Cardiovascular Effects of Fingolimod Are Mostly Transient

HONOLULU – The first approved oral medication for multiple sclerosis causes transient reductions in heart rate and atrioventricular conduction and a sustained increase in blood pressure, according to investigators who analyzed pooled data from two phase III trials.

The cohorts from the two phase III clinical trials of fingolimod (Gilenya) for relapsing-remitting muscular sclerosis involved 854 patients treated with the currently approved dosage of fingolimod (0.5 mg/day), 849 patients on a higher dosage (1.25 mg/day), 418 patients on placebo, and 431 patients treated with weekly intramuscular injections of 30 mcg interferon beta-1a (Avonex) for 1-2 years.

The investigators measured vital signs hourly for 6 hours after starting treatment and at quarterly follow-up visits. Patients underwent an ECG before the first dose, 6 hours after treatment initiation, and if they developed symptoms during those 6 hours, as well as at selected follow-up visits. The studies did not use continuous ECG monitoring because they were designed to mimic treatment initiation in a neurologist’s office.

Heart rates hit a nadir approximately 4-5 hours after starting fingolimod, and then began to increase, Dr. John DiMarco reported at the annual meeting of the American Academy of Neurology. By 2 weeks after starting therapy, heart rates in the fingolimod groups were almost back to baseline, and thereafter were similar to baseline heart rates in the placebo group. As expected, some tachycardia was seen on interferon therapy.

In the first 6 hours of treatment, the lowest measured heart rate was below 35 beats per minute (bpm) in one patient on fingolimod 1.25 mg/day and one patient on interferon. Heart rates fell to as low as 35-39 bpm in six patients on fingolimod 1.25 mg/day, reported Dr. DiMarco, a cardiologist and professor of medicine at the University of Virginia, Charlottesville.

A heart rate nadir of 40-44 bpm was seen in approximately 1% of the low-dose fingolimod group, 3% of the high-dose fingolimod group, 0.2% of the placebo group, and no patients on interferon. A nadir of 45-54 bpm was measured in 18% on low-dose fingolimod, 29% on high-dose fingolimod, 6% on placebo, and 3% on interferon.

The lowest heart rate was 55-64 bpm in 49% on low-dose fingolimod, 50% on high-dose fingolimod, 37% on placebo, and 33% on interferon. Heart rates never fell below 65 bpm in 32% on low-dose fingolimod, 18% on high-dose fingolimod, 56% on placebo, and 64% on interferon.

Patients could be discharged at the 6-hour follow-up if any slowing in heart rate had started to return toward baseline, the heart rate was at least 55 bpm or greater than 80% of the baseline rate, and the patient had no symptoms related to bradycardia and no new, clinically relevant abnormality on ECG.

Observation beyond the 6-hour period was required in 12% on low-dose fingolimod, 18% on high-dose fingolimod, 3% on placebo, and 1% on interferon. Clinicians chose to hospitalize 2% of patients on fingolimod 0.5 mg/day, 3% of patients on 1.25 mg/day, 0.5% of patients on interferon, and none on placebo.

"Most of these hospitalizations and even the prolonged observations were driven by the study criteria and not by symptoms," Dr. DiMarco noted.

Symptoms of bradycardia were seen in 0.5% of patients on 0.5 mg/day fingolimod, 1% of patients on 1.25 mg/day, and no patients in the other groups. All symptoms were described as mild or moderate in severity.

Conduction abnormalities also were more common within 6 hours of taking low-dose fingolimod (7%) or high-dose fingolimod (13%), compared with placebo or interferon (4% each). First-degree atrioventricular (AV) block was seen in 5% on low-dose fingolimod, 10% on high-dose fingolimod, 2% on placebo, and 3% on interferon. A Wenckebach second-degree AV block was seen in 0.2% on low-dose fingolimod, 0.7% on high-dose fingolimod, and no patients in the other groups. Two patients (0.2%) in the high-dose fingolimod group developed 2:1 second-degree AV block.

One patient in the low-dose fingolimod group and three in the high-dose fingolimod group were treated for heart rate or conduction abnormalities, although two of these patients were asymptomatic. Fingolimod was discontinued after the first dose in 1% of the high-dose group. In the others, the AV conduction changes attenuated with continued therapy and returned to baseline levels by 1 month.

"Most episodes of bradycardia could be managed just with observation. Active intervention was rarely required," Dr. DiMarco said.

