•Addition of immunotherapy for treatment of metastatic non-small lung cancer does not increase cardiovascular toxicity.•Treatment with immunotherapy and chemotherapy had 19 % lower hazards for ...cardiovascular toxicity as compared with chemotherapy alone.•This study did not find any significant increase in pericarditis, myocarditis or cardiomyopathy associated with immunotherapy use.•Immunotherapy might have cardio-protective effects with unclear mechanism and needs further exploration.
In recent years immunotherapy has escalated to frontline treatment options for metastatic non-small cell lung cancer. Cardiovascular toxicity from chemotherapeutic agents is well described in this patient population with common underlying risk factors like smoking. We explored cardiovascular toxicity form the addition of immune checkpoint inhibitors to traditional chemotherapy.
This is a retrospective study from SEER-Medicare datasets which represents 34 % of the US population. This study included patients age ≥ 65 years-old with newly diagnosed metastatic non-small cell lung cancer between the years 2013 and 2015. Patients were divided into 2 cohorts, one who received traditional chemotherapy only (control arm) and the others who received immune checkpoint inhibitors in addition to traditional chemotherapy (study arm). The primary endpoint was the hazards of new cardiovascular toxicity in the study versus the control arm.
We identified 6405 patients who met our study criteria. Of these, 5730 patients received chemotherapy only while 675 patients received chemotherapy and immune checkpoint inhibitors. Results showed that the hazard ratio for all cardiovascular toxicity was 0.81 (95 % CI:0.72−0.91, p = 0.0003) in patients who received immune checkpoint inhibitors with chemotherapy. Among the subgroups, hazards ratio for acute coronary syndrome was 0.82 (95 % CI: 0.64–1.05, p = 0.10), hazards ratio for heart failure was 0.74 (95 % CI: 0.62−0.88, p = 0.0007), hazards ratio for cardiac arrhythmia was 0.72 (95 % CI: 0.63−0.82, p < 0.0001) and hazards ratio for heart blocks was 0.48 (95 % CI: 0.30−0.76, p < 0.0001). There was no significant difference in hazards for cardiomyopathy, pericarditis, and myocarditis between the two cohorts. Patients above 75 years, with comorbidities and pre-existing heart disease, were at higher risk.
Results from this study are reassuring that adding immune checkpoint inhibitors to chemotherapy is safe and does not result in increased cardiovascular toxicity but instead showed lower hazards.
The epidemiology of coronary artery disease (CAD) has shifted, with increasing prevalence of cardiometabolic disease and decreasing findings of obstructive CAD on myocardial perfusion imaging (MPI). ...Coronary microvascular dysfunction (CMD), defined as impaired myocardial flow reserve (MFR) by positron emission tomography (PET), has emerged as a key mediator of risk. We aimed to assess whether PET MFR provides additive value for risk stratification of cardiometabolic disease patients compared with single-photon emission computed tomography (SPECT) MPI.
We retrospectively followed patients referred for PET, exercise SPECT, or pharmacologic SPECT MPI with cardiometabolic disease (obesity, diabetes, or chronic kidney disease) and without known CAD. We compared rates and hazards of composite MACE (annualized cardiac mortality or acute myocardial infarction) among propensity-matched PET and SPECT patients using Poisson and Cox regression. Normal SPECT was defined as a total perfusion deficit (TPD) <5% reflecting the absence of obstructive CAD. Normal PET was defined as TPD <5% plus MFR ≥2.0.
Among 21,544 patients referred from 2006-2020, cardiometabolic disease was highly prevalent (PET: 2308 67%, SPECT: 9984 55%) and higher among patients referred to PET (p <0.001). Obstructive CAD findings (TPD >5%) were uncommon (PET: 21% and SPECT 11%). Conversely, impaired MFR on PET (<2.0) was common (62%). In propensity-matched analysis over a median 6.4-year follow-up, normal PET identified low-risk (0.9%/year MACE) patients, and abnormal PET identified high-risk (4.2%/year MACE) patients with cardiometabolic disease; conversely, those with normal pharmacologic SPECT remained moderate-risk (1.6%/year, p<0.001 compared to normal PET).
