The antiseizure medication pregabalin, which is commonly prescribed for chronic pain, has been linked to an increased risk for heart failure (HF), particularly in those with a history of cardiovascular disease (CVD), new data suggested.
In a cohort of more than 240,000 Medicare beneficiaries with noncancer chronic pain, initiation of pregabalin was associated with a 48% higher risk for new-onset HF overall and an 85% higher risk in those with a history of CVD than initiation of gabapentin.
The study was published online on August 1 in JAMA Network Open.
Widely Prescribed Medications
Chronic pain affects up to 30% of adults aged 65 years or older. Nonopioid medications, such as the gabapentinoids pregabalin and gabapentin, are widely prescribed for chronic pain, the investigators, led by Elizabeth Park, MD, Columbia University Irving Medical Center in New York City, noted.
Pregabalin has greater potency than gabapentin in binding to the α2δ subunit of the L-type calcium channel and therefore may be associated with an increased risk for HF through actions to cause sodium/water retention.
To investigate further, investigators evaluated 246,237 Medicare beneficiaries between 2014 and 2018, including 18,622 (8%) new pregabalin users and 227,615 (92%) new gabapentin users. All patients were aged 65-89 years, had chronic noncancer pain, and had no history of HF.
The researchers used inverse probability of treatment weighting to adjust for an extensive list of 231 covariates to reduce confounding and attempted to closely emulate a hypothetical target trial in which Medicare patients filled new prescriptions for pregabalin or gabapentin for noncancer pain.
During 114,113 person-years of follow-up, 1470 patients had a hospital admission or emergency department visit for HF. The rate of HF per 1000 person-years was 18.2 for pregabalin and 12.5 — translating to roughly six additional HF events annually for every 1000 patients treated with pregabalin — with an adjusted hazard ratio (HR) of 1.48.
The difference was even more pronounced in patients with a history of CVD, with an adjusted HR of 1.85. An increased risk for outpatient HF diagnoses was also seen (adjusted HR, 1.27), but there was no difference in all-cause mortality between groups.
The authors said the findings further support current recommendations from the European Medicines Agency to exercise caution when prescribing pregabalin to older adults with CVD.
The American Heart Association currently lists pregabalin, but not gabapentin, as a medication that may cause or exacerbate HF.
Immediate Clinical Implications
The co-authors of an invited commentary noted that the study provides “timely and clinically relevant insights” into the cardiovascular safety of these two widely used gabapentinoids.
From a clinical standpoint, the findings have “immediate clinical implications,” wrote Robert Zhang, MD, with Weill Cornell Medicine, New York City, and Edo Birati, MD, Tzafon (Poriya) Medical Center, Poriya, Israel.
For older adults with chronic pain, particularly those with CVD, “clinicians should weigh the potential cardiovascular risks associated with pregabalin against its analgesic benefits. This is particularly relevant given the growing use of gabapentinoids in older populations and ongoing polypharmacy issues in this age group,” Zhang and Birati advised.
“Furthermore, if pregabalin use is associated with new-onset HF, it raises the possibility that the drug may unmask underlying subclinical cardiovascular disease, which suggests a need for careful cardiac evaluation prior to prescribing this medication,” they added.
“The study serves as an important reminder that not all gabapentinoids are created equal and that in the pursuit of safer pain control, vigilance for unintended harms remains paramount,” the investigators concluded.
The study had no commercial funding. The authors and editorial writers reported having no relevant disclosures.
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