Cardiovascular Drug Interactions With Nirmatrelvir/Ritonavir in Patients With COVID-19: JACC Review Topic of the Week.

Nirmatrelvir-ritonavir (NMVr) is used to treat symptomatic, nonhospitalized patients with coronavirus disease-2019 (COVID-19) who are at high risk of progression to severe disease. Patients with cardiovascular risk factors and cardiovascular disease are at a high risk of developing adverse events from COVID-19 and as a result have a higher likelihood of receiving NMVr. Ritonavir, the pharmaceutical enhancer used in NMVr, is an inhibitor of the enzymes of CYP450 pathway, particularly CYP3A4 and to a lesser degree CYP2D6, and affects the P-glycoprotein pump. Co-administration of NMVr with medications commonly used to manage cardiovascular conditions can potentially cause significant drug-drug interactions and may lead to severe adverse effects. It is crucial to be aware of such interactions and take appropriate measures to avoid them. In this review, we discuss potential drug-drug interactions between NMVr and commonly used cardiovascular medications based on their pharmacokinetics and pharmacodynamic properties.

Impact of cancer and cardiovascular disease on in-hospital outcomes of COVID-19 patients: results from the american heart association COVID-19 cardiovascular disease registry.

BACKGROUND: While pre-existing cardiovascular disease (CVD) appears to be associated with poor outcomes in patients with Coronavirus Disease 2019 (COVID-19), data on patients with CVD and concomitant cancer is limited. The purpose of this study is to evaluate the effect of underlying CVD and CVD risk factors with cancer history on in-hospital mortality in those with COVID-19. METHODS: Data from symptomatic adults hospitalized with COVID-19 at 86 hospitals in the US enrolled in the American Heart Association's COVID-19 CVD Registry was analyzed. The primary exposure was cancer history. The primary outcome was in-hospital death. Multivariable logistic regression models were adjusted for demographics, CVD risk factors, and CVD. Interaction between history of cancer with concomitant CVD and CVD risk factors were tested. RESULTS: Among 8222 patients, 892 (10.8%) had a history of cancer and 1501 (18.3%) died. Cancer history had significant interaction with CVD risk factors of age, body mass index (BMI), and smoking history, but not underlying CVD itself. History of cancer was significantly associated with increased in-hospital death (among average age and BMI patients, adjusted odds ratio [aOR] = 3.60, 95% confidence interval [CI]: 2.07-6.24; p < 0.0001 in those with a smoking history and aOR = 1.33, 95%CI: 1.01-1.76; p = 0.04 in non-smokers). Among the cancer subgroup, prior use of chemotherapy within 2 weeks of admission was associated with in-hospital death (aOR = 1.72, 95%CI: 1.05-2.80; p = 0.03). Underlying CVD demonstrated a numerical but statistically nonsignificant trend toward increased mortality (aOR = 1.18, 95% CI: 0.99-1.41; p = 0.07). CONCLUSION: Among hospitalized COVID-19 patients, cancer history was a predictor of in-hospital mortality. Notably, among cancer patients, recent use of chemotherapy, but not underlying CVD itself, was associated with worse survival. These findings have important implications in cancer therapy considerations and vaccine distribution in cancer patients with and without underlying CVD and CVD risk factors.

Consensus disease definitions for neurologic immune-related adverse events of immune checkpoint inhibitors.

