Effects of isometric handgrip training on blood pressure among hypertensive patients seen within public primary healthcare: a randomized controlled trial

ABSTRACT BACKGROUND: Meta-analyses have demonstrated that isometric handgrip training (IHT) decreases blood pressure in hypertensive individuals. Nonetheless, most studies were conducted in laboratory settings and its effects in real-world settings remain unclear. OBJECTIVE: To analyze the eﬀects of IHT on office and ambulatory blood pressure in hypertensive patients attended within primary healthcare. DESIGN AND SETTING: Randomized controlled trial conducted in primary healthcare units within the Family Health Program, Petrolina, Pernambuco, Brazil. METHODS: 63 hypertensive patients (30-79 years old; 70% female) were randomly allocated into IHT or control groups. IHT was performed three times per week (4 x 2 minutes at 30% of maximal voluntary contraction, one-minute rest between bouts, alternating the hands). Before and after the 12-week training period, office and ambulatory blood pressure and heart rate variability were obtained. The signiﬁcance level was set at P < 0.05 (two-tailed testing) for all analyses. RESULTS: IHT signiﬁcantly decreased office systolic blood pressure (IHT: 129 ± 4 versus 121 ± 3 mmHg, P < 0.05; control: 126 ± 4 versus 126 ± 3 mmHg, P > 0.05), whereas there was no effect on diastolic blood pressure (IHT: 83 ± 3 versus 79 ± 2 mmHg, P > 0.05; control: 81 ± 3 versus 77 ± 3 mmHg, P > 0.05). Heart rate variability and ambulatory blood pressure were not altered by the interventions (P > 0.05 for all). CONCLUSION: IHT reduced office systolic blood pressure in hypertensive patients attended within primary care. However, there were effects regarding diastolic blood pressure, ambulatory blood pressure or heart rate variability. CLINICALTRIALS.GOV IDENTIFIER: NCT03216317.


INTRODUCTION
Hypertension impacts over one billion people worldwide and is the main risk factor for heart and cerebrovascular diseases, accounting for 13% of global deaths. [1][2][3] The therapeutic approach for hypertensive patients includes drug therapy and lifestyle changes in association with drug therapy, with the aim of reducing blood pressure (BP) to the target normal range (< 130/80 mmHg). 2 Previous meta-analyses have shown that isometric handgrip training (IHT) decreases office BP in hypertensive patients by more than 5 mmHg after a few weeks. [4][5][6][7][8][9] The American College of Cardiology and the American Heart Association have recently recommended IHT as a potential alternative strategy for lowering BP, but with a low level of evidence. 10 From a clinical point of view, reductions in BP are relevant when this impacts on BP levels during a major part of the time. Interestingly, the effects of IHT on ambulatory BP, which is more related to cardiovascular events than office BP, have not been demonstrated. In fact, in three previous studies, despite significant reductions in office BP, no effects on ambulatory BP were shown among hypertensive individuals after IHT, thus suggesting that there was a need for further studies. [11][12][13] The benefits of IHT comprise its ease of application and the short time needed for doing the exercise. Therefore, it is ideal for application within primary care, in non-laboratory settings.

OBJECTIVE
In this study, we analyzed the effects of IHT on office and ambulatory BP in hypertensive patients attended at a primary healthcare unit. Our hypothesis was that IHT would reduce BP similarly in non-laboratory settings. The exclusion criteria were any of the following situations: (a) changes to the type or dose of blood pressure control medicine;

Experimental approach to the problem
(b) engaging in another exercise program; or (c) taking part in less than 80% of the isometric handgrip training sessions.

Randomization and allocation
The participants were block-randomized using a random number table (using the website https://www.randomizer.org), with stratification according to sex and baseline office systolic BP (done by a researcher who did not participate in the subject recruitment or data collection), into two groups: IHT group and control group. The allocation information was concealed from the researchers performing the measurements.

