AHA Scientific Sessions 2020
The American Heart Association Scientific Sessions 2020 were presented in a virtual format November 13-17, 2020.
- SGLT2 inhibition may have favorable effects on heart failure independent of glycemic control
- Dual imaging identifies cause of MINOCA in more than 80% of women
- ‘Nocebo’ effect explains 90% of symptoms in patients who quit statins because of side effects
- Novel treatments deliver positive results for populations with substantial cardiovascular morbidity and mortality
- Rate of CV complications substantial, but lower than expected in hospitalized COVID-19 patients
- Spectrum of cardiovascular toxicities with immunotherapy for cancer is wide
SGLT2 inhibition may have favorable effects on heart failure independent of glycemic control
Presenter: Juan J. Badimon, PhD
In patients with stable heart failure with reduced ejection fraction (HFrEF) without a diagnosis of diabetes, the sodium-glucose cotransporter 2 (SGLT2) inhibitor improved indices of cardiac remodeling compared with placebo.
Results from the EMPA-TROPISM trial—Are the "Cardiac Benefits" of Empagliflozin Independent of Its Hypoglycemic Activity? (NCT03485222)—demonstrated benefits of empagliflozin on cardiac volume, mass, function, and architecture and a significant improvement in cardiopulmonary capacity in this patient population, reported Juan J. Badimon, PhD, director of the Atherothrombosis Research Unit at the Icahn School of Medicine at Mount Sinai, New York City.
“Our data suggest that specific inhibition of the SGLT receptor could be a new therapeutic strategy for the treatment of HFrEF independently of the glycemic status,” he said.
In previous trials of patients with type 2 diabetes, SGLT2 inhibitors improved cardiovascular and renal outcomes, including heart failure hospitalizations, evidence of the presence of a class effect. Whether these improvements would extend to patients with HFrEF without diabetes formed the rationale of the single-center EMPA-TROPISM trial. A total of 84 patients with New York Heart Association class II to III heart failure and a left ventricular (LV) ejection fraction less than 50% and who had stable symptoms and were on therapy for heart failure within the previous 3 months were randomized in double-blind fashion to 6 months of empagliflozin 10 mg/day or placebo.
Mean age of participants was 61.9, 36% were women, and 50% were of Hispanic/Latino ethnicity; 76% of patients were on a statin, 85% on an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, 89% on a beta blocker, 54% on a loop diuretic, 66% on an antiplatelet agent, and 41% on an angiotensin receptor neprilysin inhibitor. The mean LVEF was 36.5%.
Two patients in each arm were lost to follow-up, leaving 40 in each arm for analysis.
The change in left ventricular end-systolic volume from baseline to 6 months, a coprimary end point, was -26.6 mL in the empagliflozin arm compared with -0.54 mL in the placebo arm (P < .001). The change in LV end-diastolic volume, the other co-primary end point, was 25.1 mL in those randomized to empagliflozin vs -1.5 in the patients randomized to placebo (P < .001).
Secondary outcomes also favored empagliflozin. From baseline to 6 months, the change in LV ejection fraction was -6.0% in the empagliflozin group vs -0.1% in the placebo group (P < .001), the change in LV mass was -17.8 g/m2 in the empagliflozin group vs 4.1 g/m2 in the placebo group (P < .001), the change in peak oxygen uptake was 1.1 mL/kg/min in the empagliflozin arm vs -0.5 mL/kg/min in the placebo arm (P = .017), and the change in the 6-minute walk test was 82 m in the empagliflozin arm vs -35 m in the placebo arm (P < .001).
“Therefore, with all of these changes, we should not be surprised when the patient-reported quality of life was significantly improved in the empagliflozin group compared with the placebo group,” said Dr. Badimon. The score on the Kansas City Cardiomyopathy Questionnaire improved from baseline by 37% in the empagliflozin arm compared with 5% in the placebo arm.
Dr. Badimon has disclosed no relevant relationships.
Dual imaging identifies cause of MINOCA in more than 80% of women
Presenters: Harmony Reynolds, MD, Martha Gulati, MD and Donald Lloyd Jones, MD, ScM
The underlying cause of myocardial infarction (MI) with nonobstructive coronary arteries (MINOCA) can be determined in more than 80% of women using a multimodal imaging strategy consisting of coronary optical coherence tomography (OCT) and cardiac magnetic resonance imaging (MRI), according to findings from the Women’s Heart Attack Research Program (HARP),1 an international multicenter study investigating the causes of MI in women referred for cardiac catheterization.
