Blood pressure control and stroke or bleeding risk in anticoagulated patients with atrial fibrillation: Results from the ROCKET AF Trial

Clinical Investigation

Blood pressure control and stroke or bleeding risk in anticoagulated patients with atrial fibrillation: Results from the ROCKET AF Trial Sreekanth Vemulapalli, MD, a Anne S. Hellkamp, MS, a W. Schuyler Jones, MD, a Jonathan P. Piccini, MD, MHS, a Kenneth W. Mahaffey, MD, b Richard C. Becker, MD, c Graeme J. Hankey, MD, d Scott D. Berkowitz, MD, e Christopher C. Nessel, MD, f Günter Breithardt, MD, g Daniel E. Singer, MD, h Keith A. A. Fox, MB, ChB, i and Manesh R. Patel, MD a Durham, NC; Stanford, CA; Cincinnati, OH; Perth, Australia; Whippany, Raritan, NJ; Münster, Germany; Boston, MA; and Edinburgh, United Kingdom

Background We conducted a retrospective analysis examining the association between systolic blood pressure (SBP) or hypertension bracket and stroke risk in patients with atrial fibrillation (AF). Methods The study included 14,256 anticoagulated patients in the ROCKET AF trial. Cox proportional hazards models were used to compare the risk of adverse outcomes by European Society of Cardiology hypertension bracket and screening SBP. Results

In total, 90.5% of patients had hypertension (55.8% controlled, 34.6% uncontrolled). The adjusted risk of stroke or systemic embolism (SE) increased significantly for every 10–mm Hg increase in screening SBP (hazard ratio [HR] 1.07, 95% CI 1.02-1.13). There was a trend toward an increased adjusted risk of stroke or SE in patients with controlled (HR 1.22, 95% CI 0.89-1.66) and uncontrolled hypertension (HR 1.42, 95% CI 1.03-1.95) (P = .06). In contrast, the adjusted risk of major bleeding was similar between hypertensive brackets and did not vary significantly by screening SBP. The benefit of rivaroxaban versus warfarin in preventing stroke or SE was consistent among patients regardless of SBP (P interaction = .69).

Conclusions In a trial of anticoagulated patients with AF, increasing screening SBP was independently associated with stroke and SE, and one-third of patients had uncontrolled hypertension. The relative effectiveness and safety of rivaroxaban versus warfarin were consistent across all levels of screening SBP. A single SBP may be an important factor in reducing the overall risk of stroke and SE in anticoagulated patients with AF. (Am Heart J 2016;178:74-84.)

Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with a significantly increased risk of stroke and systemic thromboembolism. Hypertension is a frequent comorbidity among patients with AF 1,2 and an independent risk factor for stroke, with greater stroke risk associated with increasing systolic blood pressure (SBP). 3,4 Current guidelines suggest SBP control in patients with cardiovascular disease 5,6; however, few

From the aDuke Clinical Research Institute, Duke University Medical Center, Durham, NC, b Stanford University, Stanford, CA, cUniversity of Cincinnati, Cincinnati, OH, dUniversity of Western Australia, Crawley, Perth, Australia, eBayer HealthCare Pharmaceuticals, Whippany, NJ, fJanssen Research & Development, Raritan, NJ, gDepartment of Cardiovascular Medicine, University Hospital of Münster, Münster, Germany, hMassachui setts General Hospital and Harvard Medical School, Boston, MA, and University of Edinburgh and Royal Infirmary of Edinburgh, Edinburgh, United Kingdom. Submitted January 15, 2016; accepted May 2, 2016. Reprint requests: Sreekanth Vemulapalli, MD, Box 3026, Duke University Medical Center, Durham, NC, 27710. E-mail: [email protected] 0002-8703 © 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ahj.2016.05.001

reports have evaluated the significance of SBP, rather than the presence or absence of hypertension, as a risk factor for stroke in AF. Furthermore, studies of SBP and stroke risk in AF have mostly been limited to patients not treated with anticoagulation, 2,7–11 with only 3 analyses of anticoagulated patients with AF. 12–14 As a result, AF 15–17 and hypertension 5,6 guidelines do not make specific recommendations regarding SBP control in patients with AF treated with warfarin or novel oral anticoagulants. Consequently, practitioners are left to extrapolate general blood pressure targets 5,6 in these patients. In this substudy of the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF), 18 we (1) describe the rate of stroke and non–central nervous system systemic embolism and bleeding outcomes in patients as a function of screening SBP and hypertension bracket and (2) evaluate the relative effectiveness and safety of rivaroxaban versus warfarin as a function of screening SBP and hypertension bracket.

