Cardiovascular Disease in Patients With Breast Cancer Treated in the Modern Era.

AIMS: With improving cancer survivorship, cardiovascular disease (CVD) has become a leading cause of death in breast cancer (BC) survivors. At present, there is no prospectively validated, contemporary risk assessment tool specific to this patient cohort. Accordingly, we sought to investigate long-term cardiovascular outcomes in early-stage BC patients utilising a well characterised database at a quaternary referral centre. With the assembly of this cohort, we have derived a BC cardiovascular risk index titled the 'CRIB (Cardiovascular Risk Index in Breast Cancer)' to estimate the risk of a major adverse cardiovascular event (MACE) in women undergoing treatment for BC. METHODS: A retrospective cohort study was conducted examining all female patients aged ≥18 years of age who underwent treatment for early-stage BC at a cancer centre in Melbourne, Australia, between 2009 and 2019. The primary aim of this study was to assess causes and predictors of MACE. RESULTS: A total of 1,173 women with early-stage BC were included. During a median follow-up of 4.4 (1.8-6.7) years, 80 (6.8%) women experienced a MACE. These women were more likely to be older, with a high burden of cardiovascular risk factors and were more likely to have a history of established coronary artery disease (CAD) (p≤0.001 for all). A CRIB ≥3 (2 points: renal impairment, 1 point: age ≥65 years, body mass index [BMI]>27, diabetes, hypertension, history of smoking) demonstrated moderate discrimination (c-statistic 0.75) with appropriate calibration. A CRIB ≥3, which represented 23.9% of our cohort, was associated with a high risk of MACE (odds ratio [OR] 17.85, 95% confidence interval [CI] 6.36-50.05; p<0.001). A total of 138 (11.8%) women died during the study period. Mortality was significantly higher in patients who experienced a MACE (HR 2.72, 95%CI 1.75-4.23; p<0.001). CONCLUSION: Cardiovascular risk stratification at the time of BC diagnosis using the novel CRIB may help guide surveillance and the use of cardioprotective therapies as well as identify those who require long-term cardiac follow-up.

Long-term mortality in asymptomatic patients with stable ischemic heart disease undergoing percutaneous coronary intervention.

OBJECTIVES: Patients with stable ischemic heart disease (SIHD) may present with a variety of symptoms including typical angina, angina equivalents such as dyspnea or no symptoms. We sought to determine whether symptom status affects periprocedural safety and long-term mortality in patients undergoing PCI. METHODS: Prospectively enrolled consecutive patients undergoing PCI for SIHD at six hospitals in Australia between 2005 to 2018 as part of the Melbourne Interventional Group registry. Symptom status was recorded at the time of PCI and patients undergoing staged PCI were excluded. RESULTS: Overall, 11,730 patients with SIHD were followed up for a median period of 5 years (maximum 14.0 years, interquartile range 2.2-9.0 years) with 1,317 (11.2%) being asymptomatic. Asymptomatic patients were older, and more likely to be male, have triple-vessel disease, with multiple comorbidities including renal failure, diabetes and heart failure (all P < .01). These patients had significantly higher rates of periprocedural complications and major adverse cardiovascular events at 30-days. Long-term mortality was significantly higher in asymptomatic patients (27.2% vs 18.0%, P < .001). On cox regression for long-term mortality, after adjustment for more important clinical variables, asymptomatic status was an independent predictor (Hazard ratio (HR) 1.39 95% CI 1.16-1.66, P < .001). CONCLUSIONS: In a real-world cohort of patients undergoing revascularization for SIHD, absence of symptoms was associated with higher rates of periprocedural complications and, after adjustment for more important clinical variables, was an independent predictor of long-term mortality. As the primary goal of revascularization in SIHD remains angina relief, the appropriateness of PCI in the absence of symptoms warrants justification.

Invasive versus conservative management in patients aged ≥85 years presenting with non-ST-elevation myocardial infarction.

