This transcript has been edited for clarity.
Michelle L. O’Donoghue, MD, MPH: Hi. This is Dr. Michelle O’Donoghue, reporting for Medscape from the American Heart Association Scientific Sessions taking place in the vibrant city of Chicago. Today I have the pleasure of speaking with Dr. Sanjit Jolly, an esteemed interventional cardiologist at McMaster University in Hamilton, Canada, who is also a prominent clinical trialist associated with the Population Health Research Institute. Thank you for being here with me today.
You have unveiled some compelling findings over the past few months that hold significant clinical implications for the treatment of our patients. Specifically, we’re discussing the CLEAR SYNERGY (OASIS 9) trial, which utilized a sophisticated 2 x 2 factorial design to test two distinct hypotheses regarding the effectiveness of colchicine and spironolactone in patients suffering from an acute myocardial infarction (MI).
CLEAR SYNERGY (OASIS 9)
Sanjit S. Jolly, MD, MSc: Yes. The EPHESUS trial primarily focused on a population of patients who exhibited heart failure during their hospitalization, with low ejection fraction as a criterion for inclusion only if the patient had diabetes. Consequently, a significant majority of trial participants were heart failure patients. Our goal was to evaluate whether the routine use of spironolactone could provide benefits similar to those observed with ACE inhibitors, potentially improving patient outcomes.
Jolly: There was the ALBATROSS trial, which led by Gilles Montalescot, demonstrated a reduction in mortality among STEMI patients treated with colchicine even in those without heart failure, but this was a subgroup analysis needing validation.
O’Donoghue: There is increasing interest in mineralocorticoid receptor antagonists (MRAs), particularly within heart failure populations with preserved ejection fraction. Notably, MRAs had not been specifically scrutinized post-MI until now.
Jolly: strong>Our study randomized 7062 patients across 14 countries over a four-year span. These trials, particularly those that are investigator-initiated and largely grant-supported, present specific challenges. We had to adapt our sample size during the trial as the event rates were lower than anticipated. We amended our primary outcomes to incorporate co-primary endpoints and conducted a recurrent event analysis for cardiovascular (CV) death along with new or worsening heart failure.
Spironolactone Post-MI Results
Jolly: strong>We found no significant benefit concerning either co-primary endpoint. The hazard ratio stood at 0.89, indicating no observable effect on CV death, MI, stroke, or heart failure overall. However, we documented a notable reduction in new or worsening heart failure.
We conducted a prespecified on-treatment analysis which revealed approximately a 20% reduction in both CV death and new or worsening heart failure, suggesting a potential exploratory significance, despite our primary analysis following the intention-to-treat principle.
Jolly: strong>Fewer than 1% of patients enrolled had heart failure at the time of presentation, leaving 99% of our study population without any heart failure indications. This study focuses primarily on patients with no signs of heart failure, while approximately 39% had anterior MI.
Jolly: strong>While we did observe increased instances of hyperkalemia, it remained relatively uncommon, with incidences at 1% among those given spironolactone compared to 0.5% in the control group. Moreover, gynecomastia was reported in approximately 2% to 3% of participants receiving spironolactone, highlighting its known side effects.
Jolly: strong>Current guidelines endorse spironolactone for patients exhibiting signs or symptoms of heart failure, particularly with reduced ejection fraction or diabetes. This study raises nuanced considerations for prescribing practices.
Jolly: strong>There is compelling evidence indicating that practitioners are not optimally utilizing MRAs. Data from the NCDR[[National Cardiovascular Data Registry]illustrates that most patients post-MI with heart failure do not receive an MRA. While we excel at prescribing statins and possibly ACE inhibitors, MRAs remain underutilized.
Jolly: strong>If you’re addressing a younger patient with an inferior STEMI undergoing primary PCI, the probability of deriving benefits from MRAs appears very minimal given their lower risk of heart failure. On the other hand, elderly patients presenting with STEMI may have significantly elevated risk factors that warrant MRA treatment consideration.
Colchicine Post-MI Findings
O’Donoghue: Turning now to the findings regarding colchicine, there has been considerable interest, yet its routine use remains contentious across several regions worldwide. Recent trials suggest clinical benefits associated with colchicine in managing coronary artery disease (CAD), specifically in the post-MI population.
