Population attributable fraction estimates of cardiovascular diseases in different blood pressure levels in a large-scale cross-sectional study: a focus on prevention strategies and treatment coverage : Blood Pressure Monitoring

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Clinical Methods and Pathophysiology

Population attributable fraction estimates of cardiovascular diseases in different blood pressure levels in a large-scale cross-sectional study: a focus on prevention strategies and treatment coverage

Keykhaei, Mohammada,b,*; Rezaei, Negara,c,*; Roshani, Shahina; Montazeri, Fatemea; Nasserinejad, Maryama,d; Azadnajafabad, Sinaa; Mohammadi, Esmaeila; Ghasemi, Erfana; Rezaei, Nazilaa; Farrokhpour, Hosseina; Foroumadi, Rohame; Bagheri, Saynae; Moghimi, Manaa; Larijani, Bagherc; Farzadfar, Farshada,c

Author Information
Blood Pressure Monitoring 28(1):p 1-10, February 2023. | DOI: 10.1097/MBP.0000000000000612



Hypertension is one of the major modifiable risk factors in developing cardiovascular diseases (CVD) [1]. Despite the abundant developments in CVD treatment, it remains among the leading causes of mortality and disease burden, resulting in approximately 9.1 million deaths and 180.0 million disability-adjusted life years globally in 2019 [2]. Also, Iran has tackled emerging challenges in the path toward overcoming the imposed burden of the disease. CVD is a multi-factorial condition where the combination of risk factors could affect the susceptibility of a person to develop CVD over time. Consistently, CVD risk factors could be split into two categories encompassing nonmodifiable and modifiable risk factors [3].

Hypertension is considered the foremost preventable risk factor for all-cause mortality and CVD [4]. In 2015, the SBP of at least 110–115 mmHg, commonly referred to as the theoretical minimum exposure level was the major contributor to preventable death at the global level [5]. According to a previous survey on metabolic risk factors in Iran, high SBP was accounted for 41 000 and 39 000 deaths in men and women, respectively, in 2005 [6]. Based on the Tehran Lipid and Glucose Study, in terms of CVD prediction, hypertension was associated with a more significant proportion of CVD compared with traditional risk factors, including hypercholesterolemia, low high-density lipoprotein C (HDL-C), diabetes and current smoking [7]. Owing to the increases in exposures to risk factors, lack of physical activity and aging of the global population, the number of adults with elevated blood pressure increased significantly from 1975 to 2015, with the largest changes in low- and middle-income regions [4,8]. On the other hand, high-income countries have experienced a modest decrease during the same period. As a result, these disparities in the incidence pattern of hypertension necessitate the implementation of screening and therapeutic interventions, particularly in low- and middle-income countries, to mitigate the influx of CVD [4,8].

The population attributable fraction (PAF) illustrates an estimate of the proportion of disease that can be attributed to a specific risk factor and is often expressed as percentages. This measurement provides insights into the proportion of the disease burden that can be eradicated if exposure to a certain risk factor were decremented to the best possible level [9,10]. For instance, if a certain risk factor has a 0.60 PAF for a given disease, it means that the risk factor is responsible for 60% of the population with the specific disease. Given the pivotal impact of hypertension on CVD progression, measuring the PAF for CVD associated with hypertension could be of utmost importance. Hence, we applied the Iranian stepwise approach for surveillance (STEPs) 2016 data to ascertain the PAF for CVD in different levels of blood pressure. We hypothesized a priori that hypertension would have different magnitude by age and sex. Besides, we investigated the potential effectiveness of antihypertensive agents at the population level to determine the best strategy for the targeted population at the risk of CVD development due to altered blood pressure.


Ethical consideration

The protocol of this study was approved by the Ethics Committee of Tehran University of Medical Sciences (IR.TUMS.VCR.REC.1398.1006). The study was conducted according to the principles of the 1975 declaration of Helsinki.

All participants have provided informed consent. No individual data of participants are reported in this survey, and all personal information remained confidential.

