Handgrip strength is not associated with risk of venous thromboembolism: a prospective cohort study

Abstract

Objectives. Consistent evidence suggests an inverse and independent association between handgrip strength and arterial thrombotic disease. However, whether handgrip strength is related to future risk of venous thromboembolism (VTE) is uncertain. We sought to assess the prospective association between handgrip strength and VTE risk. Design. Handgrip strength was assessed using a hand dynamometer in a population-based sample of 864 men and women aged 61–74 years without a history of VTE at baseline in the Kuopio Ischemic Heart Disease prospective cohort study. Handgrip strength was allometrically scaled to account for the effect of body weight (handgrip strength/body weight^2/3) and to normalize the data. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated for VTE. Results. During a median (interquartile range) follow-up of 17.2 (12.1–18.3) years, 58 VTE events were recorded. The risk of VTE did not significantly decrease per 1 standard deviation increase in normalized handgrip strength in age- and sex-adjusted analysis (HR 0.89; 95% CI 0.65–1.22). The association remained similar in analyses adjusted for several established and emerging risk factors (HR 0.90; 95% CI 0.65–1.25). The corresponding adjusted HRs were 1.10 (95% CI: 0.56–2.18) and 1.15 (95% CI: 0.57–2.34), respectively, when comparing the extreme tertiles of normalized handgrip strength values. Conclusions. Normalized handgrip strength is not associated with future VTE risk in an older Caucasian population. Large-scale studies in other populations and age-groups are warranted to generalize these findings.

Keywords:

• Handgrip strength
• venous thromboembolism
• cohort study

Introduction

The role of physical activity in the prevention of atherosclerotic vascular disease and mortality is well established [1]. Physical activity has also been recently shown to be associated with reduced risk of venous thromboembolism (VTE) [2]. Venous thromboembolism which comprises of deep vein thrombosis (DVT) and pulmonary embolism (PE), constitutes a significant public health burden, given its substantial morbidity, premature mortality, as well as high costs to health systems [3,4]. Venous thromboembolism and atherosclerotic cardiovascular disease (CVD) are closely related disease conditions and they seem to share common risk factors such as obesity and cigarette smoking [5–7]. Evidence suggests they share common pathophysiological mechanisms such as coagulation, platelet activation and dyslipidaemia [8]. Physical fitness is a strong predictor of future health status [9] with its main components being cardiorespiratory fitness (CRF) and muscular fitness [10]. The inverse and independent relationship between CRF and vascular diseases is well established [9]. Limited but emerging evidence suggests CRF may also be linked to VTE risk [11–14]. The main components of muscular fitness include muscular strength, muscular endurance and muscular power [10]. Among these, muscular strength has been the most widely studied in terms of its relationship to health outcomes. Handgrip strength has commonly been used as a typical measure of muscular strength. The emerging evidence on the inverse and independent relationship between handgrip strength and atherosclerotic CVD is consistent [15,16]. Given the overall evidence and inter-relationship between physical fitness, atherosclerotic CVD, and VTE, we hypothesized that handgrip strength may be linked to the risk of VTE. A previous evaluation of the association between handgrip strength and VTE risk in individuals aged 70 years and older by Engbers and colleagues demonstrated that low handgrip strength (<15th percentile) was associated with a 2.3 times higher risk of VTE compared to high handgrip strength ((>15th percentile) [17]; however, this evaluation was limited by the use of a case-control design which is characterised by lack of temporality. In this context, we sought to assess the prospective association between handgrip strength and VTE risk in a general population-based cohort of Finnish men and women. We accounted for the effect of body weight on handgrip strength using allometric scaling to normalize the data.