Jolly: Our on-treatment analysis revealed a striking hazard ratio of nearly 1—indicating no significant clinical benefit. I’ve ceased prescribing colchicine as the data evidenced that its impact on patient outcomes was neutral.
O’Donoghue: You noted that you observed no correlation between colchicine and ischemia-driven revascularization in your results, which is pertinent given the speculation surrounding its role in restenosis management.
Jolly: Our findings confirmed that colchicine did not yield favorable outcomes regarding subsequent revascularization events.
O’Donoghue: An interesting aspect to explore would be whether patients exhibiting higher degrees of baseline inflammation could benefit from colchicine treatment. Although a reduction in hs-CRP was observed, patients were not selected based on having elevated hs-CRP levels.
Jolly: In the LoDoCo2 trial, notably, hs-CRP measurements were quite low, making further investigation essential. Testing colchicine in this specific inflammatory context may yield further insights.
Is the Anti-inflammatory Hypothesis Dead?
Jolly: The narrative surrounding inflammation may not imply a universal approach to targeting it. Trials involving agents such as methotrexate showed no efficacy, while canakinumab demonstrated only modest effects with certain risks attached. The ongoing evaluation of IL-6 inhibitors presents an intriguing area for future research.
We must focus on identifying precise targets within the inflammation pathway and conduct further trials to better understand their implications. When posed with whether the inflammatory hypothesis is indeed “dead,” I would firmly argue that is far from the truth. We have established that inflammation is a vital predictor of outcomes, yet we still lack clarity regarding whether targeted manipulation of inflammation will lead to improvement.
Thank you again for your insights into this compelling subject. We look forward to observing how these findings will influence upcoming clinical guidelines.
Jolly: Presenting here holds special significance for me, especially following the recent loss of my father, a dedicated cardiologist in Winnipeg for 25 years. He would have been immensely proud.
O’Donoghue: Thank you for sharing that touching sentiment. Signing off for Medscape, this is Dr. Michelle O’Donoghue bringing you this timely and informative discussion.
Michelle O’Donoghue is a cardiologist at Brigham and Women’s Hospital and senior investigator with the TIMI Study Group. A strong believer in evidence-based medicine, she relishes discussions about the published literature. A native Canadian, Michelle loves spending time outdoors with her family but admits with shame that she’s never strapped on hockey skates.
The Heart of the Matter: Analyzing the CLEAR SYNERGY Trial with Dr. Sanjit Jolly
By the moonlit charisma of Jimmy Carr, the peculiar antics of Rowan Atkinson, the sardonic wit of Ricky Gervais, and the energetic charm of Lee Evans.
Gather ’round, fellow denizens of the digital realm, as we embark on a heart-stopping journey—pun intended—through the recent trials and tribulations presented at the American Heart Association Scientific Sessions. Today, we dish out the juicy findings from the CLEAR SYNERGY trial led by the esteemed Dr. Sanjit Jolly, interventional cardiologist and resident data magician from McMaster University. Buckle up; it’s about to get real, real fast.
Spirited Discussions on Spironolactone
So, what’s the buzz about spironolactone? Dr. Jolly set forth on a quest not just for the faint of heart but for those currently beating the odds in the realm of acute myocardial infarction (MI). Historically, we’ve dished out spironolactone as a life preserver for patients post-MI with heart failure and low ejection fractions. However, in this glorious trial of 7062 souls across 14 nations (yes, we’ve taken a global approach), the aim was to see if we could cast a wider net.
The bottom line? Major bummer alert: the data came back telling us to pump the brakes. The co-primary endpoints for cardiovascular death and new or worsening heart failure didn’t budge. The hazard ratio was 0.89—like being told you’re just slightly underwhelming at a party. And let’s not even get started on the gynecomastia numbers—2% to 3% of the spironolactone group. Gentlemen, might want to keep an eye on your chests! But hey, it’s still better than appearing on a reality TV show.