BACKGROUND: Guidelines recommend early coronary angiography (CA) in patients with non-ST-elevation myocardial infarction (NSTEMI) irrespective of age. However, elderly patients are less likely to be treated according to these guidelines due to their perceived high risk and medical comorbidities. Whether an invasive strategy is associated with improved survival in patients aged ≥85 years remains uncertain due to their exclusion from randomised trials. AIMS: Patients were stratified based on whether they underwent invasive management with CA with a view to revascularisation versus conservative management. The primary outcome was long-term mortality. METHODS: Consecutive patients aged ≥85 years presenting to a tertiary centre with NSTEMI between 2008 and 2018 were included in this retrospective cohort study. RESULTS: Of 7591 patients with NSTEMI, 1052 patients aged ≥85 years were included. Ninety-nine (9.4%) patients underwent CA. Those undergoing CA were more likely to be younger, male, live independently, without mobility or cognitive issues (all P < 0.01). Overall, 495 (47%) patients died during a mean follow up of 1.3 ± 1 year. On Cox regression, after adjusting for age, pre-morbid functional status, cognition and cardiovascular risk factors, invasive management was the strongest predictor for survival (hazard ratio 0.47; 95% confidence interval 0.26-0.85; P = 0.01). Invasive management was associated with a trend to increased risk of in-hospital bleeding (6.1% vs 2.6%; P = 0.054) with no significant difference in stroke (2.0% vs 3.8%; P = 0.37). CONCLUSION: In patients aged ≥85 years who presented with NSTEMI, invasive management was associated with improved survival without significant differences in bleeding or stroke. A randomised controlled study assessing the efficacy and safety of invasive management in very elderly patients with NSTEMI is warranted.

Factor Xa Inhibition for the Treatment of Venous Thromboembolism Associated With Cancer: A Meta-Analysis of the Randomised Controlled Trials.

BACKGROUND: Venous thromboembolism (VTE) is a common cause of morbidity and mortality in cancer patients. Until recently, guidelines recommended the use of low-molecular weight heparin (LMWH) as standard of care for VTE in patients with cancer. Despite the proven efficacy of direct oral anticoagulants (DOACs) for treatment of VTE, there is equipoise supporting their use in cancer patients. METHODS: A systematic review of PubMed, Medline and EMBASE identified four randomised controlled trials (RCTs) in patients with cancer and VTE comparing a factor Xa inhibitor (FXaI) to LMWH. A meta-analysis was performed with a primary outcome of VTE recurrence and key secondary outcomes of major bleeding, clinically relevant non-major bleeding (CRNMB) and gastrointestinal (GI) bleeding. RESULTS: Four RCTs with 2,907 patients were included. 1,451 patients were randomised to FXaI and 1,456 to LMWH. VTE recurrence was lower in the FXaI group (RR 0.62, 95%CI 0.44-0.87; p=0.01; I2=24.90), with an absolute risk difference of -4% equating to a number needed to treat of 25 for prevention of recurrent VTE with FXaI. No significant difference in major bleeding was noted between groups (RR 1.33, 95%CI 0.84-2.11; p=0.23). Rates of GI bleeding (RR 1.87, 95%CI 1.06-3.29; p=0.03) and CRNMB (RR 1.57, 95%CI 1.11-2.23; p=0.01) were greater with FXaIs. CONCLUSION: In patients with cancer and VTE, the rate of VTE recurrence was significantly lower with FXaI than with LMWH without an increased risk of major bleeding. Our data supports the use of FXaIs as the standard of care for the treatment of VTE in this population.

Transcatheter aortic valve replacement in patients with a history of cancer: Periprocedural and long-term outcomes.

BACKGROUND: A history of cancer is incorporated into the surgical risk assessment of patients undergoing surgical aortic valve replacement through the Society for Thoracic Surgeons score. However, the prognostic significance of cancer in patients treated with transcatheter aortic valve replacement (TAVR) is unclear. As the cancer survivorship population increases, it is imperative to establish the efficacy and safety of TAVR in patients with severe symptomatic aortic stenosis (AS) and a history of malignancy. OBJECTIVES: The primary goal of this study was to assess the periprocedural outcomes and long-term mortality in patients with a history of cancer undergoing TAVR. METHODS: A systematic review of PubMed, MEDLINE, and EMBASE was conducted to identify studies reporting outcomes in patients with a history of malignancy undergoing TAVR. A meta-analysis was performed using a random-effects model with a primary outcome of all-cause mortality and cardiac mortality at the longest follow-up. On secondary analyses, procedural safety was assessed. RESULTS: A total of 13 observational studies with 10,916 patients were identified in the systematic review. Seven studies including 6,323 patients were included in the quantitative analysis. Short-term mortality (relative risk [RR] 0.61, 95%CI 0.36-1.01; p = .06) and long-term all-cause mortality (RR 1.24, 95%CI 0.95-1.63; p = .11) were not significantly different when comparing patients with and without a history of cancer. No significant difference in the rate of periprocedural complications including stroke, bleeding, acute kidney injury, and pacemaker implantation was noted. CONCLUSION: In patients with severe AS undergoing TAVR, a history of cancer was not associated with adverse short or long-term survival. Based on these findings, TAVR should be considered in all patients with severe symptomatic AS, irrespective of their history of malignancy.

