Risk for Heart Attack, Stroke or Death Can Double or Triple in Older Adults Concurrently Taking Multiple Medications with Cardiovascular Side Effects

Using multiple medications with known cardiovascular adverse effects at the same time doubled, and sometimes tripled, the risk for a heart attack, stroke or death among older adults with no prior cardiovascular disease, according to new research published in Pharmacoepidemiology & Drug Safety.  

Many prescription and over-the-counter medications commonly used by older adults are associated with serious, potentially fatal cardiovascular adverse effects. For example, non-steroidal anti-inflammatory drugs (NSAIDs), antipsychotics, bronchodilators, and opioid analgesics have all been found to increase risk of myocardial infarction, stroke, fatal coronary heart disease or sudden cardiac death.

In fact, nearly one-third of the medications identified by the authors have cardiovascular adverse effects listed as a black box warning—the most serious safety warning that can be required by the Food and Drug Administration. It was unknown how cardiovascular risks change with polypharmacy—or the concurrent use of multiple medications—among older adults.

“Although the cardiovascular risks of specific medications or drug classes is generally well-recognized, the cumulative impact on cardiovascular risk associated with the concurrent use of these medications was not known prior to this study,” said corresponding author Dima M Qato, a senior fellow at USC Schaeffer Center and Hygeia Centennial Chair and associate professor and Director of the Program on Medicines and Public Health at USC School of Pharmacy.

The link between polypharmacy and increased cardiovascular risk was limited to medications with potential cardiovascular adverse effects. The researchers also find no association between the number of medications without cardiovascular adverse effects and cardiovascular risk.

“Our findings build on prior studies focusing on individual products and suggest there is an additive risk of serious cardiovascular events associated with the use of two or more medications with cardiovascular side effects,” said Qato.

Half of adults studied were taking at least one medication with a known risk of a cardiovascular adverse effect

Qato and her colleagues used publicly-available data from the Atherosclerosis Risk in Communities (ARIC) study to conduct a population-based cohort study of 3,669 community-dwelling older adult participants ages 61–86 years old with no history of cardiovascular disease. They investigated the incidence of major cardiovascular events—heart attack, stroke, heart disease and mortality—over a nine-year period between 2006 and 2015 among people taking multiple medications with cardiovascular adverse effects. They compared these patient outcomes to the outcomes of patients taking multiple medications that do not carry these risks.  

Fifty percent of participants were taking at least one medication with a cardiovascular adverse effect, 12% were concurrently taking two medications and 6% were concurrently taking three medications.

The researchers found that older adults using concurrent medications associated with cardiovascular adverse effects had double or triple the risk of a major cardiovascular event occurring when compared to those not using these medications. The risk increased with the number of medications concurrently used. For example, older adults taking three or more experienced the highest rates of stroke, heart attack or death.

Polypharmacy may undermine the effectiveness of medications intended to reduce cardiovascular risk

The increased cardiovascular risk associated with the concurrent use of medications with cardiovascular side effects was observed in all groups regardless of underlying cardiovascular risk, including among individuals taking antihypertensives, antidiabetic agents and statins.  

For example, the researchers estimate the risk of having a heart attack is greater among statin users concurrently taking multiple medications with cardiovascular adverse effects compared to statin users concurrently taking multiple medications that do not have these adverse effects.

“Cardiovascular prevention efforts, including statin treatment guidelines for primary prevention, should consider incorporating information on the cardiovascular safety profiles of medications commonly used at the same time by older adults,” said Katharine Ozenberger, first author of the study and a research affiliate with the Program on Medicines and Public Health at the USC School of Pharmacy and a PhD candidate in the Department of Pharmacy Systems, Outcomes, and Policy at the University of Illinois at Chicago. 

“Our data indicate that simply prescribing statins for cardiovascular prevention without considering the cardiovascular risks of other medications a patient is taking may sometimes increase, and not reduce, the risk of stroke, heart attack or death in older patients,” explains Ozenberger.

Combinations that involve opioids associated with greatest increase in cardiovascular risk

When compared to other medication combinations that also have cardiovascular adverse effects, the increase in cardiovascular risk was greatest among individuals using combinations that involve opioids. Specifically, the risk of having a major cardiovascular event was two times higher among older adults concurrently using opioid painkillers in combination with NSAIDs, antidepressants and/or bronchodilators.

“These findings suggest that polypharmacy should be considered when investigating the risk of opioid-related overdose and fatalities in older adults,” said Qato. “It is important to understand the adverse effects of prescription medications concurrently used with opioid analgesics – aside from benzodiazepines – when preventing and addressing the growing problem of  fatal and non-fatal opioid overdoses in the U.S.”

Risk varied within drug classes, treatment options with reduced risk

Among medications that have the potential to cause cardiovascular adverse effects, the authors found that cardiovascular risk varied within a drug class. For example, among NSAIDs – a class where all medications have a black-box warning for the increased risk of serious cardiovascular events – the cardiovascular risk for meloxicam was nearly two times greater than for ibuprofen. Similarly, within opioid analgesics, oxycodone was associated with a two to three-fold greater incidence of cardiovascular events when compared to other opioid analgesics.

“These findings suggest that there are alternative, potentially safer, treatment options available, including for the treatment of pain,” Qato said.  “Clinicians should consider the additive cardiovascular risk of current or newly prescribed medications when treating older patients that use multiple medications, and potentially start patients on, or switch them to, medications that have a lower cardiovascular risk profile.”

G. Caleb Alexander, Jung-Im Shin and Eric A. Whitsel co-authored the study.