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Cardiovascular risk management in COPD patients: impact of the new Dutch guideline.

BACKGROUND
Patients with COPD have an independent increased risk of cardiovascular (CV) disease. CV-risk (CVR) assessment should be offered to all COPD-patients according to the new Dutch 'CVR management' (CVRM) guideline (May-2019).


AIM
To evaluate the impact of this new guideline for the care of COPD-patients in primary care.


DESIGN AND SETTING
A retrospective study within five primary healthcare centres located in the Netherlands.


METHODS
In accordance with the guideline we estimated and categorized the CVR of all COPD-patients. Data from 2014-2019 were used for the qualitative risk assessment based on comorbidities, and the quantitative Systematic Coronary Risk Assessment (SCORE). In addition, we investigated the guideline-based follow-up.


RESULTS
Of the 391 COPD-patients, 84.1% (n=329) had complete data on CVR assessment: 90.3% (n=297) had a (very)-high risk and 9.7% (n=32) a low-to-moderate risk. Of the patients with (very)-high risk, 73.4% (n=218) received guideline-based follow-up (primary care: 95.4%, secondary care: 4.6%). In 15.9% (n=62) of all COPD-patients, the CVR profile was not measured and of the (very)-high-risk patients, 26.6% (n=79) was not enrolled in a CV-care program.


CONCLUSION
Whereas in the majority of patients the CVR is already known, for one out of six COPD-patients this CVR still has to be assessed according to the recently updated guideline. Moreover, once a (very)-high risk has been assessed, as a consequence CV treatment of risk factors should be intensified in one out of four COPD-patients. Adherence to the new CVRM guideline could provide improvement in CVRM in more than a third of all COPD-patients.


INTRODUCTION
Approximately 30-50% of deaths in chronic obstructive pulmonary disease (COPD) patients are attributed to cardiovascular (CV) events (e.g. myocardial infarction). [1][2][3][4] The relative risk of CV morbidity is 2.5 times higher compared to individuals without COPD, sharing the same classic CV risk (CVR) factors (e.g. smoking). 5,6 Whether this relative risk of 2.5 on CV morbidity also holds for CV mortality remains unclear. However, it implies that COPD is an independent predictor for CV disease (CVD).
There is increasing evidence that oxidative stress causes pulmonary inflammation and that the remaining circulating pro-inflammatory mediators (cytokines) cause systemic inflammation and induce atherosclerosis. 7 In addition, the altered mediators of oxidative stress (NO) in vascular endothelial cells influence the vessel tone causing vascular dysfunction, a key driver of CVD. 7 In a population-based cohort study in Dutch community-dwelling middle-aged and elderly persons, a ∼30% increased risk of sudden cardiac death in subjects with COPD was found. 2 The Dutch 'Multidisciplinary guideline on cardiovascular risk management' (CVRM) was used nationally in the last two decades to reduce CVD morbidity and death in the Netherlands. Based on aforementioned insight from recent research, the in 2019 updated Dutch CVRM guideline advises to offer all COPD patients CVR assessment. 8,9 The guideline promotes early treatment for CVR factors in patients with a very-high or high CVR by chronic-disease-management strategies.
Reduction of CVR will require optimal implementation of CVRM. [10][11][12] To align the quality improvement of CVRM with the stressed importance of CVR assessment every five years in all COPD patients, more insight is needed into whether and how CVR assessment is currently performed in the COPD population. The aim of this study is to evaluate the impact of the new guideline for the care of COPD patients in primary care. In how many COPD patients should CVR profiles be measured and what is the proportion of patients in which treatment should be intensified?

Study population and setting
Within five primary healthcare centres located in the centre of the in the Netherlands, we conducted a retrospective study using routine care data of patients with COPD (ICPC code R95). In accordance with the CVRM guideline we investigated their CVR using the qualitative risk assessment based on CV-related comorbidities, and when absent, we used the quantitative risk assessment: Systematic CVRM is a guideline-based approach to determine and treat all relevant CVR factors to prevent the development of (recurrent) CVD. Patients with any CVR factor have an indication to determine the CVR profile and estimate their CVR by risk assessment. In patients with a low-tomoderate risk, the risk is re-estimated every five years. Patients with very-high or high CVR are enrolled in a CV-care program.

Data collection
CVR profiles were extracted over five years (01-09-2014 till 31-08-2019), of which most recent measurements in the electronic medical records (EMR) were used. Enrolment rates for the CV-care A c c e p t e d M a n u s c r i p t -B J G P O p e n -b j g p o p e n 2 0 X 1 0 1 1 3 9 programs were collected on 31-08-2019. Patients at the healthcare centres had consented for use of their routine care data for scientific purpose and quality improvement evaluation.