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Methods The methods used in the ROCKET AF trial have been previously reported. 18 Briefly, ROCKET AF was a prospective, multicenter, international, double-blind, randomized controlled trial in patients with nonvalvular AF and moderate to high risk of stroke based on a CHADS2 (Congestive heart failure, Hypertension, Age N/= 75 years, Diabetes mellitus, Prior Stroke or TIA or Thromboembolism2) score of at least 2. Patients were randomly assigned to 20 mg once daily of rivaroxaban (15 mg once daily in patients with a creatinine clearance of 30-49 mL/min) or dose-adjusted warfarin (target international normalized ratio 2.5, range 2.0-3.0). Patients were excluded from ROCKET AF if they had prosthetic heart valves, had hemodynamically significant mitral stenosis, had creatinine clearance of b30 mL/min, had a recent stroke or systemic embolic event, or were at risk of bleeding. The study protocol was reviewed and approved by the institutional review board or ethics committee at each participating site and by the coordinating center’s institutional review board. All patients were required to provide written informed consent before randomization.

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sion were further subdivided into the following brackets: bracket 1, SBP ≥140 and b160 mm Hg; and bracket 2, SBP ≥160 mm Hg. Patients without a history of hypertension on the case report form were included in the no-hypertension cohort regardless of SBP at screening. Patients were considered to have improved hypertension bracket from screening to study exit if their hypertension bracket decreased according to the following hierarchy: uncontrolled hypertension N controlled hypertension N no hypertension. If there was no change in hypertension bracket from screening to study exit, the patient was categorized as unchanged. A hierarchical increase in hypertension bracket from screening to study exit was deemed as worsened hypertension bracket.

Blood pressure measurement Blood pressure was measured by study personnel using a sphygmomanometer after patients were in a semirecumbent position for 5 minutes. Blood pressure was measured at the study screening visit (within 30 days of randomization) and at any early or planned study exit visit. To investigate the relationship between blood pressure and cardiovascular outcomes, only screening blood pressures were used because study exit blood pressures generally occurred after the outcomes of interest. Interval blood pressure assessments were not analyzed because they were not protocolized and were therefore generally associated with adverse events.

Outcomes The primary efficacy outcome was stroke or systemic embolism. The secondary efficacy outcomes included stroke, ischemic stroke, hemorrhagic stroke, myocardial infarction (MI), all-cause death, vascular death, and the composite of stroke, systemic embolism, vascular death, or MI. Efficacy end points were measured until the time of site notification of study termination. Efficacy analyses excluded patients (n = 93) from 1 site because of violations of good clinical practice. The primary safety end point was a combination of major or nonmajor clinically relevant (NMCR) International Society of Thrombosis and Hemostasis bleeding. 19 Safety end points were measured for the duration of study drug exposure plus 2 days. Bleeding events involving the central nervous system that met the definition of stroke were designated as hemorrhagic strokes and were included in both the primary efficacy and safety end points. All events were adjudicated using predefined end point definitions by an independent clinical events committee that was blinded to treatment assignment.