The Colchicine Conundrum
Now, let’s turn our gaze to the notorious colchicine, the inexplicable pharmacological cocktail that people keep trying to shove down our throats like overripe fruit in a summer picnic. Dr. O’Donoghue pointed out that while there’s a frenzy of evidence supporting colchicine in coronary artery disease (CAD), its post-MI usage is still hotly debated.
But alas, after our beloved Dr. Jolly assessed over 600 outcomes, it turns out colchicine didn’t deliver a love letter to patients either. An on-treatment analysis rendered a sobering hazard ratio hovering nearly at 1, leaving many physicians—including a few whose names I couldn’t mention for legal reasons—quitting on colchicine faster than I could quit making New Year’s resolutions.
The Great Debate: Anti-inflammatory Hypothesis
As Dr. Jolly mused about inflammation, it’s clear we need to stop expecting a magic bullet to solve all our woes. While the inflammatory hypothesis is clinging on tighter than a toddler with their favorite toy, targeted approaches may require a new angle. Why? Because throwing a bunch of medications at inflammation is like throwing spaghetti at the wall to see what sticks—inefficient, and quite messy!
With no clear victory in the colchicine corner and spironolactone’s results appearing flat as a deflated balloon at a kid’s birthday party, we are left pondering: What is the future of treating post-MI patients? Are we even looking in the right direction?
Conclusion: Guidelines in Flux
As Dr. Jolly eloquently noted—the real challenge lies in translating research into practice. So even if we unearthed nuggets of wisdom, such as the low uptake of mineralocorticoid receptor antagonists (MRAs) post-MI, the question remains: are we ready to embrace change? Spoiler: not quite yet.
At the end of the day, one thing’s for sure: the heart will keep beating, whether we prescribe spironolactone, colchicine, or just a good old-fashioned dose of common sense. The guidelines will surely evolve, perhaps even to suggest treating older patients with the gentlest of approaches, while the rest of us would do well to just listen to our hearts—and maybe leave the clinical protocol critiques to the experts!
Signing off with a mix of cheek, charm, and a dash of heart-smart humor, I urge you all to keep your ear to the ground—or is it your heart to the beat? Either way, until next time!
Keep your hearts healthy, and your humor sharper!
How do hs-CRP measurements influence the interpretation of trial outcomes related to anti-inflammatory treatments in patients with cardiovascular conditions?
With the specter of efficacy lurking in the shadows, the results indicated that colchicine wasn’t the miracle anti-inflammatory that many had wished for. To make matters spicy, a lack of correlation with ischemia-driven revascularization kept the flames of controversy flickering. As Dr. O’Donoghue noted, exploring whether patients with heightened baseline inflammation might receive a flicker of benefit could be the next logical step. However, just because you have the right ingredients doesn’t always mean you’ll bake the perfect cake—especially when the availability of hs-CRP measurements skewed previously hopeful outcomes.
Is the Anti-inflammatory Hypothesis Toast?
And now, dear readers, we arrive at a pivotal question: is the anti-inflammatory hypothesis truly in its coffin? Dr. Jolly emphasized that inflammation remains a crucial player in cardiovascular outcomes, despite the lackluster results seen with agents such as methotrexate and the mixed bag that is canakinumab. Rather than sweeping the concept under the rug, he advocates for targeted investigations as the key to unlocking the enigma of inflammation’s role in heart disease.
Closure with a Personal Touch
Before wrapping this discussion in a neat bow, Dr. Jolly shared a poignant moment that resonated deep within the auditorium, reflecting on the recent loss of his father, a cardiologist himself. It was a heartfelt reminder of the human side of medicine—the blend of grief, passion, and the relentless pursuit of knowledge that keeps the wheels of cardiovascular research turning.
As the session wound down, Dr. O’Donoghue closed her remarks, thanking Dr. Jolly for his insights and emphasizing the importance of evolving clinical guidelines based on robust data. With many questions still unanswered and new avenues for exploration emerging from the trials, the discussion leaves us eager for what lies ahead in the world of cardiovascular science.
Stay tuned as we continue to unravel the complexities of heart health, invite diverse perspectives, and foster a community driven by a shared passion for evidence-based practice. Until next time, remember: every beat counts!
