Tinzaparin (Innohep®) and risk of death in the elderly with renal impairment

The Vigilance Branch of HSA would like to bring to the attention of healthcare professionals, the results of the clinical study, Innohep® in Renal Insufficiency Study (IRIS), suggesting that tinzaparin (Innohep®, LEO Pharma) may increase the risk for death, compared to unfractionated heparin (UFH) when used to treat elderly patients with renal insufficiency.

Innohep® is a low molecular weight heparin indicated for treatment of deep-vein thrombosis (DVT) and pulmonary embolism (PE) as well as for the thromboprophylaxis in patients with high risk of venous thromboembolism (eg, in patients with total hip replacement).

Innohep® in Renal Insufficiency Study (IRIS)

The IRIS study was a multi-centre European study designed to compare the safety profile of Innohep® with UFH in the initial treatment of acute DVT in patients greater than 70 years of age with impaired renal function (i.e. patients > 70 years with estimated creatinine clearance of < 30ml/min or patients > 75 years with estimated creatinine clearance of < 60 ml/min). In the study, patients were randomised to treatment with either Innohep® (fixed dose of 175IU/kg subcutaneous injection once daily) or UFH (IV bolus followed by subcutaneous injections twice daily) for at least 5 days followed by oral anti-coagulant treatment for at least 90+/-5 days.

Interim analysis

During the planned interim analysis, an increase in all-cause mortality in the Innohep® arm compared to the UFH arm was identified, which led to a premature discontinuation of the study. At the time the study was stopped, 350 patients had completed 90 days of follow-up. Of these, 23 of the 176 (13%) patients in the Innohep® group versus 9 of the 174 (5%) patients in the UFH group had died.1

Following the termination of the study, although patient recruitment was stopped, all patients who were previously enrolled and had completed the subcutaneous period with Innohep® or UFH treatment continued the study according to the protocol. When the total enrolled population had been followed up to day 90, there were a total of 537 patients who were evaluated. Of these 537 patients, 11.2% patients in the Innohep® group (n=269) and 6.3% patients in the UFH group (n=268) had died (p=0.049).2,3 The difference in mortality was not due to recurrent VTE or bleeding. Most of the difference in mortality was in those aged 90 years and above (9.4% in the UFH group vs. 30.8% in the Innohep® group). Below 90 years, the mortality rates were 5.9% vs. 7.8%, respectively.3

A review of risk factors suggested an imbalance at randomisation with a higher percentage in the Innohep® group having risk factors for death. When adjusted for baseline characteristics using multiple regression analysis, the relative risk of dying in the Innohep® group versus the UFH group was found not to be statistically significant. In addition, four parameters were found to be correlated to mortality, namely ongoing malignancy, infectious disease, age > 90 years and cardiac insufficiency. All of these four identified risk factors for death were found to be more common in the Innohep® group than the UFH group.3

Regulatory actions by the US Food and Drug Administration (FDA)

In response to the interim finding of the IRIS study, showing an increase in all-cause mortality in patients receiving Innohep®, the US FDA posted a public communication highlighting these results on their website.2 Although it was understood that FDA is still finalising their safety review of Innohep® and had not concluded on the association between Innohep® and mortality, the US product insert was updated to describe the interim study results in the labelling of Innohep®, suggesting that Innohep® increases the risk of death for elderly patients (i.e. 70 years of age and older) with renal insufficiency. A Dear Healthcare Professional Letter (DHCPL) was also issued to the healthcare professionals to inform them of the interim results of the IRIS study as well as the package insert update.3

Local Situation

To date, HSA has not received any local ADR reports related to the use of Innohep®. HSA is working with the company to strengthen the local package insert for Innohep® to caution on the use of Innohep® in patients with renal impairment and to monitor patients for anti-factor Xa activity.

Healthcare professionals are advised to take into consideration the above safety update when prescribing Innohep® to their patients and to report all suspected adverse reactions associated with Innohep® to the Vigilance Branch of HSA.

References

  1. FDA Communication about an ongoing safety review of Innohep®  http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm136254.htm
  2. Celgene – DHCPL on important Innohep® safety information http://www.fda.gov/downloads/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm128135.pdf
  3. Leizorovicz A.Tinzaparin Compared to Unfractionated Heparin for Initial Treatment of Deep Vein Thrombosis in Very Elderly Patients with Renal Insufficiency: the IRIS Trial. Blood 2008; 112(11): 166
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