Cardiometabolic disease is common among patients referred for MPI and is associated with heterogenous level of risk. Compared with pharmacologic SPECT, PET with MFR can detect nonobstructive CAD including CMD and can more accurately discriminate low-risk from higher-risk individuals.
Condensed Abstract: Nonobstructive forms of CAD are common among people with cardiometabolic disease and are associated with increased cardiovascular (CV) risk. The objective of this study was to determine whether myocardial flow reserve (MFR) on PET MPI, a measure of coronary microvascular function, provides additive value to identify low-risk and high-risk CM disease patients compared with SPECT MPI. We found that preserved MFR identifies a low-risk group of patients with cardiometabolic disease compared to normal pharmacologic SPECT. PET MFR may provide additive prognostic utility to identify low-risk CM patients compared with SPECT.
Clinical lipid measurements do not show the full complexity of the altered lipid metabolism associated with diabetes mellitus or cardiovascular disease. Lipidomics enables the assessment of hundreds ...of lipid species as potential markers for disease risk.
Plasma lipid species (310) were measured by a targeted lipidomic analysis with liquid chromatography electrospray ionization-tandem mass spectrometry on a case-cohort (n=3779) subset from the ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation). The case-cohort was 61% male with a mean age of 67 years. All participants had type 2 diabetes mellitus with ≥1 additional cardiovascular risk factors, and 35% had a history of macrovascular disease. Weighted Cox regression was used to identify lipid species associated with future cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death) and cardiovascular death during a 5-year follow-up period. Multivariable models combining traditional risk factors with lipid species were optimized with the Akaike information criteria. C statistics and NRIs were calculated within a 5-fold cross-validation framework.
Sphingolipids, phospholipids (including lyso- and ether- species), cholesteryl esters, and glycerolipids were associated with future cardiovascular events and cardiovascular death. The addition of 7 lipid species to a base model (14 traditional risk factors and medications) to predict cardiovascular events increased the C statistic from 0.680 (95% confidence interval CI, 0.678-0.682) to 0.700 (95% CI, 0.698-0.702; P<0.0001) with a corresponding continuous NRI of 0.227 (95% CI, 0.219-0.235). The prediction of cardiovascular death was improved with the incorporation of 4 lipid species into the base model, showing an increase in the C statistic from 0.740 (95% CI, 0.738-0.742) to 0.760 (95% CI, 0.757-0.762; P<0.0001) and a continuous net reclassification index of 0.328 (95% CI, 0.317-0.339). The results were validated in a subcohort with type 2 diabetes mellitus (n=511) from the LIPID trial (Long-Term Intervention With Pravastatin in Ischemic Disease).
The improvement in the prediction of cardiovascular events, above traditional risk factors, demonstrates the potential of plasma lipid species as biomarkers for cardiovascular risk stratification in diabetes mellitus.
URL: https://clinicaltrials.gov. Unique identifier: NCT00145925.
Some trials have reported diminished efficacy for statins in the elderly, and in women compared with men. We examined the efficacy and safety of evolocumab by patient age and sex in the FOURIER ...trial, the first major cardiovascular outcome trial of a PCSK9 inhibitor.