Prognostic significance of suboptimal secondary prevention pharmacotherapy after acute coronary syndromes.

BACKGROUND: Optimal secondary prevention pharmacotherapy is the cornerstone of post-acute coronary syndrome (ACS) management. The prognostic impact of not receiving five guideline-recommended therapies is poorly described. AIM: To ascertain the prognostic significance of suboptimal pharmacotherapy in ACS survivors. METHODS: Consecutive patients with ACS from the Melbourne Interventional Group registry who were alive at 30 days following their index percutaneous coronary intervention were included. Patients were divided into three categories based on the number of secondary prevention medications prescribed. The optimal medical therapy (OMT), near-optimal medical therapy (NMT), suboptimal medical therapy (SMT) groups were prescribed 5, 4 and ≤ 3 medications, respectively. Primary endpoint was long-term mortality. Cox-proportional hazard modelling was undertaken to assess independent predictors of survival. RESULTS: Of the 9375 patients included, 5678 (60.6%) received OMT, 2903 (31.0%) received NMT and 794 (8.5%) received SMT. Patients receiving SMT were older, more likely to be female and had higher burden of comorbidities (renal impairment, congestive heart failure, diabetes, peripheral vascular disease; P < 0.01 for all). SMT was associated with higher long-term mortality at 3.9 ± 2.2 years when compared to NMT and OMT (16.8% vs 10.5% vs 8.2%, P < 0.001). Compared to OMT, SMT was an independent predictor of long-term mortality (hazard ratio, HR 1.62, 95% confidence interval, CI 1.30-2.02, P < 0.01) while NMT was associated with a clinically significant 14% mortality hazard (HR 1.14, 95% CI 0.97-1.34, P = 0.11). CONCLUSIONS: There is a graded long-term hazard associated with not receiving OMT after an ACS. Improvements in secondary prevention pharmacotherapy models of care are warranted to further decrease the long-term mortality.

SMARTphone Based Cardiovascular Risk Reduction in BREAST Cancer Patients (SMART-BREAST): A Randomised Controlled Trial Protocol.

INTRODUCTION: Breast cancer survivors are at greater risk for cardiovascular-related mortality compared to women without breast cancer. Accordingly, attention to reducing the risk of cardiovascular disease must be a priority in the long-term management of these patients. With the exponential rise in cancer survivors, there is a need for innovative cardio-oncology programs. This paper describes the study design of a randomised controlled trial assessing the effectiveness of a smartphone-based cardiovascular risk reduction program in improving physical activity and cardiovascular health in patients undergoing treatment for breast cancer. METHODS AND ANALYSIS: The aim of this study is to assess the efficacy and usability of a smartphone-based model of care for exercise promotion, cardiovascular risk reduction and community engagement in women undergoing treatment for breast cancer. This will be achieved by testing our personalised smartphone application "BreastMate", as an adjunct to standard care in a single-blinded, parallel, randomised controlled trial. The primary outcome of the trial is change in exercise capacity, as measured by the 6-minute walk test distance at 12 months compared to baseline. Secondary endpoints include improvements in cardiovascular risk factor status and quality of life, received dose intensity of chemotherapy and major adverse cardiovascular events. ETHICS: Multicentre ethical approval has been granted by the Austin Hospital (HREC/47081/Austin/2018). DISSEMINATION OF RESULTS: The analysed results will be published in a peer reviewed journal on completion of the clinical trial. REGISTRATION DETAILS: SMART-BREAST has been prospectively registered with the Australia and New Zealand Clinical Trials Registry (ANZCTR12620000007932).

Ischaemic heart disease and Cancer: competing malignant conditions.

BACKGROUND: The growing population of cancer survivors and their high frequency of cardiovascular disease have resulted in a dramatic increase in cancer patients requiring cardiovascular intervention. However, there is a lack of evidence to guide optimal management in this complex population who have historically been excluded from cardiovascular trials. DISCUSSION: We review the recently published meta-analysis by Roule et al. The findings of this analysis demonstrate that patients with cancer presenting with acute coronary syndrome (ACS) have increased rates of in-hospital cardiovascular mortality, bleeding and one-year cardiovascular mortality. All-cause mortality measured in-hospital and at one-year were also significantly greater in cancer patients as was all-cause mortality in cancer patients that undergo percutaneous coronary intervention (PCI). In contrast to the short-term outcomes, rates of long-term cardiovascular mortality did not differ significantly between groups. Patient-specific assessment of risk, accounting for disease characteristics and treatment, and close communication with oncology providers is vital in defining optimal treatment strategies in this population.

