Hypertension is frequent in patients with atrial fibrillation (AF) and is an independent risk factor for stroke. The Randomized Evaluation of Long Term Anticoagulant TherapY (RE-LY) trial found dabigatran 110 mg (D110) and 150 mg twice daily (D150) noninferior or superior to warfarin for stroke reduction in patients with AF, with either a reduction (D110) or similar rates (D150) of major bleeding. Baseline characteristics and outcomes were compared in patients with and without hypertension. The quality of blood pressure control was also assessed. In RE-LY, 14,283 patients (78.9%) had hypertension. The mean blood pressure at baseline was 132.6 ± 17.6/77.7 ± 10.6 and 124.8 ± 16.7/74.6 ± 10.0 mm Hg for patients with and without hypertension, respectively. More patients with hypertension were diabetic (25.6% vs 14.8%, p <0.001), women (38.6% vs 28.3%, p <0.001), and had greater CHADS 2 (2.3 vs 1.4, p <0.001) and CHA 2 DS 2 -VASc scores (3.8 vs 2.8, p <0.001). Mean blood pressure in all treatment arms in hypertensive patients was similar (130 ± 18/76 ± 11 mm Hg) during the trial. The efficacy and safety of D110 and D150 compared to warfarin were similar (p = nonsignificant) in hypertensive (stroke/systemic embolism rate of 1.47%, 1.20%, and 1.81% and major bleed rate of 2.89%, 3.70%, and 3.69% in the D110, D150, and W, respectively) and normotensive patients (stroke/systemic embolism rate of 1.79%, 0.78%, and 1.36% and major bleed rate of 2.84%, 2.37%, and 3.03% per year in the D110, D150, and W, respectively). Hypertensive patients had more major bleeds (3.39% vs 2.76%; p = 0.007). Intracranial bleeds were similar (0.47% vs 0.31%; p = 0.12). In conclusion, patients with hypertension in RE-LY were more likely female, diabetic, with a greater CHADS 2 and CHA 2 DS 2 -VASc scores. Blood pressure control in RE-LY was excellent. The benefits of dabigatran over warfarin, including a substantial reduction of intracranial hemorrhage, were similar in both hypertensive and non-hypertensive patients.
The objective of this analysis was to compare the baseline characteristics and outcomes in patients with and without hypertension and to evaluate the efficacy and safety of dabigatran (150 and 110 mg twice daily) compared to well controlled warfarin in patients with nonvalvular atrial fibrillation (AF) and hypertension in the phase 3 Randomized Evaluation of Long Term Anticoagulant TherapY (RE-LY) trial. We also sought to evaluate the level of blood pressure control during the trial.
Methods
Patients included in the RE-LY trial were aged ≥18 years with AF and with at least 1 additional risk factor for stroke (i.e. previous ischemic stroke, transient ischemic attack [TIA] or systemic embolism; left ventricular dysfunction; age ≥ 75 years; age ≥ 65 years with diabetes mellitus, history of coronary artery disease or hypertension).
The primary efficacy end point was incidence of stroke (including hemorrhagic) or non–central nervous system systemic embolism, hereafter referred to as systemic embolic event (SEE). The other efficacy end points included vascular death (including deaths from bleeding) and all deaths.
Safety end points included major bleeding events (defined as bleeding associated with a reduction in hemoglobin level of ≥20 g/l or leading to transfusion of ≥2 U of blood or packed cells, or symptomatic bleeding in a critical area or organ and intracranial bleeding [ICH]).
Patient characteristics and outcomes were compared between patients diagnosed with and without hypertension at trial entry by means of t -test or chi-square test. The main effect of hypertension (analyzed by comparison of outcomes in patients with hypertension vs patients without hypertension) and the relative efficacy of each dose of dabigatran versus warfarin were analyzed by hazard ratios from time-to-event analyses. Interactions of hypertension (yes or no) with treatment were evaluated using Cox proportional hazard models. The level of blood pressure control during the trial was assessed at baseline and at follow-up visits and was reported as mean (±standard deviation [SD]).
