Incidence of cardiac AEs related to pembrolizumab
We joined the three tables of DRUG (4,134,536 reports), REAC (1,280,060 reports), and DEMO (775,566 patients) by ID number. We removed duplicate data from the DRUG and REAC tables [24]. As noted above, causes of AEs fall into three categories: "suspected drugs," "concomitant drugs," or "interaction." Of these, all data included in the category of "suspected drugs," were extracted and used as the "data table" (2,021,907 reports).
We analysed this data table and obtained 15,306 reports of AEs caused by pembrolizumab. Of these, 399 cardiac AEs were reportedly associated with pembrolizumab (Fig. 1). Patient characteristics are shown in Table 1. Approximately 75.4% of patients were male. According to the age distribution of the study population, cardiac AEs occurred most frequently among individuals in their 70s (41.4%).
Table 1
Characteristics of patients exhibiting cardiac adverse events related to pembrolizumab
Variable | Value (%) |
Number of patients | 399 |
Sex | |
Male | 301 (75.4) |
Female | 90 (22.6) |
Unknown | 8 (2.0) |
Age | |
30s | 6 (1.5) |
40s | 20 (5.0) |
50s | 45 (11.3) |
60s | 89 (22.3) |
70s | 165 (41.4) |
80s | 59 (14.8) |
90s | 2 (0.5) |
Unknown | 13 (3.3) |
Among the types of cardiac AEs caused by pembrolizumab, reported numbers of myocarditis, cardiac failure, immune-mediated myocarditis, pericardial effusion, cardiac tamponade, atrial fibrillation, cardiac arrest, myocardial infarction, hypertension, pericarditis, cardio-respiratory arrest, cardiomyopathy, arrhythmia, acute myocardial infarction, stress cardiomyopathy, ventricular tachycardia, cardiac failure congestive, blood pressure decreased, cardiac failure acute, hypotension, pericarditis malignant, and angina pectoris with pembrolizumab were 67, 50, 41, 38, 25, 25, 17, 14, 12, 12, 11, 10, 10, 9, 9, 8, 8, 8, 7, 7, 6 and 5, respectively (Table 2). RORs with a lower limit of the 95% CI > 1 comprised myocarditis (5.62, 95% CI 4.40–7.18, P < 0.001), immune-mediated myocarditis (49.90, 95% CI 34.82 − 71.52, P < 0.001), pericardial effusion (4.39, 95% CI 3.18–6.07, P < 0.001), cardiac tamponade (5.51, 95% CI 3.69–8.22, P < 0.001), pericarditis (2.11, 95% CI 1.19–3.73, P = 0.018), and pericarditis malignant (39.34, 95% CI 15.80–97.99, P < 0.0001).
Table 2
Numbers of reports and RORs of cardiac adverse events related to pembrolizumab
Variable | Cases (n) | Non-cases (n) | Rate (%) | ROR | 95% CI | P-value |
Myocarditis | 67 | 15,239 | 0.44 | 5.62 | 4.40–7.18 | < 0.001 |
Cardiac failure | 50 | 15,256 | 0.33 | 0.56 | 0.43–0.74 | < 0.001 |
Immune-mediated myocarditis | 41 | 15,265 | 0.27 | 49.90 | 34.82–71.52 | < 0.001 |
Pericardial effusion | 38 | 15,268 | 0.25 | 4.39 | 3.18–6.07 | < 0.001 |
Cardiac tamponade | 25 | 15,281 | 0.16 | 5.51 | 3.69–8.22 | < 0.001 |
Atrial fibrillation | 25 | 15,281 | 0.16 | 1.03 | 0.70–1.52 | 0.839 |
Cardiac arrest | 17 | 15,289 | 0.11 | 0.65 | 0.40–1.04 | 0.077 |
Myocardial infarction | 14 | 15,292 | 0.09 | 0.66 | 0.39–1.11 | 0.126 |
Hypertension | 12 | 15,294 | 0.08 | 0.30 | 0.17–0.52 | < 0.001 |