The rise in blood pressure on fingolimod was small, but sustained and statistically significant, starting within 2-6 months of treatment initiation. Systolic and diastolic blood pressure increases averaged 1-2 mm Hg on 0.5 mg/day fingolimod and 1-3 mm Hg on 1.25 mg/day fingolimod, compared with the placebo group.

"The significance of these findings is uncertain," he said.

Rates of hypertension adverse events were higher in the fingolimod groups – 4% on the lower dose and 5% on the higher dose – compared with the placebo group (3%) or the interferon group (2%). The proportions of patients who needed antihypertensive therapy, however, were similar between groups: 5% on low-dose fingolimod, 6% on high-dose fingolimod, 6% on placebo, and 4% on interferon.

Patients who were treated responded to standard antihypertensive therapy.

Data for the analysis came from the Efficacy and Safety of Fingolimod in Patients With Relapsing-Remitting Multiple Sclerosis (FREEDOMS) trial and from the Trial Assessing Injectable Interferon vs. FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS). Both were international, multicenter, randomized double-blind trials.

Both trials excluded patients with moderate to severe cardiovascular disease. At baseline, 3%-4% in each treatment group had a cardiovascular disorder and 5%-7% had hypertension.

The current analysis was funded by Novartis, which markets fingolimod. Dr. DiMarco disclosed financial relationships with Novartis, Medtronic, St. Jude Medical, Astellas, Sanofi-Aventis Pharmaceuticals, and Boston Scientific. His associates in the study have been employees of Novartis, have held stock in the company, or disclosed other financial relationships with Novartis and other pharmaceutical companies.

HONOLULU – The first approved oral medication for multiple sclerosis causes transient reductions in heart rate and atrioventricular conduction and a sustained increase in blood pressure, according to investigators who analyzed pooled data from two phase III trials.

The cohorts from the two phase III clinical trials of fingolimod (Gilenya) for relapsing-remitting muscular sclerosis involved 854 patients treated with the currently approved dosage of fingolimod (0.5 mg/day), 849 patients on a higher dosage (1.25 mg/day), 418 patients on placebo, and 431 patients treated with weekly intramuscular injections of 30 mcg interferon beta-1a (Avonex) for 1-2 years.

The investigators measured vital signs hourly for 6 hours after starting treatment and at quarterly follow-up visits. Patients underwent an ECG before the first dose, 6 hours after treatment initiation, and if they developed symptoms during those 6 hours, as well as at selected follow-up visits. The studies did not use continuous ECG monitoring because they were designed to mimic treatment initiation in a neurologist’s office.

Heart rates hit a nadir approximately 4-5 hours after starting fingolimod, and then began to increase, Dr. John DiMarco reported at the annual meeting of the American Academy of Neurology. By 2 weeks after starting therapy, heart rates in the fingolimod groups were almost back to baseline, and thereafter were similar to baseline heart rates in the placebo group. As expected, some tachycardia was seen on interferon therapy.

In the first 6 hours of treatment, the lowest measured heart rate was below 35 beats per minute (bpm) in one patient on fingolimod 1.25 mg/day and one patient on interferon. Heart rates fell to as low as 35-39 bpm in six patients on fingolimod 1.25 mg/day, reported Dr. DiMarco, a cardiologist and professor of medicine at the University of Virginia, Charlottesville.

A heart rate nadir of 40-44 bpm was seen in approximately 1% of the low-dose fingolimod group, 3% of the high-dose fingolimod group, 0.2% of the placebo group, and no patients on interferon. A nadir of 45-54 bpm was measured in 18% on low-dose fingolimod, 29% on high-dose fingolimod, 6% on placebo, and 3% on interferon.

The lowest heart rate was 55-64 bpm in 49% on low-dose fingolimod, 50% on high-dose fingolimod, 37% on placebo, and 33% on interferon. Heart rates never fell below 65 bpm in 32% on low-dose fingolimod, 18% on high-dose fingolimod, 56% on placebo, and 64% on interferon.

Patients could be discharged at the 6-hour follow-up if any slowing in heart rate had started to return toward baseline, the heart rate was at least 55 bpm or greater than 80% of the baseline rate, and the patient had no symptoms related to bradycardia and no new, clinically relevant abnormality on ECG.

Observation beyond the 6-hour period was required in 12% on low-dose fingolimod, 18% on high-dose fingolimod, 3% on placebo, and 1% on interferon. Clinicians chose to hospitalize 2% of patients on fingolimod 0.5 mg/day, 3% of patients on 1.25 mg/day, 0.5% of patients on interferon, and none on placebo.