Study design and participants

Participants recruited in this study were obtained from Iran STEPs 2016 survey [11], based on 30 540 enrolled participants. Through a cluster random sampling method, urban and rural populations of 30 provinces of Iran were divided into 3105 clusters, which were subcategorized into 12 age-groups (25–19, 30–34, 35–39, 40–44, 45–49, 50–54, 55–59, 60–64, 65–69, 70–74, 75–79 and +80). Gender classification was performed to facilitate understanding of the specific risk and impact of medical coverage on each sex. Blood pressure measurement was performed for 27 738 participants, of whom 573 (2%) patients with missing SBP or DBP data were excluded. Treatment status was obtained from self-reports of taking antihypertensive medication. In addition, more details have been provided in the STEPs study protocol [11].


As the essential variable of this study, blood pressure was measured by trained staff for three times, each 5 min apart, with calibrated Omron M7 digital sphyg142 manometers, with appropriate size cuffs covering at least 80% of the right arm. Of note, the first records were discarded, whereas estimations of the second and third records were used to calculate the mean value for SBP and DBP [12]. We defined CVD as a history of rheumatic heart disease, ischemic heart disease, ischemic stroke, hemorrhagic stroke, arterial fibrillation and flutter, aortic aneurysm, peripheral vascular disease, endocarditis, other cardiomyopathies and other cardiovascular and circulatory diseases, according to the global atlas on CVD prevention and control [13]. Principle component analysis (PCA) was applied to these measures. Quintiles of the primary component of PCA were scaled from 1 (first quintile; the poorest) to 5 (fifth quintile; the richest) [11].

Blood pressure classification

The theoretical minimum of SBP was estimated to be a mean 115 mmHg [5]. Moreover, patients were divided into normal and hypertensive groups based on the American College of Cardiology/American Heart Association (ACC/AHA) 2017 guideline [12].

Population attributable fraction

The contribution of a risk factor to the incidence, related complications and mortality of a disease is determined by the PAF. Indeed, PAF is a proportional reduction in incidence or mortality of disease if exposure to a specific risk factor (e.g. SBP less than 130 mmHg) were insignificant [10]. Noticeably, the occurrence of disorders is commonly mediated by several risk factors, and elimination of each risk factor could lead to modification of the overall risk of the disease. It should be borne in mind that due to the multiplex interplay between risk factors and their corresponding outcomes, cumulative PAFs for a disease can result in more than 100% in a population [14].

The PAF is calculated with the following equation: PAF=RpRR(X).f(X)dX1RpRR(X).f(X)dX,  if X is continuous

Based on the STEPs 2016 study, hypertension is a continuous variable. In this equation, f (X) indicates the distribution of a risk factor (X) [6]. RR (X) is a relative risk compatible with a specific risk factor. In this study, RR of CVD and strokes were obtained from the global burden of hypertension based on age for low/high-risk group [15]. Also, the mortality rate was retrieved from the national and subnational burden of diseases, injuries, and risk factors (NASBOD) study [16]. The international classification of diseases, tenth revision (ICD10) codes regarding the CVDs are presented in Supplementary Table 1, Supplemental digital content 1, https://links.lww.com/BPMJ/A171.

This study was performed in different phases as provided below:

Phase 0

In this phase, PAF and mortality attributed to the mean blood pressure for CVD were measured in different age and sex groups, irrespective of their health status. This phase could illuminate the overall pattern of CVD in the population. The determination of CVD diseases linked to hypertension was based on the global burden of disease (GBD) studies [17,18].

Phase 1

In the second phase, participants were appraised based on their blood pressure levels. Regarding the normal distribution of blood pressure, measurements equal to or higher than 130 mmHg were considered as the high-risk group for CVD. Regarding the blood pressure theoretical minimum range of 115 mmHg, 115≤SBP<130 mmHg was determined as the low-risk population. This phase enabled us to investigate Geoffrey Rose’s strategy indicating the failure of preventive strategies in high-risk groups due to the loss of a large number of preventable cases in low-risk groups [19].

Phase 2

In the third phase, PAF was divided into two groups, including normal (SBP less than 130 mmHg and no history of antihypertensive treatment) and high-risk (SBP equal and more than 130 mmHg or taking antihypertensive medication) groups, which is in accordance with the ACC/AHA 2017 guideline [12]. This phase aimed to evaluate the PAF based on blood pressure levels and treatment status.

