Heart failure pharmacotherapy and cancer: pathways and pre-clinical/clinical evidence.

Heart failure (HF) patients have a significantly higher risk of new-onset cancer and cancer-associated mortality, compared to subjects free of HF. While both the prevention and treatment of new-onset HF in patients with cancer have been investigated extensively, less is known about the prevention and treatment of new-onset cancer in patients with HF, and whether and how guideline-directed medical therapy (GDMT) for HF should be modified when cancer is diagnosed in HF patients. The purpose of this review is to elaborate and discuss the effects of pillar HF pharmacotherapies, as well as digoxin and diuretics on cancer, and to identify areas for further research and novel therapeutic strategies. To this end, in this review, (i) proposed effects and mechanisms of action of guideline-directed HF drugs on cancer derived from pre-clinical data will be described, (ii) the evidence from both observational studies and randomized controlled trials on the effects of guideline-directed medical therapy on cancer incidence and cancer-related outcomes, as synthetized by meta-analyses will be reviewed, and (iii) considerations for future pre-clinical and clinical investigations will be provided.

Cardiovascular organ damage in relation to hypertension status in patients with ankylosing spondylitis.

PURPOSE: Hypertension is a major cardiovascular (CV) risk factor in ankylosing spondylitis (AS) patients. Less is known about the prevalence of CV organ damage in relation to hypertension status in AS patients. MATERIALS AND METHODS: CV organ damage was assessed by echocardiography, carotid ultrasound and pulse wave velocity (PWV) by applanation tonometry in 126 AS patients (mean age 49 ± 12 years, 39% women) and 71 normotensive controls (mean age 47 ± 11 years, 52% women). CV organ damage was defined as presence of abnormal left ventricular (LV) geometry, LV diastolic dysfunction, left atrial (LA) dilatation, carotid plaque or high pulse wave velocity (PWV). RESULTS: Thirty-four percent of AS patients had hypertension. AS patients with hypertension were older and had higher C-reactive protein (CRP) levels compared to AS patients without hypertension and controls (p < 0.05). The prevalence of CV organ damage was 84% in AS patients with hypertension, 29% in AS patients without hypertension and 30% in controls (p < 0.001). In multivariable logistic regression analyses, having hypertension was associated with a fourfold increased risk of CV organ damage independent of age, presence of AS, gender, body mass index, CRP, and cholesterol (odds ratio (OR) 4.57, 95% confidence interval (CI) 1.53 to 13.61, p = 0.006). In AS patients, presence of hypertension was the only covariable significantly associated with presence of CV organ damage (OR 4.40, 95% CI 1.40 to 13.84, p = 0.011). CONCLUSIONS: CV organ damage in AS was strongly associated with hypertension, pointing to the importance of guideline-based hypertension management in AS patients.

What is the context? Ankylosing spondylitis (AS) is an inflammatory disease primarily affecting the spine. Patients with AS have increased risk for cardiovascular disease. High blood pressure (hypertension) is both very common in AS patients, and a major risk factor for developing cardiovascular disease. Hypertension leads to structural and functional changes in the heart and arteries, referred to as cardiovascular organ damage. However, little is known about the prevalence of cardiovascular organ damage in AS patients with hypertension.What is new? Using ultrasound and tonometry, we assessed organ damage in the heart and arteries in AS patients with hypertension and compared them to AS patients with normal blood pressure as well as a group of healthy controls. We found that 84% of the AS patients with hypertension had cardiovascular organ damage, compared to 29% of AS patients with normal blood pressure and 30% of controls. Independent of other risk factors, hypertension was associated with a fourfold increased risk of cardiovascular organ damage in AS patients.What is the impact? These findings are important because cardiovascular organ damage is potentially reversible with treatment. Our results underline the significance of guideline-directed hypertension management in AS patients to reduce cardiovascular disease.

All-cause and cause-specific mortality in rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis: a nationwide registry study.