"Most of these hospitalizations and even the prolonged observations were driven by the study criteria and not by symptoms," Dr. DiMarco noted.

Symptoms of bradycardia were seen in 0.5% of patients on 0.5 mg/day fingolimod, 1% of patients on 1.25 mg/day, and no patients in the other groups. All symptoms were described as mild or moderate in severity.

Conduction abnormalities also were more common within 6 hours of taking low-dose fingolimod (7%) or high-dose fingolimod (13%), compared with placebo or interferon (4% each). First-degree atrioventricular (AV) block was seen in 5% on low-dose fingolimod, 10% on high-dose fingolimod, 2% on placebo, and 3% on interferon. A Wenckebach second-degree AV block was seen in 0.2% on low-dose fingolimod, 0.7% on high-dose fingolimod, and no patients in the other groups. Two patients (0.2%) in the high-dose fingolimod group developed 2:1 second-degree AV block.

One patient in the low-dose fingolimod group and three in the high-dose fingolimod group were treated for heart rate or conduction abnormalities, although two of these patients were asymptomatic. Fingolimod was discontinued after the first dose in 1% of the high-dose group. In the others, the AV conduction changes attenuated with continued therapy and returned to baseline levels by 1 month.

"Most episodes of bradycardia could be managed just with observation. Active intervention was rarely required," Dr. DiMarco said.

The rise in blood pressure on fingolimod was small, but sustained and statistically significant, starting within 2-6 months of treatment initiation. Systolic and diastolic blood pressure increases averaged 1-2 mm Hg on 0.5 mg/day fingolimod and 1-3 mm Hg on 1.25 mg/day fingolimod, compared with the placebo group.

"The significance of these findings is uncertain," he said.

Rates of hypertension adverse events were higher in the fingolimod groups – 4% on the lower dose and 5% on the higher dose – compared with the placebo group (3%) or the interferon group (2%). The proportions of patients who needed antihypertensive therapy, however, were similar between groups: 5% on low-dose fingolimod, 6% on high-dose fingolimod, 6% on placebo, and 4% on interferon.

Patients who were treated responded to standard antihypertensive therapy.

Data for the analysis came from the Efficacy and Safety of Fingolimod in Patients With Relapsing-Remitting Multiple Sclerosis (FREEDOMS) trial and from the Trial Assessing Injectable Interferon vs. FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS). Both were international, multicenter, randomized double-blind trials.

Both trials excluded patients with moderate to severe cardiovascular disease. At baseline, 3%-4% in each treatment group had a cardiovascular disorder and 5%-7% had hypertension.

The current analysis was funded by Novartis, which markets fingolimod. Dr. DiMarco disclosed financial relationships with Novartis, Medtronic, St. Jude Medical, Astellas, Sanofi-Aventis Pharmaceuticals, and Boston Scientific. His associates in the study have been employees of Novartis, have held stock in the company, or disclosed other financial relationships with Novartis and other pharmaceutical companies.

HONOLULU – The first approved oral medication for multiple sclerosis causes transient reductions in heart rate and atrioventricular conduction and a sustained increase in blood pressure, according to investigators who analyzed pooled data from two phase III trials.

The cohorts from the two phase III clinical trials of fingolimod (Gilenya) for relapsing-remitting muscular sclerosis involved 854 patients treated with the currently approved dosage of fingolimod (0.5 mg/day), 849 patients on a higher dosage (1.25 mg/day), 418 patients on placebo, and 431 patients treated with weekly intramuscular injections of 30 mcg interferon beta-1a (Avonex) for 1-2 years.

The investigators measured vital signs hourly for 6 hours after starting treatment and at quarterly follow-up visits. Patients underwent an ECG before the first dose, 6 hours after treatment initiation, and if they developed symptoms during those 6 hours, as well as at selected follow-up visits. The studies did not use continuous ECG monitoring because they were designed to mimic treatment initiation in a neurologist’s office.

Heart rates hit a nadir approximately 4-5 hours after starting fingolimod, and then began to increase, Dr. John DiMarco reported at the annual meeting of the American Academy of Neurology. By 2 weeks after starting therapy, heart rates in the fingolimod groups were almost back to baseline, and thereafter were similar to baseline heart rates in the placebo group. As expected, some tachycardia was seen on interferon therapy.