Methods

Study design and population

This study was reported in accordance with the STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) guidelines for reporting observational studies in epidemiology (Supplementary Material 1) [18]. Participants in the current analyses were part of the Kuopio Ischemic Heart Disease (KIHD) risk factor study, a prospective population-based cohort study designed to investigate risk factors for vascular disease and other chronic disease outcomes. The study recruitment methods, blood sample collection procedures and examinations have been described previously [19]. The initial cohort comprised a representative sample of men randomly recruited from the city of Kuopio and surrounding rural communities in eastern Finland using a population register. These participants underwent re-examinations at 4 years, 11 years and 20 years after study entry. In the 11-year follow-up re-examinations, women were invited to join the study and they formed part of the cohort employed for this analysis. A total of 2358 participants (1007 men and 1351 women) aged 53–74 years at baseline were initially recruited [19]. Of the 2072 participants found to be potentially eligible, 193 did not agree to participate, 66 did not respond to the invitation and 39 declined to provide informed consent, which left 1774 participants (Supplementary Material 2) [19]. The current analysis is based on 864 men and women with complete information on handgrip strength, relevant covariates, and VTE events, who had baseline examinations conducted from March 1998 to December 2001. The research protocol was approved by the institutional review board of the University of Kuopio and Kuopio University Hospital, Kuopio, Finland (License number 143/97). Written informed consent was obtained from all participants and all study procedures were conducted according to the Declaration of Helsinki.

Assessment of handgrip strength, risk markers and outcome

Handgrip strength of the dominant hand for each participant was measured by a hand dynamometer (in kPa; Martin-Balloon-Vigorimeter; Gebrüder Martin, Tuttlingen, Germany). The MartinVigorimeter is known for its high reliability and accuracy, especially in older patients [20]. Two measurements were taken and the mean of both values was used for analysis. The dynamometers were calibrated at the beginning of each test and there was a one-minute resting gap between both handgrip measurements. Absolute values of handgrip strength were allometrically scaled to account for the influence of body weight and to normalize the data (normalized handgrip strength = handgrip strength/body weight^2/3) [21]. All results were multiplied by 100 for easier readability.

All first lifetime VTE events that occurred from study enrollment through to 2017 were included. The diagnosis of DVT or PE required positive imaging tests and they were identified by computer linkage to the National Hospital Discharge Registry data maintained by the Finnish Institute for Health and Welfare. The medical documents for each potential VTE case were cross-checked in detail and VTE events were validated by two physicians who were blinded to the exposures. The ICD 10 codes (I26, I80 and I82) were used to code and classify each potential VTE case.

Statistical analysis

Using descriptive analyses, baseline characteristics were presented as means (standard deviation, SD) or medians (interquartile range, IQR) for continuous variables and percentages for categorical variables. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using Cox proportional hazard models after confirming no substantial departure from the assumptions of proportionality of hazards [22]. Normalized handgrip strength was modeled as both continuous [per SD increase] and categorical (tertiles) exposures. In a subsidiary analysis, normalized handgrip strength was also modelled as percentiles (≥15th percentile versus <15th percentile) to maintain consistency with a previous study [17]. Hazard ratios were adjusted for in three models: (1) unadjusted; (2) age and sex; and (3) plus body height, smoking status, prevalent coronary heart disease (CHD), history of diabetes mellitus, use of lipid medication, physical activity, and prevalent cancer. All statistical analyses were conducted using Stata version MP 16 (Stata Corp, College Station, Texas).

Results

The overall mean (SD) age of study participants at study entry was 69 (3) years and 47.2% were males. The mean (SD) values of normalized handgrip strength and weight were 0.48 (0.22) kPa/kg^2/3 and 75.5 (12.9) kg, respectively (Table 1). During a median (IQR) follow-up of 17.2 (12.1–18.3) years, a total of 58 VTE cases (annual rate 4.54/1000 person-years at risk; 95% CI: 3.51–5.87) occurred. The high VTE event rate potentially reflects the older age, high body mass and high prevalence of CHD in the study sample (Table 1); these are all established risk factors for VTE [23]. The HR for VTE per 1 SD increase in normalized handgrip strength in unadjusted analysis was 0.91 (95% CI: 0.67–1.22), which remained similar when adjusted for age and sex 0.89 (95% CI: 0.65–1.22) and further adjustment for established risk factors and other potential confounders (body height, smoking status, prevalent CHD, history of type 2 diabetes, use of lipid medication, physical activity, and prevalent cancer) 0.90 (95% CI: 0.65–1.25) (Table 2). The corresponding adjusted HRs were 1.13 (95% CI: 0.58–2.17), 1.10 (95% CI: 0.56–2.18), and 1.15 (95% CI: 0.57–2.34), respectively, when comparing the top versus bottom tertiles of normalized handgrip strength. The non-significant association remained when the risk was assessed by comparing participants above the 15th percentile normalized handgrip strength with those below below (Supplementary material 3).

