Long-term Risk Factor Control Linked to Survival in COURAGE Substudy

The results should be a “call to action” for healthcare professionals to better encourage lifestyle interventions in their patients, study author says.

Long-term Risk Factor Control Linked to Survival in COURAGE Substudy

For patients with stable ischemic heart disease, the greater number of risk factors they have under control, the more likely they are to survive long-term, according to a new analysis of the COURAGE trial.

“This should emphasize what most of us already believe, which is that controlling the factors that contribute to atherosclerosis reduces death. And yet, it is somewhat alarming how poorly we control risk factors,” lead author David Maron, MD (Stanford University School of Medicine, CA), told TCTMD. “The most surprising part of this analysis was that most of the effect was in the lifestyle risk factors, and we're not very good as a profession at motivating and guiding patients to make lifestyle changes. So I think that this hopefully will be a call to action to pay attention to the nonglamorous and frankly nonprescription interventions that we should be making for patients with coronary artery disease.”

This hopefully will be a call to action to pay attention to the non-glamorous and frankly non-prescription interventions that we should be making for patients with coronary artery disease. David Maron

Published online ahead of its print publication November 6, 2018, in the Journal of the American College of Cardiology, the study included 2,102 stable ischemic heart disease patients from COURAGE who had available data on six specific risk factors—systolic BP, LDL cholesterol, smoking, physical activity, diet, and body mass index (BMI)—and were followed for a mean of 6.8 years.

Overall, 22.5% of patients died during follow-up, and there was a relationship between survival and higher numbers of risk factors controlled (P < 0.001). Multivariate analysis showed that not smoking, engaging in regular physical activity, having a systolic BP < 130 mm Hg, and following the American Heart Association (AHA) Step 2 diet were the strongest predictors of long-term survival.

For each additional risk factor controlled, the risk of mortality fell by 16% (adjusted HR 0.84; 95% CI 0.79-0.92). Compared with patients who achieved none or only one risk factor goal, those who had four risk factors controlled had a 36% lower mortality (P = 0.04). For the 3% of patients who had all six risk factors at goal, their mortality was 73% lower than that of individuals with only 0 or 1 controlled (P = 0.02).

Notably, there were no links between guideline-directed medication and risk-factor goal attainment, nor PCI and long-term survival.

According to Maron, this analysis was inspired by and confirms the findings of a similar substudy of the BARI 2D trial that was published in 2015. “We don't really have a test of medical therapy versus no medical therapy in the COURAGE trial, but because there was a spectrum of goal attainment among the participants, I thought that we might be able to find a mortality signal among those who were less able to reach risk factor goals,” he said.

Some might see these results as “obvious,” Maron allowed, but he said he was surprised to find that achieving LDL goals and statin use did not have a strong effect on mortality in this study. “It took some time to come to understand why that is likely the case,” he said. Namely, the researchers write, the high rate and limited variability in statin use throughout the trial may have hindered their ability to note a link between the drugs and lower survival. Additionally, the authors suggest that if newer drugs like PCSK9 inhibitors and anti-inflammatories had been used in COURAGE that “survival benefits from pharmacological intervention might have emerged.”

Maron also highlighted the fact that while—famously—PCI did not improve survival in COURAGE, lifestyle modifications did. Still, he acknowledged limitations of the study, namely, its observational nature and the fact that patients weren’t randomized to optimal medical therapy (OMT) versus no OMT. As such, “there is confounding, because people who meet risk factor goals are different from people who don't,” he said. “However, it's entirely consistent with what we know from other research and it is striking that controlling risk factors, and particularly lifestyle, did result in a lower mortality. That's really the take home for me.”

Commenting on the study for TCTMD, Laxmi Mehta, MD (The Ohio State University Wexner Medical Center, Columbus), pointed out that patients with stable CAD who feel some symptom relief after PCI need to understand that stent is not a cure, nor is it the end of their journey. “That's where [it’s worth] really reiterating to our patients the importance of attending cardiac rehab and seeing what they can do,” she said. “Sometimes they're dejected and [thinking], ‘What's the point of anything? I can't do anything,’ and really getting them to move forward and say ‘Hey, you can do stuff’ [is important]”

Breaking Old Habits

In an accompanying editorial, Vera Bittner, MD (University of Alabama at Birmingham), who was the lead author of the aforementioned BARI 2D analysis, wrote that the two substudies “taken together strongly reinforce current risk-reduction guidelines.”