Patient characteristics
Extracted patient characteristics were sex, age (years), body-mass index (BMI) (kg/m 2 ), GOLD classification (I-IV), frailty and polypharmacy. Data on frailty (proportion of deficits > 0.2 by Frailty Index) and polypharmacy (≥ 5 chronic medications) were dichotomized (yes/no) and only available for patients aged 60 years and older. 13,14

Cardiovascular-care programs
Patients with an estimated very-high or high CVR have an indication to participate in one of the CVcare programs within chronic-disease management. These programmatic consultations provide treatment and follow-up of CVR factors and can be provided in three different CV programs: 'diabetes care', 'established CVD care' or '(very)-high vascular-risk care'. Enrolment in one of these CV-care programs was extracted from the EMR.

Cardiovascular-risk assessments
After establishing the risk profiles, the CVRs were estimated using step-by-step hierarchical procedure in accordance with the guideline (figure 1). In following detailed order, each patient was assigned to one risk category based on their risk score.

Qualitative risk assessment
First, patients with DM were considered to have a 'very-high CVR', having one of the following complications or risk factors: macrovascular complication (CVD), microvascular complication (nephropathy, neuropathy, retinopathy), positive smoking status, total TC > 8 mmol/L or systolic BP ≥ 180 mmHg. 15 Remaining DM patients were considered to have a 'high CVR'. 8 Patients with established CVD (including coronary heart disease, ischaemic cerebral vascular disease, peripheral arterial disease or atherosclerosis of major arteries) without DM were classified as having a 'very-high CVR'. 8 CKD was defined as severe or moderate (figure 1). The remaining patients with severe CKD were considered as 'very-high CVR' and moderate CKD as 'high CVR'. 8 Patients with mere one serious CVR factor, such as severe hypercholesterolaemia (TC > 8 mmol/L) or severely increased BP (systolic BP ≥ 180 mmHg), were considered as 'high CVR'. 8

Quantitative risk assessment
For patients that had no data on qualitative CVR assessment, we estimated the absolute 10-year risk of fatal CVD event using the SCORE algorithm based on sex, age, smoking status, BP and TC/HDLc. 8 The guideline describes that regardless of risk factors, patients < 40 years do almost all have an absolute 'low-to-moderate CVR' and patients > 70 years an absolute 'very-high CVR'. Those patients were classified as such when having complete data regarding the SCORE.
For patients using antihypertensive therapy and/or lipid-lowering therapy the risk could not be examined by SCORE due to the use of CV medication. 8 We assumed that these medications were initiated by a quantitative estimated (very)-high CVR. We considered those patients as having an absolute 'high CVR', regardless of completeness of data.

Cardiovascular-risk categories
We classified patients as having a 'very-high' (≥ 10%), a 'high' (≥ 5% and < 10%) and a 'low-tomoderate CVR' (< 5%). For patients with incomplete data on both assessments, we were not able to assess their CVR. We considered them to have an 'unknown CVR' and only described the patient characteristics and the reported risk factors.

Analysis
Descriptive statistics were used. Data are shown as numbers with percentages or means with standard deviation. Median with interquartile range was used when variables were not normally distributed. Statistical analyses were performed using SPSS Statistics for Windows (version 25.0).

Study population
There were 43,426 patients registered within the healthcare centres, of which 391 were diagnosed with COPD; unfolding a 0.9% prevalence of COPD (figure 2).
The patient characteristics are shown in Table 1. Mean age was 67.5 years (SD = 10.8) and 46.5% was male. A total of 43.5% of the patients was currently smokers. Three out of four of the COPD population was ≥ 60 years, of those elderly patients 64.0% was frail and 56.5% used polypharmacy.

Unknown cardiovascular-risk group
Of the patients with unknown risks, 48.4% was current smokers. Almost half of the patients was ≥ 60 A c c e p t e d M a n u s c r i p t -B J G P O p e n -b j g p o p e n 2 0 X 1 0 1 1 3 9 years, of those 41.4% was frail and 24.1% used polypharmacy. The lipid spectrum was missing in 93.5%, systolic BP in 25.8% and smoking status in 16.1% (supplementary table 2).

Cardiovascular-care program
Of the 297 (very)-high-risk patients, 218 patients (73.4%) received guideline-based follow-up: 208 (95.4%) a CV-care program in primary care and 10 (4.6%) in secondary care. The remaining 79 patients (26.6%) was not enrolled in a CV-care program, as they should be ( figure 2, figure 1).

