Recurrent Events Common Among Young Patients With CAD

(UPDATED) Nearly one-third of young adults with premature coronary artery disease will have a recurrent major adverse cardiovascular event, and this risk is particularly pronounced in those with diabetes, inflammatory diseases, and those of Asian and sub-Saharan ethnicity, according to a new analysis.

Long-term follow-up of 880 people enrolled in the Appraisal of Risk Factors in Young Ischemic Patients Justifying Aggressive Intervention (AFIJI) study revealed that 264 (30%) had a recurrent event, which was defined as all-cause mortality, MI, refractory angina leading to coronary revascularization, or ischemic stroke. For the 255 patients with a nonfatal recurrent event, 36.0% would go on to have at least one additional MACE, report investigators.

“It’s a terrible thing to have a heart attack before the age of 45, very often before the age of 40,” senior investigator Gilles Montalescot, MD, PhD (Centre Hospitalier Universitaire Pitié-Salpêtrière, Paris, France), told TCTMD. “Nobody would expect to have an acute MI so young and nobody knows the progression of the disease in these types of patients. They develop the disease 20 or 25 years earlier than anybody else, and we don’t know how it evolves. Most of these patients have very good early outcomes—they don’t die because they’re in good shape—but we didn’t know what happens later on.”

The report, which was published October 7, 2019, in the Journal of the American College of Cardiology, is 20-year follow-up of AFIJI, a multicenter, prospective cohort study initiated in 1996. It was designed to characterize the patient profile, treatment, and follow-up of young adults who survived a first occurrence of CAD. Premature disease was defined as the occurrence of an acute MI or symptomatic myocardial ischemia with obstructive CAD (≥ 70% stenosis) in men and women 45 years and younger.

‘Late Prognosis Is Not Good’

At baseline, most patients were men (86.7%) and active smokers (77.3%). Many had a family history of premature CAD (40.8%) and high cholesterol levels (mean LDL cholesterol at baseline was 169 mg/dL). Additionally, one in 10 patients had a chronic inflammatory or immunosuppressive disease, including HIV, viral hepatitis, polyarthritis, or systemic lupus. Nearly all patients were taking aspirin and 93.2% were prescribed statin therapy. Additionally, 89.3% were taking beta-blockers, 60% were taking clopidogrel, and 77.6% were prescribed an ACE inhibitor or angiotensin-receptor blocker (ARB).

For the 30% of patients who had recurrent MACE, nonfatal MI was the most frequent event and was related to a new coronary lesion in 152 patients and to the initial culprit lesion in 69 patients. For the 522 patients with single-vessel disease at baseline, CAD evolved into more widespread multivessel disease in 112. The researchers note that one half of the recurrent events occurred in the first 4 years of follow-up and 75% of all events occurred in the first 10 years after the initial diagnosis of CAD.

It’s a terrible thing to have a heart attack before the age of 45, very often before the age of 40. Gilles Montalescot

In a multivariate, risk-adjusted model, persistent smoking was associated with a more than twofold increased risk of recurrent MACE (HR 2.32; 95% CI 1.63-3.28). Individuals with diabetes were also at an increased risk of recurrent events (HR 1.75; 95% CI 1.20-2.55), as were those with chronic inflammatory conditions (HR 1.58; 95% CI 1.05-2.36). Compared with Caucasians, those with a sub-Saharan ethnic background had a twofold increased risk of recurrent MACE (HR 1.95; 95% CI 1.13-3.35). Asian ethnicity was a borderline significant risk factor.

“What we see, now that we now have 20 years’ follow-up, is these patients have a lot of recurrent events,” said Montalescot. “It’s amazing how far the disease progresses. It progresses into different arteries. They have new MIs. Some of these patients have turned into heart failure [cases]. A few of them even have been transplanted. We see that if the early prognosis is not bad, the late prognosis is not good.”

ABCDE Approach to Preventing CAD

Given the high rate of recurrence, Erin Michos, MD (Johns Hopkins Medical Institute, Baltimore, MD), and Andrew Choi, MD (George Washington University School of Medicine, DC), who wrote an editorial accompanying the new report, state that even greater efforts toward preventing the development of CAD in the first place are needed.