Definition of hypertensive brackets Patients with a history of hypertension—defined as the use of antihypertensive medications or persistently elevated SBP or diastolic blood pressure (DPB) (≥140 mm Hg systolic or ≥90 mm Hg diastolic) in the 6 months prior to the screening visit—and a screening SBP documented on the case report form were included in the hypertension cohort. Study patients were further categorized into hypertensive brackets based on Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) 5 and the European Society of Cardiology (ESC) hypertension guidelines. 6 Controlled hypertension included patients with a history of hypertension on the case report form and an SBP b140 mm Hg at screening. Uncontrolled hypertension included patients with a history of hypertension on the case report form and an SBP ≥140 mm Hg at screening. Patients with uncontrolled hyperten-

Statistical analysis The current analysis was not a prespecified subgroup analysis. We used Cox proportional hazards models to assess the association of screening SBP as a continuous variable with cardiovascular outcomes for patients with and without a baseline history of hypertension. Neither study exit SBP nor an average between screening and study exit SBPs was used for these analyses because study exit SBP would have been measured after any cardiovascular event. As a result, study exit SBP likely would not have been reflective of pre-event SBP. Stratification of patients by history of hypertension was undertaken to try to account for the potential increased time of exposure to elevated SBP among those with a history of hypertension. SBP was evaluated for the linearity of its relationship with each outcome using restricted cubic splines; where nonlinearity was found, simplified versions (such as truncations) were used to characterize the relationship.

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This evaluation was carried out separately in patients with and without a history of hypertension. For each outcome, a single model was used that included terms for history of hypertension, screening SBP, and the interaction between them, as well as anticoagulant type and covariates identified as predictive of outcomes by modeling in the full ROCKET AF cohort. For efficacy outcomes, these covariates were age, sex, body mass index, geographic region, diabetes mellitus, prior stroke/transient ischemic attack (TIA), prior MI, carotid occlusive disease, congestive heart failure, hypertension, chronic obstructive pulmonary disease, paroxysmal AF, creatinine clearance (Cockroft-Gault equation), heart rate, and abstinence from alcohol use. For safety outcomes, these covariates were age, sex, geographic region, prior stroke/TIA, anemia, prior gastrointestinal bleed, chronic obstructive pulmonary disease, DPB, creatinine clearance, platelet count, albumin, prior aspirin use, vitamin K antagonist use, or thienopyridine use. Cox proportional hazards models were also used to assess the association of hypertension bracket with risk of cardiovascular outcomes. For each outcome, a single model was constructed using the same covariates as the continuous screening SBP model. All models included a term for the interaction between randomized treatment (rivaroxaban vs warfarin) and history of hypertension. For this analysis, the intention-to-treat study patients were used for all efficacy outcome analyses. Safety end points were analyzed using the on-treatment patients (patients who were randomized and received at least 1 dose of the study drug). Categorical variables are summarized as percentages (counts), and continuous variables are summarized as median (25th-75th percentiles). Outcomes are presented as events per 100 patient-years. Risk relationships are presented as adjusted hazard ratios (HRs) with 95% CIs derived from the adjusted Cox models. The time to event for each group was assessed by the Kaplan-Meier method. A level of significance of b.05 was prespecified. All analyses were performed with SAS version 9.2 (SAS Institute, Inc, Cary, NC). ROCKET AF is registered with ClinicalTrials.gov number NCT00403767.

Sources of funding This work was funded by Janssen Research & Development and Bayer HealthCare. However, the authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper, and its final contents.

Results Study patients A total of 14,264 patients with AF from 1,178 centers in 45 countries were randomly assigned to treatment in ROCKET AF between December 18, 2006, and June 17,