Up to 15% of MIs in women are classified as MINOCA, defined as symptoms compatible with a diagnosis of MI and stenosis less than 50% in all major epicardial arteries on coronary angiography, with no specific alternate diagnosis for the clinical presentation. The pathogenesis is varied and has led to uncertainty in treatment, said Harmony Reynolds, MD, associate professor of medicine, New York University Grossman School of Medicine, New York City, who presented the research.
“OCT and cardiac MRI provided useful diagnostic information independently and in combination,” she said. “Mechanisms of MINOCA in women were often similar to mechanisms of MI with obstructive coronary disease, namely atherothrombosis, with the possible contribution of coronary artery spasm.”
HARP enrolled 301 women with objective evidence of MI (elevation of troponin to above the laboratory upper limit of normal, with or without ST-segment elevation ≥ 1mm on 2 contiguous electrocardiographic leads) who were referred for cardiac catheterization with intent to perform revascularization. Patients with stenosis of at least 50% or angiographic evidence of coronary atherosclerosis were not eligible. Those eligible had coronary OCT targeting all 3 coronary vessels and cardiac MRI within 1 week of referral. MINOCA was diagnosed in 170 women, of whom 23 had contraindications to OCT and 2 had images that were not interpretable, leaving a sample of 145 women who had coronary OCT and 116 who had cardiac MRI.
The median age of the sample was 60, and 50% had a race or ethnicity other than White non-Hispanic. Median peak troponin level was 0.94 ng/mL. The presentation was ST-segment elevation in 3.5%, 44% had segmental wall abnormality on echocardiography, and 54% had a coronary angiogram reported as normal. The median maximal stenosis by core laboratory was 30%.
A culprit lesion was found by coronary OCT in 46% of women, most represented by atherosclerosis and thrombosis; 6% were found to have plaque rupture, 3% had thrombus without plaque rupture, 21% had intraplaque cavity, and 13% had layered plaque. There were no major complications of OCT, but transient spasm occurred in 46 women.
On multivariable analysis, having an OCT culprit lesion was associated with older age, abnormal angiography at the site, and diabetes, but not with the peak troponin level or with angiographic stenosis severity according to the core laboratory.
Cardiac MRI revealed an ischemic pattern of late gadolinium enhancement in 33%, indicative of infarction, and 95% of these had associated myocardial edema consistent with an acute infarction. Some 21% had a regional pattern of injury that represented ischemic injury, and 21% had a nonischemic appearance that led to an alternate diagnosis. On multivariable analysis, abnormal cardiac MRI was associated with higher levels of peak troponin, creatinine, and diastolic blood pressure, but not with OCT culprit lesion or severity of angiographic stenosis. There was no troponin threshold below which abnormal cardiac MRI was likely.
“Cardiac MRI findings correlated well with OCT culprit lesions, demonstrating that nonobstructive culprit lesions frequently cause MINOCA,” said Dr. Reynolds.
With an OCT culprit lesion, cardiac MRI evidence of infarction or regional ischemic injury was present in 75%. “Looking at it the other way, when there were ischemic cardiac MRI findings, 44% of the women had no OCT culprit, and we suspect in those MI cases that there may have been coronary artery spasm, thromboembolism, or perhaps a missed culprit lesion,” she said.
In the 116 patients who had both coronary OCT and cardiac MRI, 85% of MINOCA had a cause identified: MI was the cause in 64%, myocarditis in 15%, takotsubo syndrome in 3%, and nonischemic cardiomyopathy in 3%. By comparison, a cause was identified only 46% of the time with OCT alone (P < .001 vs multimodal imaging) and 75% with cardiac MRI alone (P < .001 vs multimodal imaging).
“OCT and cardiac MRI together provided strong scientific support for the hypothesis that plaque rupture can cause heart attack even in plaques that don’t block the artery badly, and this is the major scientific contribution of this study, building on the prior literature,” Dr. Reynolds said.
