Results:
The total number of AEs from all drugs in this study was 29,662. Amongst
these, 25,014 were from the newly approved humanized monoclonal
antibodies (daclizumab, ocrelizumab and ofatumumab) [Table 1 and
Supplemental Tables 1-3]. These include 4,010 due to daclizumab,
17,018 due to ocrelizumab, and 3,986 were due to ofatumumab.
Amongst these reported AEs for daclizumab, ocrelizumab and ofatumumab,
there were a total of 432 adverse events related to AF, CAD and heart
failure. [Table 1]. A little over 50% of these cardiac related AEs
were due to coronary artery disease. Ocrelizumab reported on the highest
number of related CAD, but in relation to its total reported AEs had the
lowest prevalence of 0.8% for CAD in comparison to daclizumab (1.5%)
and ofatumumab (1.2%) [Table 2]. Heart failure was reported around
102 reported while 99 cases reported for atrial fibrillation associated
with these three drugs [Table 1]. Ocrelizumab again had the highest
reported cases for heart failure with a total of 48 reported AEs. For
atrial fibrillation, the highest reported cases and the most prevalent
occurred with ofatumumab, which had a total of 43 reported AEs.
Tables 2 and Supplemental Tables 1-3. further characterize the cardiac
related AEs that were associated with ocrelizumab, daclizumab, and
ofatumumab. Ofatumumab and daclizumab showed male predominance (66% and
61%.4 respectively). Mortality rate was comparable among all the three
medications. More than 90% of the cases were serious.
Next, we conducted disproportionality signal analysis for daclizumab,
ocrelizumab and ofatumumab versus all other drugs in FAERS for CAD,
cardiac failure and atrial fibrillation [Table 3]. Daclizumab
reported the highest ROR for cardiac failure (2.7 with 95% CI: 1.9-3.9)
with ofatumumab comes next (1.8, 95% CI:1.5-3.2). CAD showed the same
pattern; daclizumab (ROR:3.3 with 95% CI: 2.5-4.4), ofatumumab (ROR:
3.1 with 95% CI: 2.3-4.1), and then ocrelizumab (ROR: 1.9 with 95% CI:
1.6-2.3). Interestingly, atrial fibrillation was only significantly
elevated with ofatumumab is (ROR:3.2 with 95% CI: 2.2-4.1), however,
ocrelizumab showed significantly low ROR (ROR: 0.6, 95% CI: 0.5-0.9).
Among the S1P receptor modulators (ponesimod, ozanimod, siponimod and
fingolimod), there were a total of 4,648 reported AEs. [Supplemental
Table 4]. Fingolimod showed the highest number of adverse events
followed by siponimod. There was a total of 31 cardiac related events
including atrial fibrillation, heart failure and coronary artery disease
associated with siponimod while fingolimod had 927 cardiac related
events. Siponimod and fingolimod showed a significant increase in
bradycardia with ROR of 5.6 and 7.7, respectively [Table 4]. In
addition, siponimod and fingolimod also showed a significant association
with AV block with ROR of 7.6 and 11.7, respectively which was not
observed for any of the other S1P receptor modulators.
Discussion :
The reported adverse events of the novel multiple sclerosis agents span
multiple systems. While the cardiac related adverse events of CD20/CD25
inhibitors ranges from 3.45-5.8%, few major cardiac conditions were
remarkably high. Specifically, our results showed that the risk of
atrial fibrillation, cardiac failure and coronary artery disease were
significantly elevated in patients taking daclizumab, ocrelizumab,
ofatumumab for multiple sclerosis. Interestingly, coronary artery
disease showed the highest ROR compared to the other major adverse
events. However, when compared to other CD20 inhibitors (ibritumomab,
rituximab, obinutuzumab), daclizumab,
ocrelizumab, ofatumumab were
associated with significantly lower ROR regarding atrial fibrillation,
cardiac failure and coronary artery disease.
Over the last two decades, the role of immune cell depletion via
CD20/CD25 inhibitors received considerable attention in the field of
neuroimmunology. Rituximab probably was the first CD20 inhibitors used
for multiple sclerosis, however, its cardiovascular complications are
well studied. Almost 10 years later, two major clinical trials (OPERA I
and OPERA II) investigated ocrelizumab in relapsing remitting multiple
sclerosis and elegantly revealed the therapeutic potential of
ocrelizumab. Subsequent clinical trials placed ofatumumab in therapeutic
array for multiple sclerosis. Unfortunately, Daclizumab approval for
multiple sclerosis vanished quickly after serious adverse forced the
company to withdraw the drug from the market.
While clinical studies demonstrated the cardiotoxicity of rituximab
(e.g. atrial fibrillation)[11,
12], much less is known about the new
immunomodulators associated cardiotoxicity. Clinical trials of
ocrelizumab for multiple sclerosis showed no serious adverse
events[9,
10, 13].
However, trials for rheumatoid arthritis were actually terminated after
the STAGE study showed one patient died due to myocardial infarction
after receiving 500 mg (higher dose when compared to multiple sclerosis
dose)[14,
15]. Early clinical trials on
daclizumab reported rare cases of allergic myonecrosis of the myocardium
and pleural effusions[16]. Two cases
of congestive heart failure have been reported in patients taking
daclizumab for adult T-cell
leukemia[5]. One case of atrial
fibrillation has been linked to Ofatumumab in a trial comparing
ofatumumab versus Ibrutinib[17]. Even
rarer (<1%), pericarditis, heart failure and myocardial
infarction cases were reported to be associated with ofatumumab
use[18].
Fingolimod, the first SPR modulator introduced into the market, is well
known for its cardiovascular side effects, mainly bradycardia and AV
block. The FREEDOMS and TRANSFORMS trials reported respectively 14 (3%)
and 9 (2.1%) cases of bradycardia in patients on the 1.25 mg
dose[19,
20], which were corroborated in our
study with a significantly higher ROR compared to other SPR1 modulator.
These side effects are thought to be mediated by the activation of S1P1
and S1P3 receptors in
cardiomyocytes[21]. Interestingly,
siponimod, a newer SPR1 modulator that binds more selectively to S1P1
and S1P5, was expected to have lower risk of bradycardia and AV block,
however, our study shows that siponimod also has a significantly high
ROR for bradycardia and AV block compared to the other SPR agents.
Ponesimod and ozanimod did not show high incidence of bradycardia or AV
block suggesting that these agents might be more specific.
Despite of the novelty of our
findings, certain limitations to this study are appreciated. For
example, patient’s comorbidities and other risk factors are unknown.
Additionally, cardiovascular history and baseline cardiac functioning
are not taken into account when performing these studies. Besides
patient’s risk stratification, the molecular mechanisms underlying
immunomodulators-associated cardiotoxicity remain unknown.
The importance of this study comes from the wide use of these
medications for multiple sclerosis management. While significant studies
addressed few cardiac adverse events of the novel MS therapy as
mentioned earlier, comprehensive cardiotoxicity studies are wanting. The
present study corroborates with the findings that novel MS therapy does
indeed have cardiotoxicity risk. As the use of these new agents
increases for MS treatment, the need for cardiovascular risk
stratification is much needed now than ever. Since the risk of cardiac
failure, coronary artery disease, atrial fibrillation, and bradycardia
is enhanced in patients using CD20/CD25 inhibitors and S1P modulators,
we suggest clinician to obtain baseline electrocardiography and
echocardiogram when initiating these medications. Additionally, patients
should be educated about the cardiac risk when taking these medications.
Physician are recommended to monitor the sign and symptoms of cardiac
failure and coronary artery disease during the treatment period.
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