Table 1. Baseline participant characteristics.

		Normalized handgrip strength exposure
	Overall (N = 864)	Tertile 1 (N = 288)	Tertile 2 (N = 288)	Tertile 3 (N = 288)
	Mean (SD), median (IQR), or n (%)	Mean (SD), median (IQR), or n (%)	Mean (SD), median (IQR), or n (%)	Mean (SD), median (IQR), or n (%)
Normalized handgrip strength (kPa/kg^2/3)	0.48 (0.22)	0.30 (0.06)	0.45 (0.04)	0.70 (0.25)
Questionnaire/Prevalent conditions
Age at survey (years)	69 (3)	69 (3)	69 (3)	68 (3)
Males	408 (47.2)	176 (61.1)	153 (53.1)	79 (27.4)
History of type 2 diabetes	83 (9.6)	32 (11.1)	28 (9.7)	23 (8.0)
Current smokers	81 (9.4)	23 (8.0)	27 (9.4)	31 (10.8)
History of CHD	308 (35.7)	126 (43.8)	103 (35.8)	79 (27.4)
History of cancer	89 (10.3)	26 (9.0)	30 (10.4)	33 (11.5)
Use of cholesterol medication	54 (6.3)	23 (8.0)	16 (5.6)	15 (5.2)
Physical measurements
Weight (kg)	75.5 (12.9)	86.5 (10.8)	76.5 (7.5)	63.3 (2.9)
Height (cm)	164.2 (9.0)	167.3 (9.1)	165.1 (8.3)	160.3 (8.1)
BMI (kg/m^2)	28.0 (4.3)	31.0 (4.1)	28.2 (3.2)	24.7 (2.9)
SBP (mmHg)	138 (18)	138 (18)	140 (17)	137 (18)
DBP (mmHg)	80 (9)	81 (18)	80 (8)	78 (9)
Energy expenditure of total LTPA (kcal/day)	378 (226–649)	387 (246–614)	411 (239–703)	343 (197–584)
Blood-based markers
Total cholesterol (mmol/l)	5.44 (0.94)	5.34 (0.89)	5.46 (1.00)	5.54 (0.93)
HDL-C (mmol/l)	1.24 (0.32)	1.15 (0.28)	1.22 (0.31)	1.35 (0.33)

BMI: body mass index; CHD: coronary heart disease; CI: confidence interval; DBP: diastolic blood pressure; HDL-C: high-density lipoprotein cholesterol; IQR: interquartile range; LTPA: leisure-time physical activity; SD: standard deviation; SBP: systolic blood pressure.

Table 2. Association between normalized handgrip strength and risk of venous thromboembolism.

Normalized handgrip strength (kPa/kg^2/3)	Events/Total	Model 1		Model 2		Model 3
		HR (95% CI)	p-Value	HR (95% CI)	p-Value	HR (95% CI)	p-Value
Per 1 SD increase	58/864	0.91 (0.67–1.22)	.52	0.89 (0.65–1.22)	.47	0.90 (0.65–1.25)	.53
T1 (0.12–0.38)	16/288	Ref		Ref		Ref
T2 (0.39–0.52)	22/288	1.32 (0.69–2.50)	.40	1.31 (0.6–2.49)	.42	1.36 (0.70–2.62)	.36
T3 (0.53–4.03)	20/288	1.13 (0.58–2.17)	.72	1.10 (0.56–2.18)	.78	1.15 (0.57–2.34)	.70

CI: confidence interval; HR: hazard ratio; ref: reference; SD: standard deviation; T: tertile.

Model 1: Unadjusted.

Model 2: Adjusted for age and sex.

Model 3: Model 2 plus body height, smoking status, prevalent coronary heart disease, history of type 2 diabetes, use of lipid medication, physical activity, and prevalent cancer.