In the first 6 hours of treatment, the lowest measured heart rate was below 35 beats per minute (bpm) in one patient on fingolimod 1.25 mg/day and one patient on interferon. Heart rates fell to as low as 35-39 bpm in six patients on fingolimod 1.25 mg/day, reported Dr. DiMarco, a cardiologist and professor of medicine at the University of Virginia, Charlottesville.

A heart rate nadir of 40-44 bpm was seen in approximately 1% of the low-dose fingolimod group, 3% of the high-dose fingolimod group, 0.2% of the placebo group, and no patients on interferon. A nadir of 45-54 bpm was measured in 18% on low-dose fingolimod, 29% on high-dose fingolimod, 6% on placebo, and 3% on interferon.

The lowest heart rate was 55-64 bpm in 49% on low-dose fingolimod, 50% on high-dose fingolimod, 37% on placebo, and 33% on interferon. Heart rates never fell below 65 bpm in 32% on low-dose fingolimod, 18% on high-dose fingolimod, 56% on placebo, and 64% on interferon.

Patients could be discharged at the 6-hour follow-up if any slowing in heart rate had started to return toward baseline, the heart rate was at least 55 bpm or greater than 80% of the baseline rate, and the patient had no symptoms related to bradycardia and no new, clinically relevant abnormality on ECG.

Observation beyond the 6-hour period was required in 12% on low-dose fingolimod, 18% on high-dose fingolimod, 3% on placebo, and 1% on interferon. Clinicians chose to hospitalize 2% of patients on fingolimod 0.5 mg/day, 3% of patients on 1.25 mg/day, 0.5% of patients on interferon, and none on placebo.

"Most of these hospitalizations and even the prolonged observations were driven by the study criteria and not by symptoms," Dr. DiMarco noted.

Symptoms of bradycardia were seen in 0.5% of patients on 0.5 mg/day fingolimod, 1% of patients on 1.25 mg/day, and no patients in the other groups. All symptoms were described as mild or moderate in severity.

Conduction abnormalities also were more common within 6 hours of taking low-dose fingolimod (7%) or high-dose fingolimod (13%), compared with placebo or interferon (4% each). First-degree atrioventricular (AV) block was seen in 5% on low-dose fingolimod, 10% on high-dose fingolimod, 2% on placebo, and 3% on interferon. A Wenckebach second-degree AV block was seen in 0.2% on low-dose fingolimod, 0.7% on high-dose fingolimod, and no patients in the other groups. Two patients (0.2%) in the high-dose fingolimod group developed 2:1 second-degree AV block.

One patient in the low-dose fingolimod group and three in the high-dose fingolimod group were treated for heart rate or conduction abnormalities, although two of these patients were asymptomatic. Fingolimod was discontinued after the first dose in 1% of the high-dose group. In the others, the AV conduction changes attenuated with continued therapy and returned to baseline levels by 1 month.

"Most episodes of bradycardia could be managed just with observation. Active intervention was rarely required," Dr. DiMarco said.

The rise in blood pressure on fingolimod was small, but sustained and statistically significant, starting within 2-6 months of treatment initiation. Systolic and diastolic blood pressure increases averaged 1-2 mm Hg on 0.5 mg/day fingolimod and 1-3 mm Hg on 1.25 mg/day fingolimod, compared with the placebo group.

"The significance of these findings is uncertain," he said.

Rates of hypertension adverse events were higher in the fingolimod groups – 4% on the lower dose and 5% on the higher dose – compared with the placebo group (3%) or the interferon group (2%). The proportions of patients who needed antihypertensive therapy, however, were similar between groups: 5% on low-dose fingolimod, 6% on high-dose fingolimod, 6% on placebo, and 4% on interferon.

Patients who were treated responded to standard antihypertensive therapy.

Data for the analysis came from the Efficacy and Safety of Fingolimod in Patients With Relapsing-Remitting Multiple Sclerosis (FREEDOMS) trial and from the Trial Assessing Injectable Interferon vs. FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS). Both were international, multicenter, randomized double-blind trials.

Both trials excluded patients with moderate to severe cardiovascular disease. At baseline, 3%-4% in each treatment group had a cardiovascular disorder and 5%-7% had hypertension.

The current analysis was funded by Novartis, which markets fingolimod. Dr. DiMarco disclosed financial relationships with Novartis, Medtronic, St. Jude Medical, Astellas, Sanofi-Aventis Pharmaceuticals, and Boston Scientific. His associates in the study have been employees of Novartis, have held stock in the company, or disclosed other financial relationships with Novartis and other pharmaceutical companies.