Results
Of the 18,113 patients in RE-LY, 14,283 patients (78.9%) had hypertension (systolic blood pressure ≤180 mm Hg and diastolic blood pressure ≤100 mm Hg). Patients with hypertension were more likely to have diabetes mellitus, more likely to be female, and accordingly had greater CHADS 2 and CHA 2 DS 2 -VASc scores but had heart failure and previous stroke/SEE less often compared to patients without hypertension ( Table 1 ), the latter serving as the qualifying risk factor required for inclusion into the trial.
| Hypertension † | p value | ||
|---|---|---|---|
| Present n=14,283 (78.9%) | Absent n =3830 (21.1%) | ||
| Mean (SD) age (years) | 71.6 (8.1) | 70.9 (10.5) | ns |
| Diabetes mellitus | 25.6% | 14.8% | < 0.001 |
| Sex, % Female | 38.6 | 28.3 | <0.001 |
| AF type | |||
| Persistent | 4545 (31.8%) | 1244 (32.5%) | |
| Paroxysmal | 4767 (33.4%) | 1176 (30.7%) | |
| Permanent | 4968 (34.8%) | 1407 (36.7%) | |
| Mean (SD) blood pressure (mmHg) | |||
| Systolic | 132.6 (17.6) | 124.8 (16.7) | <0.001 |
| Diastolic | 77.7 (10.6) | 74.6 (10.0) | <0.001 |
| Median CrCl,(mL/min) | 68.5 | 67.5 | ns |
| Mean (SD) baseline CHADS 2 ∗ | 2.3 (1.1) | 1.4 (0.9) | <0.001 |
| Mean (SD) baseline CHA 2 DS 2 -VASc ∗ | 3.8 (1.4) | 2.8 (1.2) | <0.001 |
| Mean (SD) baseline HASBLED | 1.3 (1.0) | 1.3 (1.0) | ns |
| Heart failure | 30.7% | 36.9% | <0.001 |
| Prior stroke/SEE/TIA, % | 21.2 | 24.3 | <0.001 |
∗ By definition these scores are 1 point higher in patients with HTN.
† Defined as systolic blood pressure ≤ 180 mm Hg and diastolic blood pressure ≤100 mm Hg.
Systolic and diastolic blood pressure (in mm Hg; mean ± SD) at baseline was greater in patients with hypertension compared to that in those without hypertension (132.6 ± 17.6 vs 124.8 ± 16.7; p <0.001 and 77.7 ± 10.6 vs 74.6 ± 10.0; p <0.001, respectively). Majority of the hypertensive patients were classified (according to Joint National Committee 7) as having high normal (n = 6,208; 43.5%) or stage 1 hypertension (n = 4,355; 30.5%). Very few patients had stage II hypertension (n = 1,372; 9.6%). Rest of the hypertensive patients (n = 2,344; 16.4%) had normal blood pressure at baseline, and 4 patients were not classified. The median time in therapeutic range (international normalized ratio 2 to 3) for warfarin-treated patients was 67.5% for hypertensive compared to 66.5% for nonhypertensive patients (p = nonsignificant).
There was no significant difference in the risk of thromboembolic outcomes (stroke/SEE) between patients with and without hypertension (1.49% vs 1.31%; p = nonsignificant; Figure 1 ). Patients with hypertension had a greater risk of major bleeding (3.39% vs 2.76%; p = 0.0068), but a similar risk of intracranial bleeding (0.47% vs 0.31%; p = 0.1174) compared to patients without hypertension ( Figure 1 ).
Analysis using blood pressure as a continuous variable demonstrated that an increase in mean and systolic blood pressure was associated with an increased risk of stroke and systemic embolism: there was a 6% to 7% increased risk of stroke for every 10 mm Hg increase in mean (p = 0.046) and systolic blood pressure (p = 0.016). An increase in diastolic blood pressure was not associated with an increased risk of stroke (p = 0.47).