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2009. From the total trial, 14,256 patients had known baseline hypertension status and screening SBP. As shown in Table I, 90.5% of patients in ROCKET AF had hypertension: 55.8% were controlled at screening, and 34.6% were uncontrolled at screening. Among patients with uncontrolled hypertension at screening, 3,958 patients (80.1%) were categorized as bracket 1 (SBP ≥140 and b160 mm Hg) and 981 patients (19.9%) were categorized as bracket 2 (SBP ≥160 mm Hg). Baseline demographic and clinical characteristics of study participants by hypertension subgroup are shown in Table I. Compared with patients without hypertension, patients with controlled and uncontrolled hypertension at screening had higher mean CHA2DS2-VASc (Congestive heart failure, Hypertension, Age N=75 years2, Diabetes mellitus, Prior Stroke or TIA or thromboembolism2, Vascular disease, Age 65 to 74 years, Sex category) scores (3.8 [standard deviation {SD} 1.2] vs 4.9 [SD 1.3] and 5.0 [SD 1.3]), higher median screening SBP (120 [25th-75th 110-130] mm Hg vs 125 [120-130] mm Hg and 146 [140-155] mm Hg), and a greater incidence of left ventricular hypertrophy on electrocardiogram (7% vs 16% and 22%, respectively). Patients with progressively worse screening hypertension bracket were older, were more likely to be female, had a higher body mass index, and were more likely to have a prior diagnosis of diabetes and congestive heart failure. Notably, creatinine clearance was similar between the 3 groups, and prior stroke/TIA/embolism was more common in patients without a history of hypertension. In terms of medications, baseline aspirin use was similar across the groups, whereas angiotensin-converting enzyme inhibitors, β-blockers, and calcium channel blockers were more common in patients with a history of hypertension.

Blood pressure control over time Among the 12,902 patients with a history of hypertension at baseline, 11,260 (87.3%) had follow-up blood pressure data available at study exit. The mean duration of follow-up for the 3 groups was 674 days for those without a history of hypertension, 690 days for the controlled hypertension group, and 687 days for the uncontrolled hypertension group. Mean SBP at screening among all hypertension subgroups was 133.1 mm Hg and decreased to 128.7 mm Hg at study exit. Mean change in SBP over the study period was −4.4 mm Hg (SD 19.1 mm Hg). Among patients with controlled SBP at screening, 80.8% remained controlled at study exit, whereas 19.2% transitioned to uncontrolled hypertension. Conversely, 60.1% of patients with uncontrolled SBP at screening transitioned to controlled SBP, whereas 39.9% remained uncontrolled (Table II). Outcomes as a function of hypertension bracket As shown in Table III, compared with those with no history of hypertension, there was a trend toward an increased adjusted risk of stroke or systemic embolism in patients with controlled hypertension (HR 1.22, 95% CI

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Table I. Baseline characteristics by hypertension status

Variable Age, y Randomized to rivaroxaban Female AF Persistent Paroxysmal New onset CHA2DS2VASc score, mean (SD) CHA2DS2VASc score 1 2 3 4 5 6 7 8 9 Presenting characteristics Body mass index, kg/m 2 SBP, mm Hg DPB, mm Hg Heart rate Creatinine clearance, mL/min Left ventricular hypertrophy on ECG Ejection fraction, % Left ventricular function Normal Mild dysfunction (EF 40%-55%) Moderate dysfunction (EF 25%-39%) Severe dysfunction (EF b25%) Baseline comorbidities Prior stroke/TIA/embolism Congestive heart failure Sleep apnea CPAP use Diabetes Prior MI Peripheral arterial disease Liver disease Alcohol use Abstinent Heavy Prior gastrointestinal bleeding COPD History of smoking Current Former Medications Prior vitamin K antagonist use Prior chronic ASA use ACE inhibitor/ARB at baseline β-Blocker at baseline Calcium channel blocker

No HTN

Controlled HTN (SBP b140 mm Hg)

Uncontrolled HTN (SBP ≥140 mm Hg)

9.5% (n = 1354)

55.8% (n = 7963)

34.6% (n = 4939)

69 (61-77) 51% (695) 29% (386)

73 (65-78) 50% (3963) 39% (3110)

73 (66-78) 50% (2470) 44% (2161)

81% 17% 2% 3.8

81% 18% 1% 4.9

(6419) (1430) (114) (1.3)

82% 17% 1% 5.0

(4028) (848) (63) (1.3)

0 12% (160) 29% (392) 33% (446) 18% (243) 7% (89) 2% (22) b1% (2) 0

0 2% (154) 10% (835) 25% (1980) 32% (2541) 20% (1560) 8% (644) 3% (218) b1% (29)

b1% 10% 10% 25% 30% 21% 10% 3% b1%

(2) (488) (488) (1217) (1458) (1033) (509) (135) (15)