OBJECTIVES: To explore mortality and causes of death among Norwegian patients with RA, PsA and axial spondyloarthritis (axSpA) compared with the general population by conducting a nationwide registry-based cohort study. METHODS: Patients with RA, PsA and axSpA were identified from the Norwegian Patient Registry based on ICD-10 codes between 2008 and 2017. Using age as the time variable, all-cause and cause-specific mortality were estimated between 2010 and 2017 with the Kaplan-Meier estimator and the cumulative incidence competing risk method, respectively. Sex-, education level-, health region- and age group-adjusted hazard ratios (HRs) for mortality were estimated using Cox regression models. RESULTS: We identified 36 095 RA, 18 700 PsA and 16 524 axSpA patients (70%, 53% and 45% women, respectively). RA and axSpA were associated with increased all-cause mortality (HR 1.45 [95% CI: 1.41, 1.48] and HR 1.38 [95% CI: 1.28, 1.38], respectively). Women but not men with PsA had a slightly increased mortality rate (HR 1.10 [95% CI: 1.00, 1.21] among women and 1.02 [95% CI: 0.93, 1.11] among men). For all patient groups as well as for the general population, the three leading causes of death were cardiovascular diseases, neoplasms and respiratory diseases. RA patients had increased mortality from all of these causes, while axSpA patients had increased mortality from cardiovascular and respiratory diseases. CONCLUSION: Even in the era of modern treatments for IJDs, patients with RA and axSpA still have shortened life expectancy. Our findings warrant further attention to the prevention and management of comorbidities.

Long-term cardiovascular prognosis of patients with type 1 diabetes after myocardial infarction.

BACKGROUND: To explore long-term cardiovascular prognosis after myocardial infarction (MI) among patients with type 1 diabetes. METHODS: Patients with type 1 diabetes surviving 90 days after MI (n = 1508; 60% male, mean age = 62.1 years) or without any type of diabetes (n = 62,785) in Finland during 2005-2018 were retrospectively studied using multiple national registries. The primary outcome of interest was a combined major adverse cardiovascular event (MACE; cardiovascular death, recurrent MI, ischemic stroke, or heart failure hospitalization) studied with a competing risk Fine-Gray analyses. Median follow-up was 3.9 years (maximum 12 years). Differences between groups were balanced by multivariable adjustments and propensity score matching (n = 1401 patient pairs). RESULTS: Cumulative incidence of MACE after MI was higher in patients with type 1 diabetes (67.6%) compared to propensity score-matched patients without diabetes (46.0%) (sub-distribution hazard ratio [sHR]: 1.94; 95% confidence interval [CI]: 1.74-2.17; p < 0.0001). Probabilities of cardiovascular death (sHR 1.81; p < 0.0001), recurrent MI (sHR 1.91; p < 0.0001), ischemic stroke (sHR 1.50; p = 0.0003), and heart failure hospitalization (sHR 1.98; p < 0.0001) were higher in patients with type 1 diabetes. Incidence of MACE was higher in diabetes patients than in controls in subgroups of men and women, patients aged < 60 and ≥ 60 years, revascularized and non-revascularized patients, and patients with and without atrial fibrillation, heart failure, or malignancy. CONCLUSIONS: Patients with type 1 diabetes have notably poorer long-term cardiovascular prognosis after an MI compared to patients without diabetes. These results underline the importance of effective secondary prevention after MI in patients with type 1 diabetes.

Preclinical cardiac organ damage during statin treatment in patients with inflammatory joint diseases: the RORA-AS statin intervention study.