FOURIER was a randomised, double blind trial, comparing evolocumab with placebo in 27,564 patients with atherosclerotic cardiovascular disease receiving statin therapy (median follow-up 2.2 years). The primary endpoint was cardiovascular death, myocardial infarction, stroke, hospitalisation for unstable angina or coronary revascularisation. Cox proportional hazards models were used to assess the efficacy of evolocumab versus placebo stratified by quartiles of patient age and by sex. There were small variations in the cardiovascular event rate across the age range (for the primary endpoint, Kaplan-Meier at 3 years 15.6%, >69 years, vs. 15.1%, ≤56 years, P = 0.45); however, the relative efficacy of evolocumab was consistent regardless of patient age (for the primary endpoint (Q1 hazard ratio, 95% confidence interval) 0.83, 0.72-0.96, Q2 0.88, 0.76-1.01, Q3 0.82, 0.71-0.95, Q4 0.86, 0.74-1.00; Pinteraction = 0.91), and the key secondary endpoint (cardiovascular death, myocardial infarction, stroke) (Q1 0.74 (0.61-0.89), Q2 0.83 (0.69-1.00), Q3 0.78 (0.65-0.94), Q4 0.82 (0.69-0.98)); Pinteraction = 0.81). Women had a lower primary endpoint rate than men (Kaplan-Meier at 3 years 12.5 vs. 15.3%, respectively, P < 0.001). Relative risk reductions in the primary endpoint and key secondary endpoint were similar in women (0.81 (0.69-0.95) and 0.74 (0.61-0.90), respectively) compared with men (0.86 (0.80-0.94) and 0.81 (0.73-0.90), respectively), Pinteraction = 0.48 and 0.44, respectively. Adverse events were more common in women and with increasing age but, with the exception of injection site reactions, there were no important significant differences reported by those assigned evolocumab versus placebo.
The efficacy and safety of evolocumab are similar throughout a broad range of ages and in both men and women.
This publication describes uniform definitions for cardiovascular and stroke outcomes developed by the Standardized Data Collection for Cardiovascular Trials Initiative and the U.S. Food and Drug ...Administration (FDA). The FDA established the Standardized Data Collection for Cardiovascular Trials Initiative in 2009 to simplify the design and conduct of clinical trials intended to support marketing applications. The writing committee recognizes that these definitions may be used in other types of clinical trials and clinical care processes where appropriate. Use of these definitions at the FDA has enhanced the ability to aggregate data within and across medical product development programs, conduct meta-analyses to evaluate cardiovascular safety, integrate data from multiple trials, and compare effectiveness of drugs and devices. Further study is needed to determine whether prospective data collection using these common definitions improves the design, conduct, and interpretability of the results of clinical trials.
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Abstract Background Studies demonstrate that lowering low-density lipoprotein cholesterol (LDL-C) using a statin is associated with significant reduction in cardiovascular events. Whether ...visit-to-visit variability in LDL-C levels affects cardiovascular outcomes is unknown. Objectives This study sought to evaluate the role of visit-to-visit variability in LDL-C levels on cardiovascular outcomes. Methods We evaluated patients with coronary artery disease and LDL-C <130 mg/dl enrolled in the TNT (Treating to New Targets) trial, randomly assigned to receive atorvastatin 80 mg/day versus 10 mg/day and with at least one post-baseline measurement of LDL-C. Visit-to-visit LDL-C variability was evaluated from 3 months into random assignment through the use of various measurements of LDL-C variability: SD, average successive variability (ASV), coefficient of variation, and variation independent of mean, with the first 2 measurements used as the primary measurements. Primary outcome was any coronary event, and secondary outcomes were any cardiovascular event, death, myocardial infarction, or stroke. Results Among 9,572 patients, SD and ASV were significantly lower with atorvastatin 80 mg/day versus 10 mg/day (SD: 12.03 ± 9.70 vs. 12.52 ± 7.43; p = 0.005; ASV: 12.84 ± 10.48 vs. 13.76 ± 8.69; p < 0.0001). In the adjusted model, each 1-SD increase in LDL-C variability (by ASV) increased the risk of any coronary event by 16% (hazard ratio HR: 1.16; 95% confidence interval CI: 1.10 to 1.23; p < 0.0001), any cardiovascular event by 11% (HR: 1.11; 95% CI: 1.07 to 1.15; p < 0.0001), death by 23% (HR: 1.23; 95% CI: 1.14 to 1.34; p < 0.0001), myocardial infarction by 10% (HR: 1.10; 95% CI: 1.02 to 1.19; p = 0.02), and stroke by 17% (HR: 1.17; 95% CI: 1.04 to 1.31; p = 0.01), independent of treatment effect and achieved LDL-C levels. Results were largely consistent when adjusted for medication adherence. Conclusions In subjects with coronary artery disease, visit-to-visit LDL-C variability is an independent predictor of cardiovascular events.
