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Evenity (Romosozumab) Cardiovascular Impact: Long-Term Evidence and Clinical Guidance

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At a glance

  • Drug / romosozumab-aqqg (Evenity), a sclerostin inhibitor given as a monthly subcutaneous injection by a healthcare provider
  • Labeled population / postmenopausal women at high risk for fracture, or who have failed or cannot tolerate other osteoporosis therapy [1]
  • Boxed warning / may increase MI, stroke and cardiovascular death; do not initiate within 1 year of MI or stroke; weigh risks with other cardiovascular risk factors [1]
  • ARCH 12-month MACE / 2.0% (41 of 2,040) versus 1.1% (22 of 2,014) with alendronate, HR 1.87 (95% CI 1.11 to 3.14) [1]
  • FRAME 12-month MACE / 0.8% (30) versus 0.8% (29) with placebo, HR 1.03 (95% CI 0.62 to 1.72) [1]
  • Treatment limit / 12 monthly doses of 210 mg; the anabolic effect wanes, and an anti-resorptive should be considered afterward [1]
  • Recent MI or stroke / boxed-warning restriction, not a Contraindications-section entry [1]

What does the boxed warning say?

The boxed warning is titled 'Potential risk of myocardial infarction, stroke and cardiovascular death.' The label states that Evenity may increase the risk of myocardial infarction, stroke and cardiovascular death [1]. It says Evenity should not be initiated in patients who have had a myocardial infarction or stroke within the preceding year, and that benefits and risks should be considered in patients with other cardiovascular risk factors [1]. If a patient has a myocardial infarction or stroke during therapy, the label says Evenity should be discontinued [1].

Recent MI or stroke is a boxed-warning restriction, not an entry in the Contraindications section. That section lists hypocalcemia and a history of systemic hypersensitivity to romosozumab-aqqg or any component of the product [1].

What did ARCH show?

ARCH randomized 4,093 postmenopausal women with osteoporosis and a fragility fracture to monthly subcutaneous romosozumab 210 mg or weekly oral alendronate 70 mg for 12 months, then open-label alendronate in both groups [2]. The label's positively adjudicated major adverse cardiac event composite (cardiovascular death, nonfatal MI and nonfatal stroke) occurred in 2.0% (41 of 2,040) versus 1.1% (22 of 2,014), hazard ratio 1.87 (95% CI 1.11 to 3.14) [1]. Myocardial infarction occurred in 0.8% versus 0.2%, stroke in 0.6% versus 0.3%, and cardiovascular death in 0.8% versus 0.6% [1].

The ARCH primary endpoints were fracture outcomes, and serious cardiovascular adverse events were adjudicated [2]. At 24 months, new vertebral fractures were 6.2% with romosozumab-to-alendronate versus 11.9% with alendronate-to-alendronate, a 48% lower risk; clinical fractures were 9.7% versus 13.0%, a 27% lower risk; nonvertebral fractures were 8.7% versus 10.6%, a 19% lower risk (P=0.04); and hip fractures were 2.0% versus 3.2%, a 38% lower risk (P=0.02) [2].

What did FRAME show?

FRAME randomized 7,180 postmenopausal women with a T-score of -2.5 to -3.5 at the total hip or femoral neck to romosozumab 210 mg or placebo monthly for 12 months, then denosumab 60 mg every 6 months for 12 months [3]. Positively adjudicated MACE occurred in 0.8% (30) of romosozumab-treated women and 0.8% (29) of placebo-treated women, hazard ratio 1.03 (95% CI 0.62 to 1.72) [1]. So the MACE imbalance appeared in the alendronate-controlled trial, not the placebo-controlled trial [1].

The two trials used different comparators and enrolled different populations, and the label reports their results separately [1][3][2].

What do the 24-month data add?

The 24-month endpoints in ARCH and FRAME are fracture outcomes, and both trials switched both arms to an anti-resorptive after 12 months [3][2]. In FRAME, new vertebral fractures at 24 months were 0.6% with romosozumab-to-denosumab versus 2.5% with placebo-to-denosumab, a 75% lower risk [3]. In ARCH, the 24-month vertebral fracture reduction was 48%, as noted above [2].

The MACE figures above come from the 12-month double-blind periods [1]. Evenity is limited to 12 monthly doses because the anabolic effect wanes; if osteoporosis therapy remains warranted, the label says continued therapy with an anti-resorptive agent should be considered [1]. After stopping without follow-on anti-resorptive therapy, bone mineral density returns to about baseline within 12 months [1].

Who is Evenity labeled for, and what about other cardiovascular risk factors?

Evenity is indicated for postmenopausal women at high risk for fracture, defined as a history of osteoporotic fracture or multiple risk factors for fracture, or for patients who have failed or are intolerant to other available osteoporosis therapy [1]. It is not labeled for men or for premenopausal women [1]. The dose is 210 mg subcutaneously once every month for 12 doses, given by a healthcare provider [1]. The label says to adequately supplement calcium and vitamin D during treatment; the trials used at least 500 mg calcium and 600 international units of vitamin D daily [1].

The Contraindications section does not list hypertension or high cholesterol [1]. For patients with other cardiovascular risk factors, the boxed warning says to consider whether the benefits outweigh the risks [1].

What should patients watch for during treatment?

The label says to monitor for signs and symptoms of myocardial infarction and stroke and to instruct patients to seek prompt medical attention if symptoms occur [1].

Frequently asked questions

Does Evenity cause heart attacks or strokes?
The label's boxed warning says Evenity may increase the risk of myocardial infarction, stroke and cardiovascular death [1]. In ARCH, MACE was 2.0% versus 1.1% with alendronate, HR 1.87 (95% CI 1.11 to 3.14), and MI was 0.8% versus 0.2% [1]. In FRAME, MACE was 0.8% versus 0.8% with placebo [1].
Is a recent heart attack or stroke a contraindication?
The label says Evenity should not be initiated in patients who have had a myocardial infarction or stroke within the preceding year [1]. That is a boxed-warning restriction, not an entry in the Contraindications section, which lists hypocalcemia and systemic hypersensitivity [1].
Was the ARCH cardiovascular difference statistically significant?
The label's MACE hazard ratio was 1.87 with a 95% CI of 1.11 to 3.14, which excludes 1 [1]. The ARCH primary endpoints were fracture outcomes, and serious cardiovascular events were adjudicated [2].
Can people with high blood pressure or high cholesterol take Evenity?
Hypertension and high cholesterol are not listed in the Contraindications section [1]. The boxed warning says to consider benefits and risks in patients with other cardiovascular risk factors [1].

References

  1. U.S. National Library of Medicine, DailyMed. Evenity (romosozumab-aqqg) injection prescribing information. Evenity (romosozumab-aqqg) injection label
  2. Saag KG, Petersen J, Brandi ML, Karaplis AC, Lorentzon M, Thomas T, et al. Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis. N Engl J Med. 2017;377(15):1417-1427. Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis
  3. Cosman F, Crittenden DB, Adachi JD, Binkley N, Czerwinski E, Ferrari S, et al. Romosozumab Treatment in Postmenopausal Women with Osteoporosis. N Engl J Med. 2016;375(16):1532-1543. Romosozumab Treatment in Postmenopausal Women with Osteoporosis
Evidence overview for romosozumab: Evenity (Romosozumab) Cardiovascular Impact: Long-Term Evidence and Clinical Guidance