27 (14.3) | 14,258 | 13 (48.2) | ||
| 2008–2012 | 52 (27.5) | 35,801 | 19 (36.6) | ||
| 2013–2018 | 82 (43.4) | 36,775 | 25 (30.6) | ||
| Trial duration, months | |||||
| <24 | 55 (29.1) | 19,019 | 14 (25.5) | 0.013 | 0.001 |
| 25–36 | 63 (33.3) | 30,569 | 21 (33.3) | ||
| 37–48 | 22 (11.6) | 15,569 | 9 (40.9) | ||
| >48 | 37 (19.6) | 28,386 | 16 (43.2) | ||
| Not available | 12 (6.3) | 4,023 | 4 (33.3) | ||
| Trial setting | |||||
| International§ | 181 (95.8) | 95,885 | 65 (35.9) | 0.054|| | - |
| United States only | 8 (4.1) | 1,681 | 6 (75.0) | ||
| Cardiotoxicity within therapeutic class# | |||||
| Yes | 86 (45.5) | 39,531 | 27 (31.4) | 0.109 | 0.149 |
| No | 103 (54.5) | 58,035 | 44 (42.7) | ||
| Excess CVD risk in preceding (safety) trials | |||||
| Yes | 60 (31.8) | 25,911 | 20 (33.3) | 0.412 | - |
| No | 129 (68.3) | 71,655 | 51 (39.5) | ||
Values are n or n (%).
The percentages reported reflect a denominator of the number of trials within the subgroup considered.
The univariate p values presented describe associations estimated using Cochran-Armitage test for trend, chi-square, or Fisher exact tests, as appropriate. Use of the Cochran-Armitage trend test for the association of time (start of enrollment or year of approval), trial size, and duration with CVD reporting yielded p values of <0.001, 0.031, 0.039, and 0.513, respectively. For the final model, all variables were considered and those with p values <0.30 (i.e., cancer type, therapeutic class, start of trial enrollment, year of approval, trial duration, and prior cardiotoxicity within therapeutic class) were included in the multivariable stepwise regression model, where a p = 0.20 significance level was used to determine variables that remained in the final multivariable model.
Several therapies were approved on the basis of breakthrough phase II data, with ongoing or as yet to be initiated phase III trials.
Most international trials, included sites in the United States as well.
Not included in multivariable model due to low (United States only) cell count.
Prior established cardiotoxicity among drugs within the same therapeutic class.
CVD = cardiovascular disease; GI = gastrointestinal