Expanding the US Food and Drug Administration-approved indications for immune checkpoint inhibitors in patients with cancer has resulted in therapeutic success and immune-related adverse events (irAEs). Neurologic irAEs (irAE-Ns) have an incidence of 1%-12% and a high fatality rate relative to other irAEs. Lack of standardized disease definitions and accurate phenotyping leads to syndrome misclassification and impedes development of evidence-based treatments and translational research. The objective of this study was to develop consensus guidance for an approach to irAE-Ns including disease definitions and severity grading. A working group of four neurologists drafted irAE-N consensus guidance and definitions, which were reviewed by the multidisciplinary Neuro irAE Disease Definition Panel including oncologists and irAE experts. A modified Delphi consensus process was used, with two rounds of anonymous ratings by panelists and two meetings to discuss areas of controversy. Panelists rated content for usability, appropriateness and accuracy on 9-point scales in electronic surveys and provided free text comments. Aggregated survey responses were incorporated into revised definitions. Consensus was based on numeric ratings using the RAND/University of California Los Angeles (UCLA) Appropriateness Method with prespecified definitions. 27 panelists from 15 academic medical centers voted on a total of 53 rating scales (6 general guidance, 24 central and 18 peripheral nervous system disease definition components, 3 severity criteria and 2 clinical trial adjudication statements); of these, 77% (41/53) received first round consensus. After revisions, all items received second round consensus. Consensus definitions were achieved for seven core disorders: irMeningitis, irEncephalitis, irDemyelinating disease, irVasculitis, irNeuropathy, irNeuromuscular junction disorders and irMyopathy. For each disorder, six descriptors of diagnostic components are used: disease subtype, diagnostic certainty, severity, autoantibody association, exacerbation of pre-existing disease or de novo presentation, and presence or absence of concurrent irAE(s). These disease definitions standardize irAE-N classification. Diagnostic certainty is not always directly linked to certainty to treat as an irAE-N (ie, one might treat events in the probable or possible category). Given consensus on accuracy and usability from a representative panel group, we anticipate that the definitions will be used broadly across clinical and research settings.

Impact of Cancer and Cardiovascular Disease on In-Hospital Outcomes of COVID-19 Patients: Results From the American Heart Association COVID-19 Cardiovascular Disease Registry.

Background: While pre-existing cardiovascular disease (CVD) appears to be associated with poor outcomes in patients with Coronavirus Disease 2019 (COVID-19), data on patients with CVD and concomitant cancer is limited. Evaluate the effect of underlying CVD and CVD risk factors with cancer history on in-hospital mortality in those with COVID-19. Methods: Data from symptomatic adults hospitalized with COVID-19 at 86 hospitals in the US enrolled in the American Heart Association’s COVID-19 CVD Registry was analyzed. The primary exposure was cancer history. The primary outcome was in-hospital death. Multivariable logistic regression models were adjusted for demographics, CVD risk factors, and CVD. Interaction between history of cancer with concomitant CVD and CVD risk factors were tested. Results: Among 8222 patients, 892 (10.8%) had a history of cancer and 1501 (18.3%) died. Cancer history had significant interaction with CVD risk factors of age, body mass index (BMI), and smoking history, but not underlying CVD itself. History of cancer was significantly associated with increased in-hospital death (among average age and BMI patients, adjusted odds ratio [aOR]=3.60, 95% confidence interval [CI]: 2.07-6.24; p<0.0001 in those with a smoking history and aOR=1.33, 95%CI: 1.01 - 1.76; p=0.04 in non-smokers). Among the cancer subgroup, prior use of chemotherapy within 2 weeks of admission was associated with in-hospital death (aOR=1.72, 95%CI: 1.05-2.80; p=0.03). Underlying CVD demonstrated a numerical but statistically nonsignificant trend toward increased mortality (aOR=1.18, 95% CI: 0.99 - 1.41; p=0.07). Conclusion: Among hospitalized COVID-19 patients, cancer history was a predictor of in-hospital mortality. Notably, among cancer patients, recent use of chemotherapy, but not underlying CVD itself, was associated with worse survival. These findings have important implications in cancer therapy considerations and vaccine distribution in cancer patients with and without underlying CVD and CVD risk factors.

Immunomodulation as Treatment for Severe Coronavirus Disease 2019: A Systematic Review of Current Modalities and Future Directions.

In severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, viral load peaks early and declines quickly after symptom onset. Severe coronavirus disease 2019 (COVID-19) is marked by aberrant innate and adaptive immune responses with an abnormal cytokine profile and multiorgan system dysfunction that persists well after viral clearance. A purely antiviral treatment strategy may therefore be insufficient, and antiviral agents have not shown a benefit later in the illness course. A number of immunomodulatory strategies are being tested, including corticosteroids, cytokine and anticytokine therapies, small molecule inhibitors, and cellular therapeutics. To date, the only drug to show a mortality benefit for COVID-19 in a randomized, controlled trial is dexamethasone. However, there remains uncertainty about which patients may benefit most and about longer-term complications, including secondary infections. Here, we review the immune dysregulation of severe COVID-19 and the existing data behind various immunomodulatory strategies, and we consider future directions of study.

Efficacy of Tocilizumab in Patients Hospitalized with Covid-19.

BACKGROUND: The efficacy of interleukin-6 receptor blockade in hospitalized patients with coronavirus disease 2019 (Covid-19) who are not receiving mechanical ventilation is unclear. METHODS: We performed a randomized, double-blind, placebo-controlled trial involving patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, hyperinflammatory states, and at least two of the following signs: fever (body temperature >38°C), pulmonary infiltrates, or the need for supplemental oxygen in order to maintain an oxygen saturation greater than 92%. Patients were randomly assigned in a 2:1 ratio to receive standard care plus a single dose of either tocilizumab (8 mg per kilogram of body weight) or placebo. The primary outcome was intubation or death, assessed in a time-to-event analysis. The secondary efficacy outcomes were clinical worsening and discontinuation of supplemental oxygen among patients who had been receiving it at baseline, both assessed in time-to-event analyses. RESULTS: We enrolled 243 patients; 141 (58%) were men, and 102 (42%) were women. The median age was 59.8 years (range, 21.7 to 85.4), and 45% of the patients were Hispanic or Latino. The hazard ratio for intubation or death in the tocilizumab group as compared with the placebo group was 0.83 (95% confidence interval [CI], 0.38 to 1.81; P = 0.64), and the hazard ratio for disease worsening was 1.11 (95% CI, 0.59 to 2.10; P = 0.73). At 14 days, 18.0% of the patients in the tocilizumab group and 14.9% of the patients in the placebo group had had worsening of disease. The median time to discontinuation of supplemental oxygen was 5.0 days (95% CI, 3.8 to 7.6) in the tocilizumab group and 4.9 days (95% CI, 3.8 to 7.8) in the placebo group (P = 0.69). At 14 days, 24.6% of the patients in the tocilizumab group and 21.2% of the patients in the placebo group were still receiving supplemental oxygen. Patients who received tocilizumab had fewer serious infections than patients who received placebo. CONCLUSIONS: Tocilizumab was not effective for preventing intubation or death in moderately ill hospitalized patients with Covid-19. Some benefit or harm cannot be ruled out, however, because the confidence intervals for efficacy comparisons were wide. (Funded by Genentech; ClinicalTrials.gov number, NCT04356937.).

Association Between Immune Checkpoint Inhibitors With Cardiovascular Events and Atherosclerotic Plaque.

BACKGROUND: Immune checkpoint inhibitors (ICIs) treat an expanding range of cancers. Consistent basic data suggest that these same checkpoints are critical negative regulators of atherosclerosis. Therefore, our objectives were to test whether ICIs were associated with accelerated atherosclerosis and a higher risk of atherosclerosis-related cardiovascular events. METHODS: The study was situated in a single academic medical center. The primary analysis evaluated whether exposure to an ICI was associated with atherosclerotic cardiovascular events in 2842 patients and 2842 controls matched by age, a history of cardiovascular events, and cancer type. In a second design, a case-crossover analysis was performed with an at-risk period defined as the 2-year period after and the control period as the 2-year period before treatment. The primary outcome was a composite of atherosclerotic cardiovascular events (myocardial infarction, coronary revascularization, and ischemic stroke). Secondary outcomes included the individual components of the primary outcome. In addition, in an imaging substudy (n=40), the rate of atherosclerotic plaque progression was compared from before to after the ICI was started. All study measures and outcomes were blindly adjudicated. RESULTS: In the matched cohort study, there was a 3-fold higher risk for cardiovascular events after starting an ICI (hazard ratio, 3.3 [95% CI, 2.0-5.5]; P<0.001). There was a similar increase in each of the individual components of the primary outcome. In the case-crossover, there was also an increase in cardiovascular events from 1.37 to 6.55 per 100 person-years at 2 years (adjusted hazard ratio, 4.8 [95% CI, 3.5-6.5]; P<0.001). In the imaging study, the rate of progression of total aortic plaque volume was >3-fold higher with ICIs (from 2.1%/y before 6.7%/y after). This association between ICI use and increased atherosclerotic plaque progression was attenuated with concomitant use of statins or corticosteroids. CONCLUSIONS: Cardiovascular events were higher after initiation of ICIs, potentially mediated by accelerated progression of atherosclerosis. Optimization of cardiovascular risk factors and increased awareness of cardiovascular risk before, during, and after treatment should be considered among patients on an ICI.