Martha Gulati, MD, chief of cardiology, University of Arizona, Phoenix, and president-elect of the American Society for Preventive Cardiology, provided commentary. “I think this is the direction we need to go. [Both imaging modalities] provide important information, and understanding the pathophysiology is important for us to care for these patients,” as each underlying cause may have its own potential treatment, she said. “It’s time for us to do the trials to figure out, for each of these cases, what is the optimal therapy.”
One limitation of the study is that very few patients with ST-elevation MI were included, and whether the mechanism for ST-elevation MI MINOCA is different isn’t known, said Dr. Gulati. In addition, only 59% had OCT of all 3 vessels, raising the possibility that some diagnoses were missed. Finally, sex differences cannot be determined because men were excluded.
“It’s a game-changer kind of study,” said Donald Lloyd Jones, MD, ScM, chair of the Committee on Scientific Sessions Program. “The take-home message for me: about three-quarters of this is good old-fashioned atherosclerosis, presenting a little bit differently than it does in men, but it’s still atherosclerosis [ie, plaque erosion, plaques with thrombus], so we have to treat these women as if they’ve got atherosclerosis. They should go home on aspirin, maybe on short-term dual antiplatelet therapy, certainly on a statin, unless we can show that it really is myocarditis on the cardiac MRI, or takutsubo, or something clearly not coronary disease.”
Reference
1. Reynolds HR, Maehara A, Kwong RY. Coronary optical coherence tomography and cardiac magnetic resonance imaging to determine underlying causes of MINOCA in women. Circulation 2020 November 14. doi:10.1161/CIRCULATIONAHA.120.052008
The presenters have disclosed no relevant relationships.
‘Nocebo’ effect explains 90% of symptoms in patients who quit statins because of side effects
Presenters: James Philip Howard, PhD, MB and Francine K. Welty, MD, PhD
An “n-of-1” study of patients who discontinued statin therapy because of side effects reveals similar intensity of symptoms between placebo and atorvastatin, both of which were significantly greater than symptom severity experienced during a no-tablet period. The findings from the Self-Assessment Method for Statin Side-effects Or Nocebo study (SAMSON) demonstrate a significant nocebo effect that, when explained to patients, enabled half of them to successfully restart a statin.1
Many people who start statins abandon them, yet placebo-controlled trials do not show excess withdrawals in the statin arms, said presenter James Philip Howard, PhD, MB, fellow at Imperial College in London, UK.
“SAMSON certainly leaves no doubt that patients really do get side effects from statin tablets, but what SAMSON shows us is that 90% of their symptomatic burden is elicited by placebo tablets, too,” he said. “Because this trial design has built in no-tablet periods, participants could see as clearly as we could the surprisingly powerful magnitude of the ‘nocebo’ effect, and this led to half of our patients happily restarting statins.”
SAMSON enrolled 60 patients who discontinued statins because of any intolerable side effect that arose within 2 weeks of initiation. Patients were given four 1-month medication bottles containing atorvastatin 20 mg, four containing placebo, and four containing nothing (empty). These were taken in a specified randomized order, 1 per month, over 1 year. There was no washout period between arms. A smartphone was used to rate symptom severity daily on a scale of 1 to 100: if symptoms became intolerable, the tablets could be stopped for that month.
The mean age of participants was 65, and 77% were taking statins for primary prevention. Participants tried a median of 2 statins before abandoning treatment. Muscle aches were the reason for abandoning statin treatment in 65% of cases.
There were 71 stoppages of tablets, 31 while on placebo (median days to stop, 18) and 40 while on atorvastatin (median days to stop, 17).
The mean symptom intensity was 8.0 during no-tablet months, 15.4 during placebo months (P < .001 vs no-tablet months), and 16.3 during statin months (P < .001 vs no-tablet months; P < .388 vs placebo months). The nocebo proportion (the ratio between incremental symptom severity while taking a placebo and the incremental symptom severity) was 0.9.
Of the 60 participants, 59 responded to a follow-up questionnaire at 6 months, at which time 30 of the 60 resumed taking a statin, 4 had planned to do so, and 1 was not able to be contacted, leaving 25 who did not plan to restart, 18 of whom stated side effects as the reason.
“The most important message from SAMSON is that side effects from statin tablets are very real, but they are mainly caused by the act of taking the tablets, not by the statin that is contained within them,” said Dr. Howard.