OBJECTIVE: Statin treatment has been associated with reduction in blood pressure and arterial stiffness in patients with inflammatory joint diseases (IJD). We tested whether statin treatment also was associated with regression of preclinical cardiac organ damage in IJD patients. METHODS: Echocardiography was performed in 84 IJD patients (52 RA, 20 ankylosing spondylitis, 12 psoriatric arthritis, mean age 61 (9) years, 63% women) without known cardiovascular disease before and after 18 months of rosuvastatin treatment. Preclinical cardiac organ damage was identified by echocardiography as presence of left ventricular (LV) hypertrophy, LV concentric geometry, increased LV chamber size and/or dilated left atrium. RESULTS: At baseline, hypertension was present in 63%, and 36% used biologic DMARDs (bDMARDs). Preclinical cardiac organ damage was not influenced by rosuvastatin treatment (44% at baseline vs 50% at follow-up, P = 0.42). In uni- and multivariable logistic regression analyses, risk of preclinical cardiac organ damage at follow-up was increased by higher baseline body mass index [odds ratio (OR) 1.3, 95% CI: 1.1, 1.5, P = 0.01] and presence of preclinical cardiac organ damage at baseline (OR 6.4, 95% CI: 2.2, 18.5, P = 0.001) and reduced by use of bDMARDs at follow-up (OR 0.3, 95% CI: 0.1, 0.9, P = 0.03). CONCLUSION: Rosuvastatin treatment was not associated with a reduction in preclinical cardiac organ damage in IJD patients after 18 months of treatment. However, use of bDMARDS at follow-up was associated with lower risk of preclinical cardiac organ damage at study end, pointing to a possible protective cardiac effect of bDMARDs in IJD patients. CLINICALTRIALS.GOV: https://clinicaltrials.gov/NCT01389388.

Smoking cessation is associated with lower disease activity and predicts cardiovascular risk reduction in rheumatoid arthritis patients.

OBJECTIVES: Smoking is a major risk factor for the development of both cardiovascular disease (CVD) and RA and may cause attenuated responses to anti-rheumatic treatments. Our aim was to compare disease activity, CVD risk factors and CVD event rates across smoking status in RA patients. METHODS: Disease characteristics, CVD risk factors and relevant medications were recorded in RA patients without prior CVD from 10 countries (Norway, UK, Netherlands, USA, Sweden, Greece, South Africa, Spain, Canada and Mexico). Information on CVD events was collected. Adjusted analysis of variance, logistic regression and Cox models were applied to compare RA disease activity (DAS28), CVD risk factors and event rates across categories of smoking status. RESULTS: Of the 3311 RA patients (1012 former, 887 current and 1412 never smokers), 235 experienced CVD events during a median follow-up of 3.5 years (interquartile range 2.5-6.1). At enrolment, current smokers were more likely to have moderate or high disease activity compared with former and never smokers (P < 0.001 for both). There was a gradient of worsening CVD risk factor profiles (lipoproteins and blood pressure) from never to former to current smokers. Furthermore, former and never smokers had significantly lower CVD event rates compared with current smokers [hazard ratio 0.70 (95% CI 0.51, 0.95), P = 0.02 and 0.48 (0.34, 0.69), P < 0.001, respectively]. The CVD event rates for former and never smokers were comparable. CONCLUSION: Smoking cessation in patients with RA was associated with lower disease activity and improved lipid profiles and was a predictor of reduced rates of CVD events.

High intensity exercise for 3 months reduces disease activity in axial spondyloarthritis (axSpA): a multicentre randomised trial of 100 patients.

BACKGROUND: Exercise is considered important in the management of patients with rheumatic diseases, but the effect of high intensity exercises on disease activity is unknown. OBJECTIVE: To investigate the effectiveness of high intensity exercises on disease activity in patients with axial spondyloarthritis (axSpA). METHOD: Assessor blinded multicentre randomised controlled trial. 100 patients (aged from their 20s to their 60s) with axSpA were randomly assigned to an exercise group or to a no-intervention control group. The exercise group performed cardiorespiratory and muscular strength exercises at high intensity over 3 months. The control group received standard care and was instructed to maintain their usual physical activity level. Primary outcome was disease activity measured with the Ankylosing Spondylitis (AS) Disease Activity Scale (ASDAS, higher score=worst) and the Bath AS Disease Activity Index (BASDAI, 0-10, 10=worst). Secondary outcomes were inflammatory markers, physical function and cardiovascular (CV)-health. There was patient involvement in the design and reporting of this study. RESULTS: 97 of the 100 (97%) randomised patients completed the measurements after the intervention. There was a significant treatment effect of the intervention on the primary outcome (ASDAS: -0.6 [-0.8 to -0.3], p<0.001 and BASDAI: -1.2 [-1.8 to -0.7], p<0.001). Significant treatment effects were also seen for inflammation, physical function and CV-health. CONCLUSION: High intensity exercises reduced disease symptoms (pain, fatigue, stiffness) and also inflammation in patients with axSpA. It improves patients' function and CV health. This debunks concerns that high intensity exercise might exacerbate disease activity in patients with axSpA. TRIAL REGISTRATION NUMBER: NCT02356874.