26 120 76 76 69 7% 53

(23-29) (110-130) (70-80) (67-86) (55-88) (99) (40-60)

28 125 78 75 66 16% 50

(25-32) (120-130) (70-80) (67-85) (51-86) (1249) (38-60)

29 146 86 77 68 22% 53

(26-33) (140-155) (80-90) (68-87) (53-87) (1089) (42-60)

45% 33% 18% 4%

(463) (336) (186) (43)

40% 35% 22% 4%

(2504) (2201) (1356) (221)

43% 38% 18% 2%

(1580) (1389) (658) (56)

88% 45% 3% 2% 19% 11% 5% 2%

(1192) (612) (40) (22) (262) (152) (71) (33)

51% 64% 5% 3% 42% 19% 6% 6%

(4033) (5117) (434) (226) (3318) (1537) (476) (443)

52% 64% 3% 1% 43% 16% 6% 5%

(2584) (3175) (171) (74) (2111) (777) (291) (271)

61% 1% 3% 7%

(828) (12) (36) (94)

65% 1% 4% 12%

(5143) (62) (323) (920)

66% 1% 3% 10%

(3237) (29) (140) (480)

(1095) (234) (25) (1.2)

8% (108) 29% (397)

6% (460) 29% (2332)

5% (241) 25% (1248)

67% 34% 39% 55% 13%

65% 37% 77% 67% 28%

58% 36% 80% 64% 32%

(905) (454) (532) (739) (171)

(5139) (2950) (6112) (5367) (2208)

(2854) (1798) (3935) (3140) (1577)

Data presented as medians (25th-75th percentiles) or % (n), unless otherwise noted. HTN, Hypertension; ECG, electrocardiography; EF, ejection fraction; CPAP, continuous positive airway pressure; COPD, chronic obstructive pulmonary disease; ASA, aspirin; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker.

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Table II. Changes in hypertension bracket between screening and study exit

Study Exit Controlled SBP Uncontrolled SBP

Screening Controlled SBP, n (%) Uncontrolled SBP, n (%) Totals

Totals

5607 (80.8%)

1331 (19.2%)

6938

2599 (60.1%)

1723 (39.9%)

4322

7906

3054

Green cellsindicate improved hypertension control. Yellow cells indicate unchanged hypertension control. Red cells indicate worsened hypertension control. SBP = systolic blood pressure.

Green cells indicate improved hypertension control. Yellow cells indicate unchanged hypertension control. Red cells indicate worsened hypertension control.

Table III. Cardiovascular and bleeding outcomes as a function of blood pressure as a categorical variable Outcome

Efficacy outcomes Stroke or systemic embolism Stroke Ischemic stroke Hemorrhagic stroke MI All-cause death Vascular death Stroke/systemic embolism/vascular death/MI Safety outcomes Major or NMCR bleeding Major bleeding Hemoglobin drop ≥2 g/dL Transfusion ≥2 U Critical organ bleed Fatal ICH NMCR bleeding

P value for any difference among groups

Controlled HTN versus no history of HTN, HR (95% CI)

Uncontrolled HTN versus no history of HTN, HR (95% CI)

.060 .054 .25 .11 .97 .048 .14 .88

1.22 1.22 1.03 2.50 0.96 0.94 0.97 1.02

(0.89-1.66) (0.88-1.68) (0.73-1.46) (0.89-7.05) (0.60-1.52) (0.77-1.16) (0.75-1.25) (0.84-1.24)

1.42 1.43 1.22 3.04 0.94 0.82 0.83 0.99

(1.03-1.95) (1.03-2.00) (0.85-1.74) (1.06-8.71) (0.58-1.53) (0.66-1.02) (0.63-1.10) (0.80-1.22)

.30 .84 .75 .74 .11 .92 .27 .19

0.95 0.96 1.06 0.92 0.87 0.90 1.01 0.93

(0.83-1.08) (0.74-1.23) (0.78-1.45) (0.63-1.36) (0.56-1.38) (0.43-1.89) (0.56-1.81) (0.81-1.08)

1.01 1.00 0.99 0.86 1.18 0.98 1.34 1.01

(0.88-1.16) (0.77-1.30) (0.72-1.38) (0.57-1.30) (0.74-1.88) (0.45-2.13) (0.73-2.46) (0.87-1.17)

ICH, Intracranial hemorrhage.