Pericarditis | 12 | 15,294 | 0.08 | 2.11 | 1.19–3.73 | 0.018 |
Cardio-respiratory arrest | 11 | 15,295 | 0.07 | 0.41 | 0.23–0.75 | 0.001 |
Cardiomyopathy | 10 | 15,296 | 0.07 | 0.95 | 0.51–1.77 | 1.000 |
Arrhythmia | 10 | 15,296 | 0.07 | 0.52 | 0.28–0.96 | 0.029 |
Acute myocardial infarction | 9 | 15,297 | 0.06 | 0.52 | 0.27–1.01 | 0.051 |
Stress cardiomyopathy | 9 | 15,297 | 0.06 | 1.39 | 0.72–2.68 | 0.318 |
Ventricular tachycardia | 8 | 15,298 | 0.05 | 0.47 | 0.23–0.94 | 0.027 |
Cardiac failure congestive | 8 | 15,298 | 0.05 | 0.36 | 0.18–0.72 | 0.001 |
Blood pressure decreased | 8 | 15,298 | 0.05 | 0.082 | 0.04–0.16 | < 0.001 |
Cardiac failure acute | 7 | 15,299 | 0.05 | 0.43 | 0.20–0.90 | 0.017 |
Hypotension | 7 | 15,299 | 0.05 | 0.22 | 0.10–0.45 | < 0.001 |
Pericarditis malignant | 6 | 15,300 | 0.04 | 39.34 | 15.80- 97.99 | < 0.001 |
Angina pectoris | 5 | 15,301 | 0.03 | 0.32 | 0.13–0.77 | 0.003 |
“Cases” indicates the number of reported cases of cardiac adverse events. ROR: reporting odds ratio; 95%CI: 95% confidence interval. Italicized P-values represent statistically significant results. We obtained data for each type of cardiac adverse event showing more than five reports. All analysed data were obtained from the Japanese Adverse Drug Event Report database. |
Signals were thus detected for these six cardiac toxicities with five or more cases reported.
Time to onset of cardiac AEs related to pembrolizumab
A histogram of the median times to onset for these six detected cardiac AE signals showed that AEs occurred from 33 to 138 days after pembrolizumab administration (Fig. 2). Median time to onset was 36 days (interquartile range [IQR] 20–74 days) for myocarditis, 33 days (IQR 21–97 days) for immune-mediated myocarditis, 45 days (IQR 19–100 days) for pericardial effusion, 71 days (IQR 36–154 days) for cardiac tamponade, 71 days (IQR 29–296 days) for pericarditis, and 138 days (IQR 67–168 days) for pericarditis malignant caused by pembrolizumab. The Weibull distribution of histograms for time to onset showed that the range of 95% CIs for shape parameter β of myocarditis, immune-mediated myocarditis, pericarditis, cardiac tamponade, pericardial effusion, and pericarditis malignant were all β = 1 (Table 3).
Table 3
Medians and Weibull parameters of cardiac adverse events
Adverse effects | Cases (n) | Median (day) (25–75%) | | Scale parameter | | Shape parameter |
| α (95%CI) | | β (95%CI) |
Myocarditis | 46 | 36 (20–74) | | 58.82 (41.28–82.71) | | 0.89 (0.71–1.10) |
Immune-mediated myocarditis | 32 | 33 (21–97) | | 63.76 (41.56–95.97) | | 0.90 (0.68–1.16) |
Pericardial effusion | 24 | 45 (19–100) | | 66.73 (44.46–97.88) | | 1.12 (0.79–1.51) |
Cardiac tamponade | 16 | 71 (36–154) | | 118.76 (69.20-197.28) | | 1.05 (0.70–1.49) |
Pericarditis | 11 | 71 (29–296) | | 117.35 (48.56-268.95) | | 0.81 (0.47–1.27) |
Pericarditis malignant | 5 | 138 (67–168) | | 188.25 (84.57-402.52) | | 1.45 (0.66–2.58) |
“Cases” indicate the number of reported cases of cardiac adverse events. 95%CI: 95% confidence interval. Detected cardiac adverse event signals were analysed to determine the time to onset. |