BACKGROUNDThe impact of pre-existing atrial fibrillation (AF) on outcomes after noncardiac surgery is not clear. OBJECTIVESWe aimed to study the impact of AF on the risk of adverse outcomes after ...noncardiac surgery in a nationwide cohort. METHODSWe identified Medicare beneficiaries admitted for noncardiac surgery from 2015 to 2019 and divided the study cohort into 2 groups: with and without AF. Noncardiac surgery was classified into vascular, thoracic, general, genitourinary, gynecological, orthopedics and neurosurgery, breast, head and neck, and transplant. We used propensity score matching on exact age, sex, race, urgency and type of surgery, revised cardiac risk index (RCRI) and CHA2DS2-VASc score, and tight caliper on other comorbidities. The study outcomes were 30-day mortality, stroke, myocardial infarction, and heart failure. We examined the incremental utility of AF in addition to RCRI to predict adverse events after noncardiac surgery. RESULTSThe study cohort included 8,635,758 patients who underwent noncardiac surgery (16.4% with AF). Patients with AF were older, more likely to be men, and had higher prevalence of comorbidities. After propensity score matching, AF was associated with higher risk of mortality (OR: 1.31; 95% CI: 1.30-1.32), heart failure (OR: 1.31; 95% CI: 1.30-1.33), and stroke (OR: 1.40; 95% CI: 1.37-1.43) and lower risk of myocardial infarction (OR: 0.81; 95% CI: 0.79-0.82). Results were consistent in subgroup analysis by sex, race, type of surgery, and all strata of RCRI and CHA2DS2-VASc score. AF improved the discriminative ability of RCRI (C-statistic 0.73 to 0.76). CONCLUSIONPre-existing AF is independently associated with postoperative adverse outcomes after NCS.
Phosphodiesterase type 5 inhibitors (PDE5i) are first-line therapy for erectile dysfunction (ED). Approximately 1–4% of PDE5i recipients co-possess nitrates, despite this combination potentially ...producing clinically significant hypotension. Real-world data in these patients and insights into prescriber rationales for co-prescription are limited.
This study investigated whether PDE5i and nitrate co-possession is associated with increased rates of cardiovascular (CV) outcomes.
Adult males with ED and PDE5i prescription and males with nitrate prescription were identified from a U.S. electronic health record database (2012–2016). Quantitative comparisons were made between patients with ED and co-possession (ED + PDE5i + nitrate), only nitrate possession (ED + nitrate and nitrate only without ED), and only PDE5i possession (ED + PDE5i).
We quantified incidence of CV outcomes in co-possession and comparator periods, calculating incidence rate ratios after propensity score matching. Prescriber rationales were derived by reviewing virtual patient records.
Over 168,000 patients had ≥1 PDE5i prescription (∼241,000 possession periods); >480,000 patients had ≥1 nitrate prescription (∼486,000 possession periods); and 3,167 patients had 3,668 co-possession periods. Non-significantly different or lower rates of CV outcomes were observed for co-possession periods vs ED + nitrate and nitrate only periods. Most CV outcome rates were non-significantly different between co-possession and ED + PDE5i periods (myocardial infarction, hospitalized unstable angina and fainting were higher with co-possession). From qualitative assessment of patient records with co-possession, 131 of 252 (52%) documented discussion with a physician regarding co-possession; 69 of 131 (53%) warned or instructed on safely managing these contraindicated medications.
Findings from this real-world study indicate that co-possession of nitrate and PDE5i prescriptions is not associated with increased rates of CV outcomes, relative to possession of nitrates alone. Physicians should and often do discuss the risks of using both medications together with their patients.