Interventions
The patients allocated to the IHT group trained three times per week, for a total of 12 weeks, in healthcare units that form part The post-intervention evaluation was performed at least 72 hours after the last exercise session.
Office BP: The office BP was measured through the Omron HEM 742 device (Omron Healthcare, Kyoto, Japan). After 10 minutes of supine rest, at least three consecutive measurements with one-minute intervals between them were assessed. The measurements were made on the right arm, with an appropriate cuff size for the arm circumference. 19 The intraclass correlation coefficient for systolic BP was 0.85, and for diastolic BP it was 0.92. 20 Ambulatory BP: The ambulatory BP was obtained through an oscillometric device (Dyna-MAPA, Cardios, Brazil) that had previously been set up for performing BP assessments every 15 minutes during the daytime period and every 30 minutes during the nighttime, based on previously reported procedures. 21 Also, patients were counseled to report crucial everyday activities, such as meals, movement from one place to another and medications.
Heart rate variability: The heart rate variability was evaluated from the RR intervals, measured through a heart rate monitor (Polar V800, Polar Electro, Kempele, Finland) in the supine position for 10 minutes. At least five minutes of stationary R-R interval data were analyzed. All analyses were carried out by a single experienced evaluator who was blind to the group allocations.
The intraclass correlation coefficient for this evaluator spanned from 0.990 to 0.993. 22 All heart rate variability analysis procedures followed previously described guidelines. 23

Statistical analyses
To determine the sample size, we used previously demonstrated data on the mean reduction and standard deviation (SD) of office systolic BP following IHT. 24 Given an expected reduction of 6.0 ± 4.6 mmHg and α of 0.05 and β of 0.20, an estimated sam- presented as means and standard errors or as 95% confidence intervals. Categorical variables were summarized as relative frequencies.

RESULTS
The recruitment and intervention periods encompassed July 2017 July to July 2018. The study flowchart is shown in Figure 1.
The groups were similar at the baseline ( Table 1).
The dropout rates were 51.6% in the isometric handgrip training group and 53.1% in the control group. Through comparing the characteristics of the patients who were included and the dropouts in the isometric handgrip training group ( Table 2), only a difference in calcium channel blocker use could be seen (P < 0.05).

Figure 2 and
The intent-to-treat analysis did not reveal any significant effect from the IHT program on any of the outcome variables measured (data not shown).

DISCUSSION
The main results of this study in a primary healthcare unit were the following: (i) IHT reduced office systolic BP among medicated hypertensive individuals; (ii) no effects were observed in relation to office diastolic BP, heart rate variability or ambulatory BP in medicated hypertensive patients.
The main novelty of this study was that the IHT program was conducted in a primary healthcare unit, which is a real-world setting for supervised training. We demonstrated that there was a reduction in office systolic BP in medicated hypertensive individuals, which corroborates previous studies conducted in laboratory or home settings. 11,14,15 The magnitude of the reduction in office systolic BP was approximately 8 mmHg, which was similar to findings from previous clinical trial studies conducted in laboratory or home settings. 8,25 Moreover, the analysis on individual responses indicated that 63% of the patients showed reductions in systolic BP of more than 5 mmHg, which may represent a reduction of at least 7% in the risks of stroke, coronary disease and death. 26  It is not clear why office systolic BP, but not diastolic BP, was found to have decreased after the 12-week training period.
One possible explanation is that the patients included in the present study presented well-controlled values for diastolic BP in the pre-intervention period (all < 90 mmHg) and, as such, may have had a lower capacity for BP reduction through IHT.
In fact, a previous study reported that individuals with higher pre-training resting BP had a greater post-training hypotensive response. 29 In the present study, 12 weeks of IHT in hypertensive individ-     contraction. 13  In the present study, we demonstrated that isometric handgrip training reduces office systolic BP in medicated hypertensive patients who were attended in primary healthcare settings.
However, we failed to show that this has any efficacy with regard to office diastolic BP, ambulatory BP or heart rate variability parameters. In addition, our dropout rate was higher than in previous studies conducted in laboratory or home settings, which suggests that caution is required in implementing isometric handgrip training in primary care settings.
The present study presents limitations that should be considered. The sample size did not allow for stratified analysis according to the medication used. This might have enabled comprehension of the mechanism(s) of BP lowering after isometric handgrip training. Generalizations of these findings to other populations (either those with advanced hypertension or other populations) must be made with care. The dropout rate in this study was higher than that we would have liked. It is not possible to assume that similar results would be observed among patients who dropped out of the program, and these data should be considered with caution. In addition, we did not do intention-to-treat analyses.
Although without any statistically significant difference, the control group was heavier than the IHT group, and this needs to be taken into account. Lack of control regarding physical activity in both groups was also a limitation, although none of the