Repurposing Immunomodulatory Therapies against Coronavirus Disease 2019 (COVID-19) in the Era of Cardiac Vigilance: A Systematic Review.

The ongoing coronavirus disease 2019 (COVID-19) pandemic has resulted in efforts to identify therapies to ameliorate adverse clinical outcomes. The recognition of the key role for increased inflammation in COVID-19 has led to a proliferation of clinical trials targeting inflammation. The purpose of this review is to characterize the current state of immunotherapy trials in COVID-19, and focuses on associated cardiotoxicities, given the importance of pharmacovigilance. The search terms related to COVID-19 were queried in ClinicalTrials.gov. A total of 1621 trials were identified and screened for interventional trials directed at inflammation. Trials (n = 226) were fully assessed for the use of a repurposed drug, identifying a total of 141 therapeutic trials using a repurposed drug to target inflammation in COVID-19 infection. Building on the results of the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial demonstrating the benefit of low dose dexamethasone in COVID-19, repurposed drugs targeting inflammation are promising. Repurposed drugs directed at inflammation in COVID-19 primarily have been drawn from cancer therapies and immunomodulatory therapies, specifically targeted anti-inflammatory, anti-complement, and anti-rejection agents. The proposed mechanisms for many cytokine-directed and anti-rejection drugs are focused on evidence of efficacy in cytokine release syndromes in humans or animal models. Anti-complement-based therapies have the potential to decrease both inflammation and microvascular thrombosis. Cancer therapies are hypothesized to decrease vascular permeability and inflammation. Few publications to date describe using these drugs in COVID-19. Early COVID-19 intervention trials have re-emphasized the subtle, but important cardiotoxic sequelae of potential therapies on outcomes. The volume of trials targeting the COVID-19 hyper-inflammatory phase continues to grow rapidly with the evaluation of repurposed drugs and late-stage investigational agents. Leveraging known clinical safety profiles and pharmacodynamics allows swift investigation in clinical trials for a novel indication. Physicians should remain vigilant for cardiotoxicity, often not fully appreciated in small trials or in short time frames.

Myocardial Steatosis Among Antiretroviral Therapy-Treated People With Human Immunodeficiency Virus Participating in the REPRIEVE Trial