Strengths of this study are the large size of the U.S. real-world patient cohort with data available for analysis, and our ability to utilize natural language processing to explore co-prescription rationales and patient-physician interactions. Limitations are the retrospective nature of the analysis and inability to establish whether recorded prescriptions were filled or the medication was consumed.
Co-exposure of PDE5i and nitrates should continue to be avoided; however, co-possession of PDE5i and nitrate prescriptions is not necessarily associated with increased CV risk. Co-possession can be successfully managed in suitable circumstances. Nunes AP, Seeger JD, Stewart A, et al. Cardiovascular Outcome Risks in Patients With Erectile Dysfunction Co-Prescribed a Phosphodiesterase Type 5 Inhibitor (PDE5i) and a Nitrate: A Retrospective Observational Study Using Electronic Health Record Data in the United States. J Sex Med 2021;18:1511–1523.
Previous studies have failed to show a cardioprotective benefit of beta-blockers in patients with stable coronary artery disease (CAD).
This study sought to determine the association between ...beta-blockers and cardiovascular events in patients with stable CAD using a new user design.
All patients aged >66 years undergoing elective coronary angiography in Ontario, Canada, from 2009 to 2019 with diagnosed obstructive CAD were included. Exclusion criteria included heart failure or a recent myocardial infarction, as well as having a beta-blocker prescription claim in the previous year. Beta-blocker use was defined as having at least 1 beta-blocker prescription claim in the 90 days preceding or after the index coronary angiography. The main outcome was a composite of all-cause mortality and hospitalization for heart failure or myocardial infarction. Inverse probability of treatment weighting using the propensity score was used to account for confounding.
This study included 28,039 patients (mean age: 73.0 ± 5.6 years; 66.2% male), and 12,695 of those (45.3%) were newly prescribed beta-blockers. The 5-year risks of the primary outcome were 14.3% in the beta-blocker group and 16.1% in the no beta-blocker group (absolute risk reduction: −1.8%; 95% CI: −2.8 to −0.8; HR: 0.92; 95% CI: 0.86-0.98; P = 0.006). This result was driven by reductions in myocardial infarction hospitalization (cause-specific HR: 0.87; 95% CI: 0.77-0.99; P = 0.031), whereas no differences were observed in all-cause death or heart failure hospitalization.
In patients with angiographically documented stable CAD without heart failure or a recent myocardial infarction, beta-blockers were associated with a small but significant reduction in cardiovascular events at 5 years.
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BACKGROUNDEmpagliflozin reduces cardiovascular death (CVD) or heart failure (HF) hospitalization (HFH) in patients with HF and preserved ejection fraction. Treatment effects and safety in relation to ...age have not been studied. OBJECTIVESThe purpose of this study was to evaluate the interplay of age and empagliflozin effects in EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction). METHODSWe grouped patients (n = 5,988) according to their baseline age (<65 years n = 1,199, 65-74 years n = 2,214, 75-79 years n = 1,276, ≥80 years n = 1,299). We explored the influence of age on empagliflozin effects on CVD or HFH (primary outcome), total HFH, rate of decline in estimated glomerular filtration rate, health-related quality of life with the Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score, and frequency of adverse events. RESULTSConsidering only patients on placebo, the incidence of primary outcomes (P trend = 0.02) and CVD (P trend = 0.003) increased with age. Empagliflozin reduced primary outcomes (P trend = 0.33), first HFH (P trend = 0.22), and first and recurrent HFH (P trend = 0.11) across all age groups with an effect being similar at ≥75 years (P interaction = 0.22) or >80 years (P interaction = 0.51). Empagliflozin improved Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score at week 52 and attenuated the decline of estimated glomerular filtration rate without age interaction (P = 0.48 and P = 0.32, respectively). There were no clinically relevant differences in adverse events between empagliflozin and placebo across the age groups. CONCLUSIONSEmpagliflozin reduced primary outcomes and first and recurrent HFH and improved symptoms across a broad age spectrum. High age was not associated with reduced efficacy or meaningful intolerability. (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction EMPEROR-Preserved; NCT0305951).
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