Unprovided cardiovascular-care program
The proportion '(very)-high-risk patients without CV-care program' was two times higher for the quantitative risk group than for the qualitative risk group (n=34, 39.5% vs. n=45, 18.6%) (figure 3).

Strengths and limitations
This study describes the assessment of CVRs and provided care for (very)-high CVR in a Dutch cohort of COPD patients. It underlines the urgency of assessment of CVR in all COPD patients, to reduce the incidence of CVD in these patients over the next decades.
Making use of reported risk factors we have identified all COPD patients with a possibly known and unknown CVR. However, we have determined CVRs by extracting data from the EMR, but we do not know whether the healthcare professional actually combined the various data to determine the CVR. This could have caused an underestimation of the 'unknown CVRs'. Therefore, we have tried to identify this underestimation by determining the '(very)-high-risk patients not enrolled in a CVcare program', given that these patients already had an indication and should be enrolled. Combining the 'unknown risks' and the '(very)-high risks without CV-care program' we were able to make a good estimation of the possible impact of the new guideline by adherence.
A clear limitation in this study is that we made some assumptions when the SCORE was not applicable. Since CV medication use is an indication for enrolment in a CV-care program, we have assumed that patients who use CV medication had a 'high CVR'. However, we do not know for sure A c c e p t e d M a n u s c r i p t -B J G P O p e n -b j g p o p e n 2 0 X 1 0 1 1 3 9 whether the healthcare professional determined this risk before starting drug therapy. In accordance with the guideline, we have also assumed that patients younger than 40 years had a 'low-to-moderate CVR' and that patients older than 70 years had a 'very-high CVR' using the SCORE.
Comparison with existing literature -The impact of the new guideline (unknown risks): According to the new Dutch guideline, the CVR should be known for every COPD patient. 3 By estimating CVRs with reported risk factors, we showed that 15.9% (n = 62) of patients had incomplete data on CVR assessment. This was mainly due to an unknown lipid spectrum. As expected, smoking status was well recorded, being a disease variable that has traditionally been a part of COPD care. This finding underlines the importance of a structured approach for recording CVR profiles into COPD disease-management program.
The primary care centres where our study was conducted are located in a newly developed large residential area near Utrecht. The average age in this area is slightly younger than the overall Dutch population (32.1 vs. 41.0 years). Since the onset of COPD exceeds middle age, the prevalence in our population is lower than nationwide prevalence (0.9% vs. 1.9%). This can very well mean that nationwide, an even larger number of COPD patients will still need CVR assessment. 16,17 Compared to the total COPD population, the unknown risk group included more younger patients and less polypharmacy, but more active smokers. Even though it is likely that younger COPD patients have a lower absolute risk of CVD, it is still important to estimate their risk. The younger the patient, the higher the relative CVR regardless of sex. 13,18,19 Therefore, the largest disease gain can be achieved for smokers starting with a guideline-based approach of risk assessment and counselling at a young age.
-Guideline adherence (CV-care program): In our study, 90.8% of the 87 COPD patients with DM did receive the CV-care program in primary care. Contrastingly received only 63.1% of the 84 COPD patients with CVD (without DM) this program. A hypothesis for the difference in care provided could be that CV care for DM patients can be standardized more easily than for the diverse CVD group that includes different diagnoses with different medical specialists. The Dutch 2018 rapport of programmatic CV care for general patients revealed also a 20% difference between CVD (without DM) and DM (65% vs. 85% in 1st line). 17 They argue for better cooperation: the specialist should refer the patient back to primary care if only CVRM is required and primary care should remain attentive to this.

Implications for practice
Consistent with the literature, our study underscores the common prevalence of CV-related comorbidities in this CV at-risk population. 21,22 COPD patients often had multimorbidity, which is frequently overlooked when diagnosing an initial chronic disease. 23 This is especially important in diseases such as COPD in which treatment is purely symptomatic and does not address underlying pathophysiological causes. Therefore, we should proactively start screening on CVR factors in COPD patients. 24,25

CONCLUSION
The implementation of effectively recording CVR factors and assessing CVRs in primary care is an important first step in the prevention of CVD in COPD patients. Whereas in the majority of patients the CVR is already known, for one out of six COPD patients this risk still has to be examined according to the recent CVRM guideline. Moreover, once a (very)-high risk has been estimated, as a consequence treatment of risk factors should be intensified in one out of four COPD patients with a (very)-high risk.
Certainly, in patients with quantitative (very)-high CVRs, attention to assure appropriate follow-up of risk factors should be increased. Adherence by healthcare professionals to the new CVRM guideline could provide improvement in CVRM in more than a third of COPD patients.