Phase 3

In the fourth phase, patients were divided into two categories based on treatment coverage, including patients receiving antihypertensive drugs regardless of SBP and patients with SBP more than 130 mmHg and without treatment coverage.

A summary of the used method and phases in each step of the study is depicted in Fig. 1.

Fig. 1:
The flowchart of method used to carry out the study. CVD, cardiovascular disease; PAF, population attributable fraction.

Statistical analysis

The simulation was conducted with regard to the normal distribution of blood pressure to estimate mean and confidence intervals (CI). PAF values are reported with a 95% CI. All the statistical analyses and plot depictions were performed using R for windows v 3.6.1 and RStudio v 1.0.136 (http://www.rproject.org/, RRID: SCR_001905) [20].


This study was conducted to determine the PAF of blood pressure in CVD in four different phases. A total number of 27 165 participants aged ≥25 years had valid blood pressure measurements and were recruited in phase 0 of the study. In the next phase, 19 713 patients were included based on high/low-risk definition. Included clinical data of participants about using antihypertensive treatment made 11 077 available contributors in phase 2 and 4048 participants in phase 3. The available data with regards to cardiovascular risks in the respected age groups are displayed in the Supplementary Table 2, Supplemental digital content 2, https://links.lww.com/BPMJ/A172.

Phase 0

Estimated PAF values for different CVD spanned from as high as 0.63 (95% CI, 0.55–0.71) for elderly females attributed to hemorrhagic stroke to values as low as 0.01 (0.01–0.01) in young females due to aortic aneurysm. In most CVD, PAF values in males aged 25–40 years were higher than in females, which reversed in the age groups more than 40 years. Appraising overall trends, PAF values had upward trends with increasing age in the female group, although several fluctuations could be found in the male group except for peripheral vascular disease. Table 1 contains details of estimated numbers in this phase among CVDs with the highest PAF. Supplementary Table 3, Supplemental digital content 3, https://links.lww.com/BPMJ/A173 includes the data regarding the PAF of the rest of CVDs.

Table 1 - Population attributable fraction attributed to the mean blood pressurea for CVD stratified by sex and age
Age group Ischemic stroke M/F ratio PAF Ischemic heart disease M/F ratio PAF
Female Male Female Male
25–29 0.01 0.01 0.31 0.03 34.87 0.01 0.01 0.30 0.03 34.82
30–34 0.04 0.01 0.31 0.03 7.72 0.04 0.01 0.31 0.03 7.70
35–39 0.20 0.02 0.32 0.03 1.64 0.19 0.02 0.31 0.03 1.64
40–44 0.36 0.03 0.35 0.03 0.99 0.34 0.03 0.33 0.03 0.98
45–49 0.44 0.04 0.42 0.04 0.95 0.43 0.04 0.40 0.03 0.95
50–54 0.55 0.04 0.47 0.04 0.86 0.53 0.04 0.45 0.04 0.85
55–59 0.56 0.04 0.52 0.04 0.92 0.55 0.04 0.50 0.04 0.92
60–64 0.56 0.04 0.51 0.04 0.90 0.56 0.04 0.51 0.04 0.91
65–69 0.58 0.04 0.49 0.04 0.85 0.59 0.04 0.50 0.04 0.85
70–74 0.55 0.04 0.45 0.04 0.82 0.57 0.04 0.48 0.04 0.83
75–79 0.53 0.04 0.45 0.04 0.85 0.56 0.04 0.48 0.04 0.86
80+ 0.49 0.04 0.41 0.03 0.82 0.56 0.04 0.47 0.04 0.83
Age Group Hemorrhagic stroke M/F RATIO PAF
25–29 0.01 0.01 0.34 0.03 34.82
30–34 0.05 0.02 0.37 0.03 7.37
35–39 0.25 0.03 0.40 0.04 1.61
40–44 0.42 0.04 0.42 0.04 0.99
45–49 0.52 0.04 0.50 0.04 0.95
50–54 0.62 0.04 0.54 0.04 0.87
55–59 0.63 0.04 0.58 0.04 0.92
60–64 0.60 0.04 0.55 0.04 0.91
65–69 0.59 0.04 0.50 0.04 0.85
70–74 0.57 0.04 0.47 0.04 0.83
75–79 0.57 0.04 0.49 0.04 0.86
80+ 0.61 0.04 0.51 0.04 0.84
aMean of blood pressure is the mean of 3 systolic pressures, measured separately.
CVD, cardiovascular diseases; PAF, population attributable fraction.

