Smoking, Drinking, and Drugs—All Signs Point to Earlier ASCVD

The recreational use of any illicit drug—cannabis, amphetamines, cocaine, or others—is associated with nearly a threefold higher risk of premature and extremely premature atherosclerotic cardiovascular disease (ASCVD), and this risk is even more pronounced in those who combine different drugs, according to a study published this week.

Overall, the risk of premature ASCVD was more than two to three times higher in individuals who used a single recreational drug, including tobacco, alcohol, or an illicit substance. The risk of premature ASCVD was over six times more likely in patients who used three recreational drugs, and nearly ninefold higher in those who used at least four recreational drugs.

“We see a dose-response, if you will,” lead investigator Dhruv Mahtta, MD, MBA (Michael E. DeBakey VA Medical Center/Baylor College of Medicine, Houston, TX), told TCTMD. “As the number of recreational substances goes up, the odds ratio and the risk of developing premature atherosclerotic cardiovascular disease also goes up.”

Mahtta pointed out that the number of patients using at least two, three, or four recreational drugs is not insignificant. For example, approximately 11% of patients with premature ASCVD were using four or more recreational drugs while nearly one-third of patients with premature ASCVD were using two or more recreational drugs.

“It translates into quite a bit of risk at the population level,” said Mahtta.

Senior investigator Salim Virani, MD, PhD (Michael E. DeBakey VA Medical Center/Baylor College of Medicine), said that given these numbers, the population attributable risk is quite high. “You can have a risk factor with an odds ratio of 10, but if only 0.1% of the population has the risk factor, then that’s fine,” he said. “Here, the proportion of patients that carry the risk is also very high. It becomes not just about the high level of risk [associated with recreational drug use], but the large number of patients who are affected by this risk factor or marker.”

Robert Page II, PharmD (University of Colorado, Aurora), who chaired the writing committee responsible for the American Heart Association’s 2020 scientific statement on cannabis and cardiovascular health, praised the new study for filling a large evidence gap. Page focused on the association between cannabis and premature ASCVD, noting the adverse cardiovascular effects of cocaine and amphetamine are more widely known, and said more studies, particularly prospective studies, are needed as cannabis is legalized worldwide and becomes more socially acceptable. Young adults, he noted, might not know their family history and not realize the potential exists for cardiovascular problems down the road.  

“One of the limitations we found when putting together the clinical science statement is that there really isn’t a lot of great data in people who are pre-ASCVD or at high risk for ASCVD,” Page told TCTMD. “The big issue is whether cannabis, like cigarette smoking, contributes to the development of events. A lot of the data published currently are in individuals who have already had an event. That’s what makes this a very interesting addition to the literature.”

More-Rigorous Counseling

The correlation between recreational drug use and ASCVD has been identified in the past, with drug use linked not only with the development of atherosclerosis but also the progression of disease, said Mahtta. In their analysis, however, the researchers wanted to further understand how recreational drug use affected younger patients.

It translates into quite a bit of risk at the population level. Dhruv Mahtta

The new study, which was published February 15, 2021, in Heart, evaluated the association between premature and extremely premature ASCVD and recreational drug use using data from the 2014-2015 nationwide VA healthcare database and the Veterans with Premature Atherosclerosis (VITAL) registry. Premature ASCVD was defined as a first event occurring before 55 and 65 years in men and women, respectively (n = 135,703). Extremely premature ASCVD was defined as a first event occurring before age 40 (n = 7,716). These patients were compared with 1,112,455 patients identified as having non-premature ASCVD.

In a partially adjusted model, which accounts for patient variables, traditional cardiovascular risk factors, and comorbidities but doesn’t adjust for the use of other recreational drugs, those with premature ASCVD were significantly more likely to use tobacco, alcohol, and other illicit drugs compared with patients with non-premature ASCVD. In the fully adjusted model, which does account for use of all other drug categories, including alcohol and tobacco, use of any illicit drug was associated with a significant risk of premature ASCVD (OR 2.87), although that risk was attenuated compared with the partially adjusted model. After full adjustment for confounders, alcohol and tobacco, individually, were associated with the lowest odds ratios for premature ASCVD (OR 1.50 and 1.97, respectively) whereas amphetamines carried the highest risk (OR 2.74).