Impact of risk factors associated with cardiovascular outcomes in patients with rheumatoid arthritis.

OBJECTIVES: Patients with rheumatoid arthritis (RA) have an excess risk of cardiovascular disease (CVD). We aimed to assess the impact of CVD risk factors, including potential sex differences, and RA-specific variables on CVD outcome in a large, international cohort of patients with RA. METHODS: In 13 rheumatology centres, data on CVD risk factors and RA characteristics were collected at baseline. CVD outcomes (myocardial infarction, angina, revascularisation, stroke, peripheral vascular disease and CVD death) were collected using standardised definitions. RESULTS: 5638 patients with RA and no prior CVD were included (mean age: 55.3 (SD: 14.0) years, 76% women). During mean follow-up of 5.8 (SD: 4.4) years, 148 men and 241 women developed a CVD event (10-year cumulative incidence 20.9% and 11.1%, respectively). Men had a higher burden of CVD risk factors, including increased blood pressure, higher total cholesterol and smoking prevalence than women (all p<0.001). Among the traditional CVD risk factors, smoking and hypertension had the highest population attributable risk (PAR) overall and among both sexes, followed by total cholesterol. The PAR for Disease Activity Score and for seropositivity were comparable in magnitude to the PAR for lipids. A total of 70% of CVD events were attributable to all CVD risk factors and RA characteristics combined (separately 49% CVD risk factors and 30% RA characteristics). CONCLUSIONS: In a large, international cohort of patients with RA, 30% of CVD events were attributable to RA characteristics. This finding indicates that RA characteristics play an important role in efforts to reduce CVD risk among patients with RA.

Disease activity is associated with reduced left ventricular systolic myocardial function in patients with rheumatoid arthritis.

OBJECTIVES: Disease activity has emerged as a new, independent risk factor for cardiovascular disease in patients with rheumatoid arthritis (RA). We tested if disease activity in RA was associated with lower left ventricular (LV) systolic function independent of traditional cardiovascular risk factors. METHODS: Echocardiographic assessment was performed in 78 patients with RA having low, moderate or high disease activity (Simplified Disease Activity Index (SDAI) >3.3), 41 patients in remission (SDAI ≤3.3) and 46 controls, all without known cardiac disease. LV systolic function was assessed by biplane Simpson ejection fraction, stress-corrected midwall shortening (scMWS) and global longitudinal strain (GLS). RESULTS: Patients with active RA had higher prevalence of hypertension and diabetes compared with patients in remission and controls (both p<0.05). LV ejection fraction (endocardial function) was normal in all three groups, while mean scMWS and GLS (myocardial function) were reduced in patients with RA with active disease compared with patients with RA in remission (95±18% vs 105±17% and -18.9±3.1% vs -20.6±3.5%, respectively, both p<0.01). Patients with RA in remission had similar scMWS and GLS as the controls. In multivariable analyses, having active RA was associated with lower GLS (ß=0.21) and scMWS (ß=-0.22, both p<0.05), both reflecting lower LV systolic myocardial function, independent of cardiovascular risk factors and LV ejection fraction. Classification of RA disease activity by other disease activity composite scores yielded similar results. CONCLUSIONS: Active RA is associated with lower LV systolic myocardial function despite normal ejection fraction and independent of traditional cardiovascular risk factors.

Rheumatoid arthritis-specific cardiovascular risk scores are not superior to general risk scores: a validation analysis of patients from seven countries.