While identifying which young, seemingly healthy adults will prematurely develop CAD is a challenge because the risk calculators aren’t designed for younger people, Michos and Choi state that physicians can turn to the latest American College of Cardiology/American Heart Association primary prevention guidelines. These guidelines promote a multipronged “ABCDE” approach that focuses on assessing risk, managing blood pressure and cholesterol, smoking cessation, healthy weight/diet, managing diabetes, and exercise promotion.

Brent Muhlestein, MD (Intermountain Healthcare Heart Institute, Salt Lake City, UT), who was not involved in the analysis, said that patients who have cardiovascular events early in life typically have an aggressive form of CAD that can be difficult to control. To TCTMD, Muhlestein pointed out that among patients with recurrent MACE in follow-up, 92.0% were taking statins, 97.3% were taking aspirin, and 80.7% were taking an ACE inhibitor/ARB. “My sense is if they hadn’t been at least that aggressive, there would have been more recurrent events,” he said. “Standard medicines given as aggressively as they were given are probably not adequate.”

To get these patients to quit smoking is critically important. Brent Muhlestein

New agents, such as the PCSK9 inhibitors alirocumab (Praluent; Sanofi/Regeneron) and evolocumab (Repatha; Amgen), would be a treatment option, said Muhlestein, while positive data from the REDUCE-IT trial also showed that icosapent ethyl (Vascepa; Amarin), a prescription omega-3 fatty acid, could reduce cardiovascular events independent of lipid levels.

With the growing awareness of the role inflammation plays in CAD development, as well as the CANTOS study showing that reducing inflammation can prevent recurrent events, Muhlestein suggested this is another avenue for treatment. Although canakinumab, which was tested in CANTOS, is not an option, colchicine, which showed favorable results in LoDoCo, might be a possible treatment, he added. “If somebody has an inflammatory process which increases the risk of plaque rupture because it destabilizes atherosclerotic plaque, they would be more likely to have a second event,” said Muhlestein.  

Ian Neeland, MD (UT Southwestern Medical Center, Dallas, TX), another physician who wasn’t involved in the study, pointed out that modifying cardiovascular risk factors often has the positive effect of decreasing C-reactive protein (CRP), a marker of inflammation. “The biggest thing for CRP tends to be adiposity, specifically visceral adiposity,” he told TCTMD. “Targeted weight loss with exercise and increased physical activity can melt away some of the visceral fat and lower CRP.”

In terms of drug therapy, Neeland said there isn’t anything he prescribes to target inflammation aside from being aggressive with optimal medical therapy and promoting the importance of lifestyle changes in high-risk patients, or in those who have had a cardiovascular event. Whereas older patients may be used to going to the doctor and have repeatedly heard the importance of lifestyle for preventing first or second cardiovascular events, a young MI patient might not have gotten the message yet. For some patients, a CAD event might be a massive shock, and they are usually unprepared for a lifetime of medicine or the drastic lifestyle changes required.

“It’s big thing to ask of a person, to totally change their life,” said Neeland. “Still, I am pretty aggressive with these folks.”      

Smoking the Biggest Risk Factor

While genetics likely play a large role in the onset of premature CAD, and are beyond the control of physicians, Montalescot also emphasized the need for aggressive risk factor control. Overall, 7.2% of patients in the AFIJI registry were not taking a statin and only 48.3% were taking a high-intensity statin. Montalescot said that some patients likely stopped their medication or reduced the dose because of side effects, or possibly because they didn’t want to take medication long-term.

“It’s not good,” said Montalescot. “We need to emphasize to these patients that they have an aggressive disease and need to stay on secondary-prevention drugs.”

Montalescot pointed out that while only 10.7% of patients in the study had diabetes at baseline, nearly 30% were diagnosed with diabetes in long-term follow-up. In these patients, the sodium-glucose co-transporter 2 inhibitors, a drug class shown to reduce clinical outcomes such as cardiovascular death and heart failure, might be a good option. “I think these drugs would probably be of great benefit in these patients,” he advised.

To TCTMD, Montalescot said that smoking is by far the biggest risk factor for poor long-term outcomes among patients with premature CAD. Despite the onset of premature disease, 50.9% of trial participants were still smoking when they had a recurrent event and 30.2% were smokers at the time of the second recurrence. Among those who had a third MACE, 35.0% were smokers.

“To get these patients to quit smoking is critically important,” added Muhlestein.