In the next step, the morality number from CVD that is attributed to hypertension in both sexes and 12 year age groups was measured. In an aortic aneurysm, males’ mortality number was higher than females, although the observed difference was not statistically significant. Also, mortality numbers in atrial fibrillation and flutter in females aged more than 70 year were higher than in males. Of note, these numbers in other cardiovascular and stroke diseases, especially in patients older than 80 year, were insignificantly larger in females. More details are displayed in Supplementary Figure 1, Supplemental digital content 4, https://links.lww.com/BPMJ/A174.

Phase 1

In this phase, PAF was measured in two divided populations as high- and low-risk groups. Interpretation of the results revealed that participants with BP ≥130 mmHg comprised the largest PAF, extending from 0.31 (0.25–0.37) in older male individuals to 0.85 (0.79–0.91) in younger females. On the other hand, participants with 115≤BP<130 mmHg, had lower PAF estimates ranging from 0.07 (0.05–0.09) to 0.39 (0.33–0.45), with similar age and sex patterns as those in the high-risk group. As illustrated in Fig. 2 and Supplementary Table 4, Supplemental digital content 5, https://links.lww.com/BPMJ/A175 the overall pattern of PAF estimates is in favor of higher values in the younger population, which is consistent with Geoffrey Rose’s hypothesis.

Fig. 2:
Trends of estimated population attributable fractions (with 95% CI) of hypertension for different CVD in phase 1. CI, confidence interval; CVD, cardiovascular diseases; PAF, population attributable fraction.

Phase 2

In phase 2, the population was divided into normal and hypertensive groups as described in the Methods section. In the hypertensive population, PAF levels were higher in younger participants, ranging from 0.28 (0.24–0.32) to 0.84 (0.78–0.90). This result is in parallel with Geoffrey Rose’s strategy pointing to consider younger patients in preventive health policy. In the normal population, PAF values were variable in different age groups. Moreover, in females with normal blood pressure, there was an up-sloping in the PAF diagram across all investigated diseases in postmenopausal and age groups more than 70 years. This was in contrast to males’ diagrams indicating a linear pattern (Fig. 3 and Supplementary Table 5, Supplemental digital content 6, https://links.lww.com/BPMJ/A176).

Fig. 3:
Trends of estimated population attributable fractions (with 95% CI) of hypertension for different CVD in phase 2. CI, confidence interval; CVD, cardiovascular diseases; PAF, population attributable fraction.

Phase 3

In this phase, treatment coverage was used for the categorization of hypertensive patients. Estimations of PAF for CVD among hypertensive patients receiving treatment lay in between 0.22 (0.16–0.28) and 0.85 (0.77–0.93), with the highest estimates in younger age groups. On the contrary, PAF spanned from 0.28 (0.20–0.36) to 0.91 (0.83–0.99) in the group not receiving treatment with a similar age pattern as the other group. Noticeably, as demonstrated in Fig. 4 and Supplementary Table 6, Supplemental digital content 7, https://links.lww.com/BPMJ/A177 the population without treatment coverage had remarkably higher attributable fractions in most of the age groups, for both sexes and different causes of CVD. In addition, these differences in the younger age group were more remarkable, indicating the critical role of timely treatment in younger adults.

Fig. 4:
Trends of estimated population attributable fractions (with 95% CI) of hypertension for different CVD in phase 3. CI, confidence interval; CVD, cardiovascular diseases; PAF, population attributable fraction.


Drawing from the data of STEPs 2016, this is the first study that ascertains age- and sex-specific attributable fractions of hypertension on CVD. As we hypothesized, PAF levels of the high-risk group were significantly higher compared with the low-risk group. Our analysis revealed that PAF levels were higher in younger and middle-aged groups in both high-risk and low-risk groups than in older age groups. Noticeably, we found that attributable fractions among hypertensive patients who received treatment were much lower than drug-naïve hypertensive participants. In terms of gender disparity, we found that PAF levels were higher in women than men in middle-aged and older age groups.