Renin-angiotensin system inhibition and risk of infection and mortality in COVID-19: a systematic review and meta-analysis.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, enters human cells by binding of its viral protein to the aminopeptidase angiotensin-converting enzyme 2 (ACE2). This has led to speculation whether treatment with renin-angiotensin system (RAS) inhibitors was associated with an increased likelihood of a positive test for COVID-19 and risk of mortality. AIMS: We performed a systematic review and meta-analysis to investigate whether RAS inhibitors increased the likelihood of a positive test or death/severe illness in patients with COVID-19. METHODS: A systematic search of MEDLINE, PubMed and EMBASE was conducted for studies stratified by the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). Pooled analysis was performed using a random-effects model. RESULTS: Seven trials of 73 122 patients were included. Overall, 16 624 (22.7%) patients had a positive COVID-19 test and 7892 (10.8%) were on a RAS inhibitor. RAS inhibitors were not associated with higher likelihood of a positive COVID-19 test result (odds ratio (OR) 0.97 (95% CI 0.97-1.05, P = 0.48) with low heterogeneity. This was comparable when stratifying by use of each medication class. The use of RAS inhibitors was also not associated with mortality or severe illness (OR 0.89, 95% CI 0.73-1.07, P = 0.21) with moderate heterogeneity. CONCLUSION: Use of ACEI or ARB was not associated with a heightened susceptibility for a positive diagnosis of COVID-19. Furthermore, they were not associated with increased illness severity or mortality due to COVID-19. Randomised controlled trials are needed to address definitively the potential benefits or harms of RAS inhibitors in patients with COVID-19.

Comparison of Long-Term Outcomes in Men versus Women Undergoing Percutaneous Coronary Intervention.

There has been a significant decrease in mortality associated with coronary artery disease (CAD) in recent decades, although at discordant rates between men and women. Using a well-established multicenter registry, we sought to examine the impact of gender on long-term mortality stratified by indication for percutaneous coronary intervention (PCI). Data from 54,440 consecutive patients (12,805, 23.5% women) undergoing PCI from the Victorian Cardiac Outcomes Registry (2013 to 2018) were analyzed. We aimed to compare gender-related differences of patients undergoing PCI for stable angina pectoris (SAP), non-ST-elevation acute coronary syndrome (NSTEACS) and ST-elevation myocardial infarction (STEMI). The primary outcome was long-term all-cause mortality. Female patients were older across all indications (SAP: 67 vs 71 years, NSTEACS: 64 vs 69 years, STEMI 61 vs 67 years; p value for all <0.001), with age-adjusted higher rates of diabetes mellitus (p value for all <0.02) and renal impairment (p value for all <0.001), and were more likely to have femoral artery access for intervention (p value for all <0.001). Unadjusted in-hospital and 30-day mortality rates were comparable between men and women across all indications. Compared to men, women had a higher rate of unadjusted long-term mortality (9.0% vs 7.37%; p <0.001). However, after adjusting for variables significant on univariate analysis, female gender was independently associated with improved long-term survival (HR 0.76, 95% CI 0.66 to 0.87; p <0.001). In conclusion, contrary to previous studies, despite being older with a differing clinical profile and interventional approach, women undergoing PCI have a long-term survival advantage.

SMARTphone-based, early cardiac REHABilitation in patients with acute coronary syndromes: a randomized controlled trial.

BACKGROUND: There are well-documented treatment gaps in secondary prevention of coronary heart disease with a lack of clearly defined strategies to assist early physical activity after acute coronary syndromes (ACS). Smartphone technology may provide an innovative platform to close these gaps. OBJECTIVES: The primary goal of this study was to assess whether a smartphone-based, early cardiac rehabilitation program improved exercise capacity in patients with ACS. METHODS: A total of 206 patients with ACS across six tertiary Australian hospitals were included in this randomized controlled trial. Participants were randomized to usual care (UC; including referral to traditional cardiac rehabilitation), with or without an adjunctive smartphone-based cardiac rehabilitation program (S-CRP) upon hospital discharge. The primary endpoint was change in exercise capacity, measured by the change in 6-minute walk test distance at 8 weeks when compared to baseline, between groups. Secondary endpoints included uptake and adherence to cardiac rehabilitation, changes in cardiac risk factors, psychological well-being and quality of life status. RESULTS: Of the 168 patients with complete follow-up (age 56 ± 10 years; 16% females), 83 were in the S-CRP. At 8-week follow-up, the S-CRP group had a clinically significant improvement in 6-minute walk test distance (Δ117 ± 76 vs. Δ91 ± 110 m; P = 0.02). Patients in the S-CRP were more likely to participate (87% vs. 51%, P < 0.001) and adhere (72% vs. 22%, P < 0.001) to a cardiac rehabilitation program. Compared to UC, patients receiving S-CRP had similar smoking cessation rates, LDL-cholesterol levels, blood pressure reduction, depression, anxiety and quality of life measures (all P = NS). CONCLUSION: In patients with ACS, a S-CRP, as an adjunct to UC improved exercise capacity at 8 weeks in addition to participation and adherence to cardiac rehabilitation (Australian New Zealand Clinical Trials Registry; ACTRN12616000426482).