However, she writes, “the importance of lifestyle change in addition to intensive pharmacological management in secondary prevention is often underestimated by patients and clinicians alike. Yet, the outcomes achieved with the COURAGE and BARI 2D case management strategies are consistent with the mortality reductions observed among patients who attended cardiac rehabilitation, a well-established multidisciplinary care model that aims to achieve comprehensive risk-factor modification through education, exercise training, promotion of lifestyle changes and medication adherence, and attention to psychosocial risk factors.”

The importance of lifestyle change in addition to intensive pharmacological management in secondary prevention is often underestimated by patients and clinicians alike. Vera Bittner

Mehta, however, stressed that while physicians are aware of the need to counsel patients on risk factors, the amount of effort, as this COURAGE analysis makes clear, may not be realistic for most physicians in practice. “To really convince a patient to quit smoking takes a long time. To work with them to figure out what are their barriers to exercising or eating healthy takes time, and that's a challenge,” Mehta said. “One of the things in this study is they had frequent visits with the patients where they were able to spend that time, and so that constant touch with the patient and keeping the patient accountable was there versus in our daily practice, you can't see patients on that frequent of a basis. From a preventative standpoint, it just doesn't work in terms of where healthcare is at this point.”

Bittner specifically mentions the difficulty physicians face in changing the behaviors in elderly patients, “even with appropriate resources.”

Mehta agreed. “Old habits are hard to break,” she said. “It is a lot more of a challenge to get them to quit smoking or change their eating habits or get them to exercise when they have joint aches or things like that. The mitigation would be really getting them into . . . cardiac rehab.” She has also had some success with inspiring change in some 70-year-old patients by persistent nagging and encouragement, she said, but added that having new information like this study will likely help convince stubborn patients to change their tune.

Enacting Change

Maron also emphasized the importance of a multidisciplinary team to help patients control their risk factors. “The physician serves as the person to emphasize the importance of making lifestyle change, but for practical purposes, usually that person is not an expert in helping people make behavior change,” he said. The care team, which might include nurses, dieticians, exercise physiologists, psychologists, and cardiac rehabilitation specialists, makes up “the people who are likely the most skilled at helping patients make change,” Maron explained, adding that perhaps there will be a growing role for mobile technologies to play in this field also.

Future research should focus on how risk factors can be best controlled, he said. “We pretty much know what works, and now we need to improve our methods for translating what we know into action, to implement our findings,” Maron said.

Mehta specifically suggested that “more studies on how to intervene better on the patients and getting them to be motivated to make the change” are needed. For example, one might compare standard cardiac rehab with more neighborhood-based programs. “And then, what are the interventions that we can [apply]—learning techniques to motivate patients—to be the change that they need to see?” she added.

That may be another key message from this analysis, Bittner observes. Only 3% of COURAGE participants (and 6% in BARI 2D) got all six risk factors under control by the 1-year mark, but “it is worth remembering that both trials found incremental benefit with every additional risk factor in control. There will always be residual risk in secondary prevention,” Bittner concludes. “The ultimate key to success lies in primordial and primary prevention.”

  • This study was supported by the Cooperative Studies Program of the US Department of Veterans Affairs Office of Research and Development, in collaboration with the Canadian Institutes of Health Research; and by unrestricted research grants from Merck, Pfizer, Bristol-Myers Squibb, Fujisawa, Kos Pharmaceuticals, Datascope, AstraZeneca, Key Pharmaceutical, Sanofi, First Horizon, and GE Healthcare, including in-kind support with U.S. Food and Drug Administration.
  • Bittner reports serving on the executive steering committee of the ODYSSEY OUTCOMES trial (Sanofi) and as national coordinator for the STRENGTH (AstraZeneca), DalGene (Dalcor), and CLEAR (Esperion) studies, all contracted through the University of Alabama at Birmingham; serving as site investigator for ARTEMIS (AstraZeneca) and COMPASS (Bayer Healthcare) studies, both contracted through the University of Alabama at Birmingham; serving as a consultant for Sanofi; and serving as a sub I on a contract between University of Alabama at Birmingham School of Public Health and Amgen to conduct epidemiological research.
  • Maron and Mehta report no relevant conflicts of interest.