The use of recreational drugs was associated with a 1.5- to threefold higher risk of extremely premature ASCVD.

To TCTMD, Virani pointed out that those who use illicit drugs are more likely to drink or smoke, but the analysis showed that even after adjusting for those more-conventional risks, illicit drug use remained associated with premature and extremely premature ASCVD. The fully adjusted risk of recreational drug use is on par with traditional risk factors, such as diabetes, high cholesterol, and elevated blood pressure, he said. For that reason, Virani believes physicians need to ask patients about their nonmedicinal drug use, particularly those who are presenting early with ASCVD, and to counsel them about these risks more rigorously than what has been done in the past.

Graded Response Between Polysubstance Use and Premature ASCVD

The researchers also observed a significant interaction by sex, with the association between recreational drug use and premature and extremely premature ASCVD stronger in women. For example, women who used cocaine, amphetamines, or cannabis had a roughly fivefold higher risk of premature disease.   

“We don’t have a good explanation for it,” said Virani of the interaction. 

It is possible women are not effectively screened for drug and alcohol problems, which precludes successful treatment, suggest the researchers. It’s also unknown if women might be more biologically susceptible to the adverse effects of drug and alcohol use. Men typically have a greater burden of ASCVD risk factors than women so the effects of drugs/alcohol on the heart might be more pronounced in women, suggested Virani. 

Page noted that the mean age of men and women in the analysis was approximately 50 years and that the cardioprotective effects of female sex tend to be lost after menopause. For him, the difference in the magnitude of risk with recreational use between men and women was compelling and needs to be explored in further prospective studies. “I have not seen data like these published before in terms of gender differences, particularly with cannabis use,” he said.

To TCTMD, Page said there are limitations to all observational studies, such as this one, pointing out that the observed association is not causation. The biggest limitation, however, is that there was no differentiation between different cannabis formulations, such as first-generation cannabis products with lower concentrations of tetrahydrocannabinol (THC) and newer commercial products, such as edibles, that have much higher THC and cannabidiol (CBD) content.

“We don’t know what forms of cannabis these veterans are using,” he said. “We don’t know whether these individuals were smoking or consuming edibles. The bulk of the evidence that suggests a red flag for developing things like stroke or MI is mostly with smoking. We don’t have the data quite yet with edibles.” If the patients were smoking cannabis, Page said the association with premature ASCVD makes sense, but if a link between edibles and early-onset disease was discovered that would be a landmark finding. 

Interaction by Gender

In an editorial, Matthew Scott, PhD, Kevin Murnane, PhD, and Anthony Wayne Orr, PhD (all LSU Health, Shreveport, LA), point out that roughly one in five young adults engage in polysubstance abuse, and that many of them are starting earlier in life. Given the graded dose-response seen in the present study, with increased risks among those who use more drugs, this is a dangerous phenomenon, they write. Beyond the risks of overdose, young people need to be aware of their long-term risk of chronic ASCVD resulting from substance abuse disorders.

“We are only young once, and we should do everything in our power to maintain that state as long as we can,” they write.

Scott, Murnane, and Orr state that while the risk of premature and extremely premature ASCVD increases with the number of substances used, methamphetamine is “particularly detrimental.” Combining methamphetamine with cocaine, or even cannabis, is associated with a much-greater risk of premature or extremely premature ASCVD, they point out. It’s even possible that the crisis of early-onset ASCVD might be occurring concomitantly with the steep rise in methamphetamine use, according to the editorialists.

Another concerning aspect of these new data is what might happen as a result of the COVID-19 pandemic. With life turned upside down through health scares, unemployment, or even the psychological stress from lockdowns, there is a worry that people are turning to recreational drugs as a form of refuge. “It’s reasonable to predict that in the coming months or years, we might see an increase in the incidence atherosclerotic cardiovascular disease, especially in these younger patients,” said Mahtta.