Efficacy of Smartphone-Based Secondary Preventive Strategies in Coronary Artery Disease.

BACKGROUND: Cardiac rehabilitation programs provide a comprehensive framework for the institution of secondary preventive measures. Smartphone technology can provide a platform for the delivery of such programs and is a promising alternative to hospital-based services. However, there is limited evidence to date supporting this approach. Accordingly, we performed a systematic review and meta-analysis examining smartphone-based secondary prevention programs to traditional cardiac rehabilitation in patients with established coronary artery disease to ascertain the feasibility and effectiveness of these interventions. METHODS: A systematic search of PubMed, MEDLINE, EMBASE, and the Cochrane Library was conducted. A meta-analysis was performed using a random-effects model with the outcomes of interest being 6-minute walk test (6MWT) distance, systolic blood pressure, low-density lipoprotein (LDL) cholesterol, and body mass index (BMI). RESULTS: A total of 8 studies with 1120 patients across 5 countries were included in the quantitative analysis. Follow-up ranged from 6 weeks to 12 months. Five studies examined all patients post acute coronary syndrome, 2 studies examined only patients undergoing percutaneous coronary intervention, and 1 study examined all patients with a diagnosis of coronary artery disease, independent of intervention. Exercise capacity, as measured by the 6MWT, was significantly greater in the smartphone group (20.10 meters, 95% confidence interval [CI] 7.44-33.97; P < .001; I 2 = 45.58). There was no significant difference in BMI reduction, systolic blood pressure, or LDL cholesterol levels between groups (P value for all > .05). CONCLUSION: Publicly available smartphone-based cardiac rehabilitation programs are a convenient and easily disseminated intervention which show merit in exercise promotion in patients with established coronary artery disease. Further research is required to establish the clinical significance of recent findings favoring their use.

Impact of Gender and Door-to-Balloon Times on Long-Term Mortality in Patients Presenting With ST-Elevation Myocardial Infarction.

Guidelines mandate emergent revascularization in patients presenting with ST-elevation myocardial infarction (STEMI) irrespective of gender. We sought to compare the door-to-balloon times and the impact of timely reperfusion on clinical outcomes in women compared with men presenting with STEMI undergoing primary percutaneous coronary intervention (PPCI). We analyzed data from 6,179 consecutive patients presenting with STEMI undergoing PPCI from the Melbourne Interventional Group registry (2005 to 2017). The primary outcome was long-term mortality. Of the 6,179 patients included 1,258 (20.3%) were female. Female patients were older (69 ± 13 vs 62 ± 12 years; p < 0.001), had more co-morbidities and had longer median symptom-to-balloon times (204 [interquartile range {IQR} 154 to 294] vs 181 [IQR 139 to 258] minutes; p < 0.001) and longer median door-to-balloon times (81 [IQR 55 to 102] vs 75 [IQR 51 to 102)] minutes; p < 0.001), while receiving less drug-eluting stents (39% vs 43%; p = 0.01) and having less radial access for PPCI (15% vs 21%; p < 0.001). Furthermore, female patients received less guideline-directed medical therapy than men with less prescription of aspirin (93.4% vs 95.4%; p = 0.02), statins (96.5% vs 97.6%; p < 0.05), and beta blockers (84.3% vs 89.4%; p < 0.001). Unadjusted in-hospital and 30-day mortality rates were higher in women (8.8% vs 6.2%, 9.8% vs 6.9%; p < 0.001). However, on Cox-proportional hazards modeling, gender was not an independent predictor of long-term mortality (hazards ratio 0.99, 95% confidence interval 0.83 to 1.18; p = 0.92) at a mean follow-up of 4.8 ± 3.5 years. In conclusion, in this large multicenter registry of patients with STEMI, women had longer ischemic times, higher risk profiles, and differing interventional approaches compared with men. Addressing these gender inequalities with early identification of symptoms, adherence to guideline-directed medical therapy, as well as higher rates of radial access and use of drug-eluting stents has the potential to further improve outcomes in women with STEMI.