In practice, many patients develop symptoms later than 2 weeks, so these findings cannot be generalized to them, and limiting enrollment to those who developed symptoms within 2 weeks of starting a statin could have biased the findings toward a nocebo effect, said discussant Francine K. Welty, MD, PhD, associate professor of medicine, Harvard Medical School, Boston.
Because statin stoppage increases the risks of stroke, myocardial infarction, and total mortality, management of side effects to permit treatment persistence is important, she said. Supplementing patients with vitamin D whose vitamin D level is below 30 ng/mL has been shown to improve statin tolerance.2
The Cleveland Clinic experience supports alternate dosing (ie, 2 to 3 times per week), she noted.3 In patients treated with alternate dosing, total mortality was 2% at 8 years, and similar to daily dosing, compared with 7% in those who discontinued statins (P = .08).
“In those who awaken at night with cramps, try morning dosing, because the cramps may occur during the day and may be less likely to affect lifestyle,” said Dr. Welty.
References
1. https://eventpilotadmin.com/web/page.php?page=IntHtml&project=AHA20&id=2195
2. Saxon DR, Eckel RH. Statin intolerance: a literature review and management strategies. Prog Cardiovasc Dis 2016; 59(2):153–164. doi:10.1016/j.pcad.2016.07.009
3. Mampuya WM, Frid D, Rocco M, et al. Treatment strategies in patients with statin intolerance: the Cleveland Clinic Experience. Am Heart J 2013; 166(3):597–603. doi:10.1016/j.ahj.2013.06.004
Dr. Howard has disclosed no relevant relationships. Dr. Welty has disclosed financial interests (grant, research support, advisor, or review panel member) with Boehringer Ingelheim.
Novel treatments deliver positive results for populations with substantial cardiovascular morbidity and mortality
Presenters: Gerasimos Filippatos, MD and Robert Rosenson, MD
In separate clinical trials, investigational therapies for the treatment of patients with chronic kidney disease (CKD) and type 2 diabetes mellitus and patients with refractory hypercholesterolemia showed the potential to reduce cardiovascular risk in these populations.
Finerenone, a nonsteroidal selective mineralocorticoid receptor antagonist that inhibits inflammation and fibrosis, reduced the risk of a composite cardiovascular outcome irrespective of a history of cardiovascular disease, with a low incidence of hyperkalemia-related treatment discontinuation, in patients with CKD and type 2 diabetes in the phase III clinical trial Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease (FIDELIO-DKD),1 announced Gerasimos Filippatos, MD, professor of cardiology, the National and Kapodistrian University of Athens, Greece.
“In patients with CKD and type 2 diabetes treated with optimized renin-angiotensin system therapy, finerenone significantly reduced the overall risk of cardiovascular events by 14% compared with placebo, and we found this effect to be similar between patients with a history of cardiovascular disease and those without, demonstrating the benefit of finerenone for both primary and secondary cardiovascular prevention,” he said.
In FIDELIO-DKD, conducted at 913 sites in 48 countries, 5,734 patients with type 2 diabetes, moderately or severely elevated levels of albumin, and an estimated glomerular filtration rate (eGFR) ≥ 25 to < 75 mL/min/1.73 m2 were randomized to finerenone at titrated dosages of 10 or 20 mg once daily or placebo. All patients were on maximally tolerated doses of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker for at least 4 weeks prior to randomization; 45.9% of patients had a history of cardiovascular disease at entry.
As reported previously, the primary outcome, a composite of kidney failure, a sustained decrease of at least 40% in the eGFR from baseline, or death from renal causes, occurred in 17.8% of the finerenone group and in 21.1% of the placebo group over a median of 2.6 years of follow-up, corresponding to an 18% relative risk reduction (hazard ratio [HR] 0.82; P = .001).2
A key secondary end point, a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure, was reduced by 14% (HR 0.86; P = .034) in the finerenone arm compared with placebo. The relative reduction in the risk of a composite outcome event with finerenone was 15% (HR, 0.85; 95% confidence interval 0.71–1.02) in patients with a history of cardiovascular disease, similar to the 14% reduction (HR, 0.86; 95% confidence interval 0.68–1.08) in those without a history of cardiovascular disease (P for interaction = .85).1
Overall, the rates of treatment-emergent adverse events were similar between the two arms, with a manageable increase in the rate of hyperkalemia in the finerenone arm. The mean increase in serum potassium was 0.2 mEq/L in the active-treatment arm vs placebo. Any hyperkalemia occurred in 18.3% of patients randomized to finerenone and in 9.0% of those randomized to placebo, and the incidence of hyperkalemia leading to permanent discontinuation was 2.3% and 0.9%, respectively.