BACKGROUND: People with human immunodeficiency virus (PWH) face increased risks for heart failure and adverse heart failure outcomes. Myocardial steatosis predisposes to diastolic dysfunction, a heart failure precursor. We aimed to characterize myocardial steatosis and associated potential risk factors among a subset of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) participants. METHODS: Eighty-two PWH without known heart failure successfully underwent cardiovascular magnetic resonance spectroscopy, yielding data on intramyocardial triglyceride (IMTG) content (a continuous marker for myocardial steatosis extent). Logistic regression models were applied to investigate associations between select clinical characteristics and odds of increased or markedly increased IMTG content. RESULTS: Median (Q1, Q3) IMTG content was 0.59% (0.28%, 1.15%). IMTG content was increased (>0.5%) among 52% and markedly increased (>1.5%) among 22% of participants. Parameters associated with increased IMTG content included age (P = .013), body mass index (BMI) ≥25 kg/m2 (P = .055), history of intravenous drug use (IVDU) (P = .033), and nadir CD4 count <350 cells/mm³ (P = .055). Age and BMI ≥25 kg/m2 were additionally associated with increased odds of markedly increased IMTG content (P = .049 and P = .046, respectively). CONCLUSIONS: A substantial proportion of antiretroviral therapy-treated PWH exhibited myocardial steatosis. Age, BMI ≥25 kg/m2, low nadir CD4 count, and history of IVDU emerged as possible risk factors for myocardial steatosis in this group. CLINICAL TRIALS REGISTRATION: NCT02344290;NCT03238755.

Cardio-oncology care in the era of the coronavirus disease 2019 (COVID-19) pandemic: An International Cardio-Oncology Society (ICOS) statement.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has given rise to a pandemic of unprecedented proportions in the modern era because of its highly contagious nature and impact on human health and society: coronavirus disease 2019 (COVID-19). Patients with cardiovascular (CV) risk factors and established CV disease (CVD) are among those initially identified at the highest risk for serious complications, including death. Subsequent studies have pointed out that patients with cancer are also at high risk for a critical disease course. Therefore, the most vulnerable patients are seemingly those with both cancer and CVD, and a careful, unified approach in the evaluation and management of this patient population is especially needed in times of the COVID-19 pandemic. This review provides an overview of the unique implications of the viral outbreak for the field of cardio-oncology and outlines key modifications in the approach to this ever-increasing patient population. These modifications include a shift toward greater utilization of cardiac biomarkers and a more focused CV imaging approach in the broader context of modifications to typical practice pathways. The goal of this strategic adjustment is to minimize the risk of SARS-CoV-2 infection (or other future viral outbreaks) while not becoming negligent of CVD and its important impact on the overall outcomes of patients who are being treated for cancer.

Management of Cardiovascular Disease During Coronavirus Disease (COVID-19) Pandemic.

Patients with pre-existing cardiovascular disease and risk factors are more likely to experience adverse outcomes associated with the novel coronavirus disease-2019 (COVID-19). Additionally, consistent reports of cardiac injury and de novo cardiac complications, including possible myocarditis, arrhythmia, and heart failure in patients without prior cardiovascular disease or significant risk factors, are emerging, possibly due to an accentuated host immune response and cytokine release syndrome. As the spread of the virus increases exponentially, many patients will require medical care either for COVID-19 related or traditional cardiovascular issues. While the COVID-19 pandemic is dominating the attention of the healthcare system, there is an unmet need for a standardized approach to deal with COVID-19 associated and other traditional cardiovascular issues during this period. We provide consensus guidance for the management of various cardiovascular conditions during the ongoing COVID-19 pandemic with the goal of providing the best care to all patients and minimizing the risk of exposure to frontline healthcare workers.

COVID-19 and immune checkpoint inhibitors: initial considerations.

COVID-19 infections are characterized by inflammation of the lungs and other organs that ranges from mild and asymptomatic to fulminant and fatal. Patients who are immunocompromised and those with cardiopulmonary comorbidities appear to be particularly afflicted by this illness. During pandemic conditions, many aspects of cancer care have been impacted. One important clinical question is how to manage patients who need anticancer therapy, including immune checkpoint inhibitors (ICIs) during these conditions. Herein, we consider diagnostic and therapeutic implications of using ICI during this unprecedented period of COVID-19 infections. In particular, we consider the impact of ICI on COVID-19 severity, decisions surrounding continuing or interrupting therapy, diagnostic measures in patients with symptoms or manifestations potentially consistent with either COVID-19 or ICI toxicity, and resumption of therapy in infected patients. While more robust data are needed to guide clinicians on management of patients with cancer who may be affected by COVID-19, we hope this commentary provides useful insights for the clinical community.