There was a mild reduction in the mean blood pressures during participation in the trial (up to 16 months) compared to baseline in all the 3 treatment arms ( Table 2 ).
| Blood Pressure | Dabigatran 150 mg bid | Dabigatran 110 mg bid | Warfarin (INR 2-3) | |
|---|---|---|---|---|
| Systolic Mean±SD (mm Hg) | Baseline | 131±17 | 131±17 | 131±17 |
| 16 month follow up visit | 130±17 | 130±18 | 130±18 | |
| Change from baseline ∗ | -1.3 to -2.0 | -1.0 to -1.3 | -0.8 to -1.8 | |
| Diastolic Mean±SD (mm Hg) | Baseline | 77±11 | 77±11 | 77±10 |
| 16 month follow up visit | 76±11 | 76±11 | 76±11 | |
| Change from baseline ∗ | -1.1 to -1.4 | -0.8 to -1.1 | -0.7 to -1.3 |
The relative benefits of dabigatran compared to warfarin were similar in patients with and without hypertension. All p values for interaction were not significant ( Table 3 ; Figures 2 and 3 ). The relative effects of safety outcomes with dabigatran compared to warfarin were similar in patients with and without hypertension (all p values for interaction were not significant; Table 3 ; Figures 2 and 3 ).
| Outcome ∗ | Patient group | Annual rate Dabigatran 110 mg bid | Annual rate Dabigatran 150 mg bid | Annual rate Warfarin | DE 110 mg vs. warfarin HR (95% CI) | DE 150 mg vs. warfarin HR (95% CI) |
|---|---|---|---|---|---|---|
| Stroke / Systemic embolism | RE-LY overall | 1.54 | 1.11 | 1.71 | 0.90 (0.74, 1.10) | 0.65 (0.52, 0.81) |
| HTN Yes | 1.47 | 1.20 | 1.81 | 0.81 (0.65, 1.02) | 0.66 (0.52, 0.84) | |
| HTN No | 1.79 | 0.78 | 1.36 | 1.32 (0.85, 2.06) | 0.57 (0.33, 0.99) | |
| p-inter = 0.0547 | p-inter = 0.6207 | |||||
| Major bleeding | RE-LY overall | 2.88 | 3.41 | 3.55 | 0.81 (0.69, 0.94) | 0.96 (0.83, 1.11) |
| HTN Yes | 2.89 | 3.70 | 3.69 | 0.78 (0.66, 0.92) | 1.00 (0.85, 1.17) | |
| HTN No | 2.84 | 2.37 | 3.03 | 0.94 (0.67, 1.32) | 0.78 (0.54, 1.11) | |
| p-inter = 0.3413 | p-inter = 0.2052 | |||||
| Intracranial bleeding | RE-LY overall | 0.19 | 0.24 | 0.77 | 0.24 (0.15, 0.40) | 0.32 (0.20, 0.49) |
| HTN Yes | 0.16 | 0.30 | 0.83 | 0.19 (0.11, 0.35) | 0.36 (0.23, 0.57) | |
| HTN No | 0.28 | 0.04 | 0.56 | 0.49 (0.19, 1.29) | 0.08 (0.01, 0.61) | |
| p-inter = 0.1131 | p-inter = 0.1531 | |||||
| Vascular death | RE-LY overall | 2.43 | 2.28 | 2.69 | 0.90 (0.77, 1.06) | 0.85 (0.72, 0.99) |
| HTN Yes | 2.36 | 2.24 | 2.62 | 0.90 (0.75, 1.08) | 0.86 (0.71, 1.03) | |
| HTN No | 2.69 | 2.41 | 2.96 | 0.91 (0.66, 1.26) | 0.82 (0.58, 1.14) | |
| p-inter = 0.9680 | p-inter = 0.7929 | |||||
| Death | RE-LY overall | 3.75 | 3.64 | 4.13 | 0.91 (0.80, 1.03) | 0.88 (0.77, 1.00) |
| HTN Yes | 3.58 | 3.65 | 4.01 | 0.89 (0.77, 1.03) | 0.91 (0.75, 1.05) | |
| HTN No | 4.37 | 3.62 | 4.56 | 0.95 (0.73, 1.24) | 0.79 (0.60, 1.04) | |
| p-inter = 0.6532 | p-inter = 0.3902 |
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