Additional phase III trials of finerenone are in progress.
In a second study, evinacumab, an investigational fully human monoclonal antibody inhibitor of angiopoietin-like 3, significantly reduced levels of low-density lipoprotein cholesterol (LDL-C) vs placebo when administered subcutaneously or intravenously to patients with refractory primary hypercholesterolemia.3
“The addition of evinacumab to standard-of-care lipid-lowering therapy in patients with refractory hypercholesterolemia may potentially facilitate more patients attaining guideline-defined LDL-C goals and in doing so, the potential to reduce the risk of cardiovascular disease events and overall mortality,” said lead investigator Robert Rosenson, MD, professor of medicine, Mount Sinai Icahn School of Medicine, New York City.
Eligible patients for the phase II study were those with a diagnosis of primary hypercholesterolemia. Heterozygous familial hypercholesterolemia was diagnosed by genotyping or by clinical diagnosis and represented 72.5% of participants in the study of subcutaneous evinacumab and 81.1% of those in the study of the intravenous form. All participants had LDL-C levels at least 70 mg/dL if they had cardiovascular disease or at least 100 mg/dL if they did not have cardiovascular disease.
At the screening visit, patients had to be receiving a stable maximally tolerated dose of a statin, with or without ezetimibe, for at least 4 weeks, and all had to be receiving a proprotein convertase subtilisin/kexin type 9 inhibitor for at least 8 weeks.
In the study of the subcutaneous regimen (n = 160), patients were randomized 1:1:1:1 to placebo or evinacumab 450 mg every week, 300 mg every week, 300 mg every 2 weeks. The mean baseline LDL-C in this group was 150.0 mg/dL. The reductions in LDL-C from baseline to week 16 in the evinacumab arms compared with placebo were 56.0% with 450 mg weekly (P < .0001), 44.0% with 300 mg weekly (P < .0001), and 29.7% with 300 mg every 2 weeks (P < .0001).
In the study of the intravenous regimen (n = 106), patients were randomized 1:1:1 to placebo or evinacumab 5 or 15 mg/kg every 4 weeks. The mean baseline LDL-C in this study was 144.5 mg/dL. Reductions in LDL-C from baseline to week 16 in the evinacumab arms compared with placebo were 50.5% in the 15-mg/kg arm (P < .0001) and 24.2% in the 5-mg/kg arm (P = .0109).
There were favorable changes in other atherogenic lipoproteins with both subcutaneous and intravenous evinacumab compared with placebo.
References
1. https://www.abstractsonline.com/pp8/?#!/9144/presentation/40168
2. Bakris GL, Agarwal R, Anker SD, et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med, October 23, 2020. doi:10.1056/NEJMoa2025845
3. https://www.abstractsonline.com/pp8/?#!/9144/presentation/40160
Dr. Filippatos has disclosed financial relationships (grant, research support, advisor, or review panel member) with Bayer, Vifor, Medtronic, Boehringer Ingelheim, Novartis, and Sanofi. Dr. Rosenson has disclosed the following: honoraria from 89Bio, Amgen, Corvidia, CVS Caremark, Kowa, Medicines Company, Regeneron, and UpToDate; stock shareholder with MediMergent; research grants with Amgen, Medicines Company, Regeneron, and Novartis (all paid to institution).
Rate of CV complications substantial, but lower than expected in hospitalized COVID-19 patients
Presenters: James A. De Lemos, MD and Fatima Rodgriguez, MD, MPH
While cardiovascular (CV) complications are an important problem in patients hospitalized with COVID-19, they are less common than initially feared, according to data from the American Heart Association national COVID-19 Disease Registry.
As of November 9, 2020, the registry includes 22,500 patient records from 109 US hospitals and medical centers.
But although the number of patients with in-hospital CV complications is lower than expected, given the scale of the pandemic and with almost 70,000 patients currently hospitalized in the United States, the aggregate number of cardiac complications remains substantial and vigilance is needed, according to presenter James A. de Lemos, MD, professor of medicine, the University of Texas Southwestern Medical Center, Dallas.