Objectives: Cardiovascular disease (CVD) risk calculators developed for the general population do not accurately predict CVD events in patients with RA. We sought to externally validate risk calculators recommended for use in patients with RA including the EULAR 1.5 multiplier, the Expanded Cardiovascular Risk Prediction Score for RA (ERS-RA) and QRISK2. Methods: Seven RA cohorts from UK, Norway, Netherlands, USA, South Africa, Canada and Mexico were combined. Data on baseline CVD risk factors, RA characteristics and CVD outcomes (including myocardial infarction, ischaemic stroke and cardiovascular death) were collected using standardized definitions. Performance of QRISK2, EULAR multiplier and ERS-RA was compared with other risk calculators [American College of Cardiology/American Heart Association (ACC/AHA), Framingham Adult Treatment Panel III Framingham risk score-Adult Treatment Panel (FRS-ATP) and Reynolds Risk Score] using c-statistics and net reclassification index. Results: Among 1796 RA patients without prior CVD [mean ( s . d .) age: 54.0 (14.0) years, 74% female], 100 developed CVD events during a mean follow-up of 6.9 years (12430 person-years). Estimated CVD risk by ERS-RA [mean ( s . d .) 8.8% (9.8%)] was comparable to FRS-ATP [mean ( s . d .) 9.1% (8.3%)] and Reynolds [mean ( s . d .) 9.2% (12.2%)], but lower than ACC/AHA [mean ( s . d .) 9.8% (12.1%)]. QRISK2 substantially overestimated risk [mean ( s . d .) 15.5% (13.9%)]. Discrimination was not improved for ERS-RA (c-statistic = 0.69), QRISK2 or EULAR multiplier applied to ACC/AHA compared with ACC/AHA (c-statistic = 0.72 for all) or for FRS-ATP (c-statistic = 0.75). The net reclassification index for ERS-RA was low (-0.8% vs ACC/AHA and 2.3% vs FRS-ATP). Conclusion: The QRISK2, EULAR multiplier and ERS-RA algorithms did not predict CVD risk more accurately in patients with RA than CVD risk calculators developed for the general population.

On the HUNT for cardiovascular risk factors and disease in patients with psoriatic arthritis: population-based data from the Nord-Trøndelag Health Study.

OBJECTIVE: To compare the presence of cardiovascular (CV) risk factors and established CV disease in patients with psoriatic arthritis (PsA) and the general population and to compare the 10-year risk of a fatal CV event calculated by the Systematic Coronary Risk Evaluation (SCORE) algorithm. METHODS: Patients with PsA (n=338) and controls (n=50 468) were recruited from the Nord-Trøndelag Health Study 3. Age-adjusted and sex-adjusted prevalence rates of CV risk factors and comorbidity were calculated and the SCORE algorithm was applied. RESULTS: There was an increased prevalence of angina pectoris (5.0% vs 3.6%, p=0.01), history of percutaneous coronary intervention (2.4% vs 1.4%, p=0.04), hypertension (45.3% vs 39.3%, p=0.01), obesity (32.0% vs 22.4%) and tobacco smoking (21.3% vs 16.4%, p=0.02) in patients with PsA compared with controls. Patients with PsA had elevated levels of C reactive protein (CRP; p<0.001), body mass index (BMI; p<0.001) and triglycerides (p=0.01). The median calculated CV risk in patients with PsA was low and comparable with controls (0.87 vs 0.83, p=0.24). The distribution across CV risk classes was similar among patients with PsA and controls. CONCLUSIONS: Patients with PsA have a higher risk of CV disease than the background population, although there was no difference between groups in 10-year risk of a fatal CV event estimated by SCORE. However, patients with PsA had elevated levels of CV risk factors not included in the SCORE algorithm, such as BMI, triglycerides and CRP.

The association of hypertension with asymptomatic cardiovascular organ damage in rheumatoid arthritis.