Discussion

Summary of main findings

Previous prospective observational data on the inverse and independent association between handgrip strength (a measure of muscular strength) and arterial thrombotic disease is plentiful [15,16]. Muscular strength has also been demonstrated to be inversely associated with cardiometabolic conditions such as type 2 diabetes and metabolic syndrome [24,25]. In this first study to evaluate the prospective association between normalized handgrip strength and risk of VTE in a general population-based cohort of older Caucasian men and women, we found no evidence of an association. These findings may seem unexpected given that a previous study based on a case-control design showed that weak handgrip strength was associated with an increased risk of VTE in individuals aged 70 years and older [17]. However, because of the lack of temporality in the study design, the findings were prone to reverse causation bias. Furthermore, our findings were unexpected given the close inter-relationship between atherosclerotic CVD, VTE and physical fitness and also the fact that handgrip strength is a measure of whole-body muscle strength, correlated with leg strength, provides a valid index of overall limb muscle strength, and characterizes physical capability [26].

Possible explanations for findings

Pathways postulated to underlie the protective effect of higher muscular strength (handgrip strength) on vascular disease have included reduction in incidence of weight gain, abdominal adiposity, insulin resistance, metabolic syndrome, and inflammation [10,27]. There is a possibility that the null association observed in our study may reflect important pathophysiologic differences between arterial thrombotic disease and VTE. There is still uncertainty as to whether arterial thrombotic disease (comprising of CHD, stroke, and peripheral artery disease) is related to VTE. It has been suggested that atherosclerotic CVD is an underlying condition and precedes the development of VTE [28]; however, evidence on the contrary also suggests this is not the case [29,30]. There is controversy as to whether any relationship between atherosclerotic CVD and VTE may reflect shared risk factors. Whereas some studies have demonstrated significant associations between traditional CVD risk factors and VTE risk [5,7], others have not [6,31]. Atherosclerotic CVD and VTE have historically been viewed as two distinct diseases [32] and based on findings that traditional risk factors for VTE and arterial thrombotic disease are not similar, it is generally believed that their pathogenesis differ [33]. On the contrary, the absence of evidence of an association could also be related to study design factors and population characteristics such as (i) low statistical power due to the low number of VTE events; (ii) regression dilution bias due to the long follow-up duration; (iii) residual confounding; and (iv) age, sex, or genetic background of the population. Given the absence of previous prospective evaluations of the associations, large-scale studies are warranted to confirm or refute these findings.

Strengths and limitations

The notable strengths of this study include the novelty (prospective cohort design), the general population-based sample of men and women with no history of pre-existing VTE at study entry, employment of the Martin Vigorimeter for measuring grip strength, long and complete follow-up of participants, and reliable data on a comprehensive panel of lifestyle factors which allowed adjustment for potential confounding. Limitations which merit mention include (i) the relatively low number of VTE events, which also precluded the ability to investigate sex-specific associations; (ii) potential residual confounding due to unmeasured confounding; (iii) inability to generalise the findings to other populations; (iv) inability to correct for regression dilution bias due to absence of repeat measurements of handgrip strength; and (v) data was available on only total VTEs which precluded the ability to evaluate specific VTE outcomes (DVT or PE).

Conclusions

Normalized handgrip strength is not associated with future VTE risk in an older Caucasian population. Large-scale studies in other populations and age-groups are warranted to generalize these findings.

Acknowledgements

We thank the staff of the Kuopio Research Institute of Exercise Medicine and the Research Institute of Public Health and University of Eastern Finland, Kuopio, Finland for the data collection in the study. These sources had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

Professor Laukkanen acknowledges support from The Finnish Foundation for Cardiovascular Research, Helsinki, Finland. Prof. Mäkikallio acknowledges support from the Division of Cardiology, Department of Internal Medicine, Oulu University Hospital, Oulu, Finland via the Finnish Governmental Research Funding (VTR) and the Päivikki and Sakari Solhberg Foundation. Dr. Kunutsor acknowledges support from the Division of Cardiology, Department of Internal Medicine, Oulu University Hospital, Oulu, Finland via the Finnish Governmental Research Funding (VTR) and the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health and Social Care.