Data entered into the registry from 8,000 patient records collected between January 1 and July 22, 2020, showed an 8.8% occurrence of a composite of in-hospital cardiac complications that included CV death, myocardial infarction, stroke, heart failure, and cardiogenic shock.1
“COVID-19 admissions have a high prevalence of cardiac risk factors and a moderately high prevalence of prior CV disease diagnoses,” said Dr. De Lemos. “More than 20% of patients hospitalized required mechanical ventilation, and 20% died or were referred for hospice.” The dominant cause of these complications are related to acute respiratory distress syndrome and high rates of respiratory mortality, he added.
The most common in-hospital CV complication was atrial fibrillation, in 8% of patients. Rates of other complications were approximately 3% for myocardial infarction; 3.8% for deep vein thrombosis or pulmonary embolism; less than 2% for new heart failure, stroke, or cardiogenic or mixed shock; and 0.3% for myocarditis.
“The vast majority of individuals hospitalized with COVID-19 have risk factors for CV disease,” he said. “Fewer than 15% had none of the traditional risk factors.”
Through September 30, 2020, in 14,889 registry patients, CV risk factors present were hypertension in almost 60%, diabetes in 35%, obesity (body mass index [BMI] > 30 kg/m2) in 45%, and hyperlipidemia in 35%. The prevalence of various forms of CV disease at hospitalization was 5% for myocardial infarction, stroke in more than 10%, heart failure in more than 10%, atrial fibrillation in 8%, and chronic kidney disease in 13%. About 4% entered having already undergone percutaneous coronary intervention or coronary artery bypass grafting.
Death through the end of September 2020 occurred in 16.7% of hospitalizations, with another 2.8% referred for hospice; 72% of deaths were due to respiratory causes, while 10% could be attributed to cardiac disease.
The registry also revealed a higher risk of hospitalization in obese patients and minorities. Almost half (43%) of the registry patients were obese or severely obese, as determined from the 7,606 patients with BMI data available, compared with 34% of adults according to the National Health and Nutrition Examination Survey.2 Compared with their non-obese peers, severely obese patients (BMI > 40 kg/m2) patients were an average of 18 years younger and were more likely to be Black. They also had about a 30% higher relative risk of in-hospital death.
Based on 7,868 patients with race or ethnicity data to July 22, 2020, one-third (33.0%) of hospitalized COVID-19 patients were Hispanic, 25.5% were non-Hispanic Black, 6.3% were Asian, and 35.2% were non-Hispanic White. By comparison, census data show that Blacks represent 10.6% of the US population and Hispanics 9.0%.3
“Overall, there were no major racial or ethnic differences in mortality,” reported Fatima Rodriguez, MD, MPH, assistant professor of cardiovascular medicine, Stanford University, Stanford, CA. “Over 50% of all deaths occurred among Black or Hispanic patients.”
In fully adjusted models, no differences in mortality or major adverse cardiac events were observed for Black, Hispanics, and Asian patients compared with non-Hispanic Whites, although Asians had higher COVID-19 disease severity at presentation.
References
1. https://eventpilotadmin.com/web/page.php?page=IntHtml&project=AHA20&id=2291
2. Hendren NS, De Lemos JA, Ayers C, et al. Association of body mass index and age with morbidity and mortality in patients hospitalized with COVID-19: results from the American Heart Association COVID-19 Cardiovascular Disease Registry. doi:10.1161/CIRCULATIONAHA.120.051936
3. Rodriguez F, Solomon N, de Lemos JA, et al. Racial and ethnic differences in presentation and outcomes for patients hospitalized with COVID-19: findings from the American Heart Association's COVID-19 Cardiovascular Disease Registry. doi:10.1161/CIRCULATIONAHA.120.052278
Dr. De Lemos has disclosed the following: honoraria from Amgen, Regeneron, Novo Nordisc, Janssen, Quidel Cardiovascular, Eli Lilly, Ortho Clinical Diagnostics, and Siemen's Diagnostic, and research grants from Roche Diagnostics and Abbott Diagnostics. Dr. Rodriguez has disclosed relevant relationships (grant, research support, advisor, or review panel member) with HealthPals, NovoNordisk, Janssen , and The Medicines Company.