BACKGROUND: The association of hypertension with asymptomatic cardiovascular organ damage in patients with rheumatoid arthritis (RA) has been little studied by echocardiography. METHODS: Echocardiography was done in 134 RA patients and 102 healthy controls. Left ventricular (LV) geometry was considered abnormal if LV mass index or relative wall thickness was increased. LV diastolic dysfunction was considered present if septal early diastolic tissue velocity <8 cm/s. Systemic arterial compliance (SAC) was assessed from stroke volume index/pulse pressure ratio. RESULTS: The hypertensive RA patients (n = 72) had higher inflammatory activity, older age and more diabetes than the normotensive RA patients (n = 62) (all p < 0.05). Rates of abnormal LV geometry, LV diastolic dysfunction and lower SAC were higher among the hypertensive RA patients (p < 0.05), but similar between normotensive RA patients and controls. Hypertension was associated with a 3-fold higher prevalence both for abnormal LV geometry (odds ratio 2.89 [95% confidence interval 1.09-7.63], p = 0.03) and for diastolic LV dysfunction (odds ratio 2.92 [95% confidence interval 1.14-7.46], p = 0.03) as well as lower SAC (ß = 0.31, p = 0.001) independent of age, gender, diabetes and inflammatory activity measured by erythrocyte sedimentation rate. CONCLUSION: The presence of asymptomatic cardiovascular organ damage in RA patients is closely associated with hypertension independent of inflammatory activity.

CRP and ASDAS are associated with future elevated arterial stiffness, a risk marker of cardiovascular disease, in patients with ankylosing spondylitis: results after 5-year follow-up.

OBJECTIVE: To identify factors associated with elevated arterial stiffness in a 5-year follow-up of patients with ankylosing spondylitis (AS). METHODS: C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), Bath AS disease activity index (BASDAI) and AS disease activity score (ASDAS) were recorded in 2003, and arterial stiffness (Augmentation Index (AIx) and pulse wave velocity (PWV)) in 2008/2009. Patients were grouped into quartiles according to baseline CRP, ESR and BASDAI and four ASDAS groups. Trend analyses were performed using ANCOVA (AIx/PWV as dependent variable) with separate models for CRP, ESR, BASDAI and ASDAS (age and gender adjusted). Independent predictors of future AIx and PWV levels were identified in multivariate linear regression models. RESULTS: In total, 85 patients participated. Increasing baseline values of CRP, ESR and ASDAS were associated with elevated AIx on follow-up (p(trend) 0.01, 0.05 and 0.04, respectively). Similar non-significant patterns were seen for PWV. In the multivariate analyses, baseline CRP and ASDAS were independently associated with future elevated AIx (p=0.03 and0.02, respectively). In the multivariate PWV model, results for CRP and ASDAS were non-significant. CONCLUSIONS: Baseline CRP and ASDAS were associated with future elevated arterial stiffness measured as AIx, supporting that disease activity is related to future risk of cardiovascular disease in patients with AS.

Disease activity and left ventricular structure in patients with rheumatoid arthritis.

OBJECTIVE: Increased left ventricular (LV) wall thickness/internal diameter ratio (relative wall thickness) was recently reported in RA patients. The aim of this study was to assess the association between LV relative wall thickness and RA disease activity. METHODS: Clinical and echocardiographic data from 129 RA patients without established cardiovascular disease and 102 controls were used. RA disease activity was assessed by different composite scores and active RA defined by the Simplified Disease Activity Index (SDAI) level exceeding the cut-off for remission (SDAI >3.3). RESULTS: The RA patients were on average 61.3 years old, 77% were women and 67% had active RA (SDAI >3.3). Patients with active RA had greater LV relative wall thickness and included more patients with treated hypertension (all P < 0.05), but had LV mass index and blood pressure comparable to patients in remission. Having active RA by the SDAI score (ß = 0.20, P = 0.008) was also independently associated with greater LV relative wall thickness after adjusting for systolic blood pressure, wall stress, age and sex in a multivariate model. This association was robust also in secondary models including other disease activity composite scores such as the Clinical Disease Activity Index and 28-joint DAS. CONCLUSION: Among RA patients, higher disease activity was independently associated with greater LV relative wall thickness, reflecting subclinical heart disease. The findings point to the importance of disease activity control in RA patients to prevent progression to clinical heart disease.