From an overall point of view, we found the highest attributable fractions of hypertension in hemorrhagic stroke, ischemic stroke and ischemic heart disease. This result is in line with that of the INERSTROKE study, which reported that hypertension was more linked with intracerebral hemorrhage compared with ischemic stroke [21]. During recent decades, Iran has encountered rapid alternation, moving from communicable diseases to noncommunicable diseases (NCDs) [22]. According to the Golestan Cohort Study, an approximate rate of 90% of premature deaths was attributable to NCDs in Iran, of which ischemic heart disease and stroke were the most preeminent causes [23]. A recent study compared the prevalence of hypertension based on two guidelines, including the Eight Joint National Committee (JNC8) and 2017 ACC/AHA, indicating that by applying the latter guideline, the prevalence of hypertension increases from 29.9 to 53.7% among the Iranian population [24] As an aspirational target, successful implementation of the mentioned strategies should narrow the gap between PAF in patients with hypertension and prehypertensive subpopulations [10]. However, from the current survey findings, we see a remarkable gap between the PAF of these groups, representing the insufficiency of the measures put in place.

Geoffrey Rose altered the paradigms of prevention by proposing two ways of approaching a disease, including high-risk and mass strategies [25]. The high-risk strategy is defined as finding and treating high-risk individuals based on the deviation of laboratory cutoffs from the normal range [25–27]. The central tenet of the mass approach, making it radical, is shifting risk factors distribution. It should be borne in mind that despite the large impacts and benefits for the community, this method has not enough effects on individuals with a prior diagnosis of the disease, which is conventionally exemplified as the ‘Prevention Paradox’ [19,25].

A key insight of the Rose theory is that a large number of individuals in the low-risk group might contribute to a higher burden of the disease compared to the small number of individuals in the high-risk group [19]. Consistent with this concept, we found that PAF levels were higher in younger and middle-aged groups in both high-risk and low-risk groups than in older age groups. This finding is consistent with those from several previous studies [10,28]. According to a study conducted by Clark, et al. [10], the population-attributable risk (PAR) for CVD associated with hypertension was higher in the age groups of lower than 60 [54.6% (37.2–68.7%)] years compared with older individuals [32.0% (11.9–48.1%)]. Besides, in the Chinese multiprovincial cohort study, stage 1 hypertension was accounted for 26.5% of CVD deaths among participants aged 35–59 years; although, no PAR association was found in the age groups of higher than 60 years [28]. Evaluation of these results reveals that there might be several explanations in this regard. First, elderly participants might have had unmeasured determinants, such as the genetic profile, which may have modified the deleterious effect of hypertension [9]. Second, the lack of sufficient screening and diagnostic tests might have led to the increased attributable risks for CVD in younger and middle-aged groups [10]. Taken together, these findings indicate that by providing adequate screening and diagnosing tests among younger adults, a population that might be undertreated; we could bring the adverse effects of hypertension sub-optimally under control.

Interpretation of the PAF for hypertension associated with CVD shows a remarkable diversity across different gender groups. With regard to the inherent nature of PAF values, comparing PAF estimations among different investigations might have essential limitations; although, these differences could empower policymakers to be noticed of possible inequities between the two sexes [29]. We found that PAF levels were higher in men than women in younger age groups. In comparison, it was higher in women than men in middle-aged and older age groups. A possible explanation for this issue might be that the protective impacts of the estrogen on the cardiovascular system (i.e. modulating the renin-angiotensin-aldosterone system and vascular remodeling process) are dramatically reversed after menopause, resulting in an increased burden of CVD compared with men [30]. In addition, we found that the attributable mortality number of hypertension on atrial fibrillation was significantly higher in women than men, due to the larger number of atrial fibrillation deaths. This finding is nearly consistent with that of Dai, et al. [31], who reported higher age-standardized mortality numbers in women than men, based on the GBD 2019 data. On the other side, we found higher attributable mortality numbers of hypertension on aortic aneurism in men, possibly originating from the larger number of deaths.