Spectrum of cardiovascular toxicities with immunotherapy for cancer is wide
Presenter: Han Zhu, MD
As the use of immunotherapy to treat cancer surges, clinicians must be aware of the risk of serious adverse cardiovascular effects such as myocarditis, arrhythmias, and atherosclerotic events. The rate of immune-related adverse events from the use of immune checkpoint inhibitor (ICI) therapy is 17% to 33% as single agents, increasing to as high as 50% when used in combination.
These effects can be extremely difficult to treat, even after discontinuation of therapy. “Although the recorded incidence of immunotherapy-induced myocarditis is rare at less than 1%, it can be quite serious, with up to a 50% mortality rate,” said Dr. Han Zhu, instructor of medicine, Stanford University School of Medicine, Stanford, CA.
Since the initial report of autopsy findings suggesting acute lymphocytic myocarditis in 2 patients treated with immunotherapy, “a wide spectrum of other ICI-associated cardiotoxicities have been characterized, including conduction disease ranging from atrial to ventricular tachyarrhythmias, as well as bradyarrhythmia, heart block, vasculitis, and pericardial disease, in addition to myocarditis,” she said.
Earlier this year, in a matched-cohort study, investigators at Harvard Medical School, Boston, MA, found a threefold increased incidence of cardiovascular events in patients after starting treatment with an ICI (hazard ratio 3.3; P < .001); and in their case-crossover analysis, the rate of cardiovascular events increased from 1.37 to 6.55 per 100 person-years at 2 years (adjusted hazard ratio 4.8; P < .001). Imaging study showed an increase in the rate of progression of total aortic plaque volume.1
The potentially fatal nature of ICI-associated cardiotoxicity and its often late presentation has prompted investigation of the potential utility of biomarker screening in early identification of cardiotoxicity. Sarocchi et al found one case of subclinical myocarditis among 59 patients with non-small-cell lung cancer who underwent serial measurement of troponin levels.2 Investigators at Memorial Sloan Kettering Cancer Center described their experience with myocarditis surveillance through the use of serial screening of troponin in 76 asymptomatic patients with advanced melanoma who were being treated with a combination of ICIs, none of whom developed myocarditis.3
Stanford has developed its own monitoring algorithm for patients receiving single-agent and dual-agent immunotherapy. High-sensitivity troponin measures are performed at every dose of immunotherapy for up to 10 cycles, based on a median time to immune event of 2.5 to 8.6 weeks, as reported by the VigiBase study authors.4
“Importantly, we have a cardio-oncology rapid troponin response team consisting of a cardiologist, myself, a medicine resident, and an oncologist to triage positive troponins that could be due to other causes, such as supply-demand mismatch and the patient’s underlying complex medical disease,” said Dr. Zhu. “As such, we actually have caught some cases of smoldering myocarditis with this algorithm.”
ICIs activate T cells, so treatment of myocarditis is targeted toward immunosuppression. Corticosteroids remain the first line of therapy, although they suppress the immune system nonspecifically and therefore lead to side effects, said Dr. Zhu. Second-line agents are targeted towards T cells and include tacrolimus, mycophenolate mofetil, antithymocyte globulin, and infliximab, and others are under study, notably abatacept, which blocks CD80 and CD86 on antigen-presenting cells.
References
1. Drobni ZD, Alvi RM, Taron J, et al. Association between immune checkpoint inhibitors with cardiovascular events and atherosclerotic plaque. Circulation 2020 Oct 2. doi:10.1161/CIRCULATIONAHA.120.049981. Published online ahead of print.
2. Sarocchi M, Grossi F, Arboscello E, et al. Serial troponin for early detection of nivolumab cardiotoxicity in advanced non-small cell lung cancer patients. Oncologist 2018; 23(8):936–942.
3. Lee Chuy K, Oikonomou EK, Postow MA, et al. Myocarditis surveillance in patients with advanced melanoma on combination immune checkpoint inhibitor therapy: the Memorial Sloan Kettering Cancer Center experience. Oncologist 2019; 24:e196–197. doi:10.1634/theoncologist.2019-0040
4. Salem JE, Manouchehri A, Moey M, et al. Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. Lancet Oncol 2018; 19(12):1579–1589. doi:10.1016/S1470-2045(18)30608-9
Dr. Zhu has disclosed no relevant relationships.