This study highlighted the pivotal role of blood pressure-lowering agents, as the individuals receiving treatment had significantly lower attributable fractions compared with drug-naïve hypertensive participants. By contrast, in a recent investigation on 12 497 black participants, individuals not receiving antihypertensive treatment had lower attributable risks compared with participants who were commenced on medication, suggesting the possible inability of pharmaceutical therapy to mitigate the adverse effects of hypertension [10]. Strikingly, it has been reported that a 10 mmHg lower SBP is associated with a 30–40% lower risk of stroke [32]. In addition, based on the 2017 ACC/AHA guideline, by a 30% reduction in the prevalence of hypertension, 6.1% of CVD cases could be prevented [33]. Also, in 2016, the approximate rate of Iranian participants who were aware of their hypertension were estimated at 37.1% regarding the 2017 ACC/AHA guidelines [24]. Taken together, looking at these findings represents that despite the important impacts of antihypertensive treatment on lowering the risk of CVD, most of the individuals in the hypertensive group are unaware of their existing conditions. Hence, these results call policymakers for more collaborative attempts to improve blood pressure screening and provide adequate access to antihypertensive medications.

So far, several community-based strategies have been implemented to achieve the aspirational targets in screening and diagnosing participants with hypertension. However, as most of the patients with hypertension are asymptomatic, moving toward this target is notably challenging [34–36]. In this regard, the Iranian government has initiated several strategies, including decreasing the consumption of salt in bread in line with the Finland and the United Kingdom’s successful policies towards reducing salt intake [14,34,35] and increasing the taxation of cigarette and other tobacco products to prevent the progression of CVD at the population level, although there still exists emerging challenges to reach health for everyone by 2030, as proposed by the WHO [23]. Considering the eligibility of only 37.2% of participants in the STEPS 2016 for pharmacologic therapy [24], nonpharmacologic interventions still play a pivotal role in the prevention and management of hypertension and CVD. However, lifestyle interventions are far from optimal in Iran, which necessitates the urgent need for developing a fundamental approach [37]. Fourth, deriving from a performed nationwide survey, policymakers should expand the number and scope of primary health care-worker programs to overcome the imposed burden of hypertension in Iran [38]. Last but not least, pharmacologic therapy remains the last resort to avert the burden of hypertension in the whole population, although recent evidence has suggested the critical impact of drug therapy on primary prevention [36]. Overall, due to the resource constraints and deficiency of financial resources, particularly in low- and middle-income countries, developing hypertension control measures regarding the cost-effective analysis, as well as increasing budgetary allocation to health care insurance, could be the principal future priorities [39].

Strengths and limitations

The key strengths of our study are as follows. First, to the best of our knowledge, this is the first study that investigates the age- and sex-specific attributable fractions of hypertension on CVD, using STEPS 2016. Besides, by utilizing a survey, which is robustly performed at the national level, the heterogeneity of data is lowered to the minimum level. Moreover, this study could introduce a new outline of the blood pressure screening method by appraising the PAF of hypertension on different CVD. Last but not least, interoperation of the results of this study could empower policymakers on their responsibility to allocate the resources more effectively. On the other side, our study might have several limitations. Owing to the variations in the calculation of PAF, comparing PAF estimations among different investigations might have essential limitations [29]. In addition, considering the theoretical inherent of PAF, appraising the influence of a single risk factor might not be feasible [40].


In this study, we investigated the attributable fractions of hypertension, as the leading preventable risk factor for all-cause mortality, on CVD. We found higher PAF levels in younger and middle-aged groups compared with older age groups. Besides, attributable fractions among hypertensive patients who received treatment were much lower than drug-naïve hypertensive participants. These findings call for more collaborative attempts to improve blood pressure screening and provide adequate access to antihypertensive medications in low- and middle-income regions.


The authors thank the Non-Communicable Diseases Research Center (NCDRC) and Tehran University of Medical Sciences (TUMS) for their valuable contribution.

This work was supported by the [Tehran University of Medical Sciences] under Grant [98-3-221-45726].

Conflicts of interest

There are no conflicts of interest.


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cardiovascular disease; hemorrhagic stroke; hypertension; PAF; STEPs

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