0.89-1.66) and uncontrolled hypertension (HR 1.42, 95% CI 1.03-1.95) (P = .06). A similar trend in adjusted risk of hemorrhagic stroke was observed (controlled hypertension: HR 2.50, 95% CI 0.89-7.05; uncontrolled hypertension: HR 3.04, 95% CI 1.06-8.71) (P = .11). The effect of hypertension bracket on stroke risk did not vary significantly by baseline CHA2DS2-VASc risk score (P interaction = .66). Further subcategorization of patients into bracket 1 (screening SBP ≥140 and b160 mm Hg) and bracket 2 uncontrolled hypertension (screening SBP ≥160 mm Hg) did not yield significant differences between groups in HRs for primary and secondary efficacy outcomes. The cumulative event rate of all-cause stroke (Figure 1) was not increased in those with bracket 2 uncontrolled hypertension but was increased in those with hemorrhagic stroke (Figure 2).

With regard to safety end points, the adjusted risk of major or NMCR bleeding, major bleeding, and intracranial hemorrhage was not significantly different between groups (Table III).

Outcomes as a function of continuous SBP For every 10–mm Hg increase in screening SBP, the risk of stroke or non–central nervous system systemic embolism (HR 1.07, 95% CI 1.02-1.13, P = .009), stroke (HR 1.07, 95% CI 1.02-1.13, P = .008), and ischemic stroke (HR 1.08, 95% CI 1.02-1.15, P = .012) increased significantly. Conversely, lower screening SBP was associated with a higher risk of vascular death (HR 0.95, 95% CI 0.90-0.99, P = .013). There was no significant relationship between screening SBP and hemorrhagic stroke or the combined end point of stroke/systemic embolism/vascular death/MI. Additionally, for every 10–

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Figure 1

Cumulative unadjusted rate of stroke or systemic embolism by hypertension bracket.

Figure 2

Cumulative unadjusted rate of hemorrhagic stroke by hypertension bracket.

mm Hg increase in screening SBP, there was no significant change in major or NMCR bleeding or intracranial hemorrhage (Table IV).

The relationship between screening continuous SBP and outcomes was linear in all cases except for all-cause mortality in patients without a history of hypertension. In

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Table IV. Cardiovascular and bleeding outcomes as a function of blood pressure as a continuous variable HR (95% CI) for 10–mm Hg increase in SBP

Outcome Efficacy outcomes Stroke or systemic embolism Stroke Ischemic stroke Hemorrhagic stroke MI All-cause death Vascular death Stroke/embolism/vascular death/MI Safety outcomes Major or NMCR bleeding Major bleeding Hemoglobin drop ≥2 g/dL Transfusion ≥2 U Critical organ bleed Fatal ICH NMCR bleeding

Interaction P value

.48 .45 .46 .49 .045 .058 .99 .18 .15 .54 .40 .88 .58 .61 .44 .048

Patients with history of HTN

Patients without history of HTN

All patients (main effect)

1.07 1.07 1.08 1.05 1.01 (0.94-1.09) 0.95 (0.91-0.98)

1.02 (1.00-1.05)

(1.02-1.13) (1.02-1.13) (1.02-1.15) (0.92-1.20)

Main effect P value

.0088 .0081 .012 .46

1.35 (1.03-1.77) 0.72 (0.54-0.95)⁎ 0.95 (0.90-0.99) 1.00 (0.97-1.03)

.013 .93

1.01 1.00 0.98 0.96 1.05 0.98 1.08

.64 .92 .55 .18 .25 .77 .15

(0.98-1.03) (0.96-1.04) (0.94-1.04) (0.89-1.02) (0.97-1.14) (0.86-1.12) (0.97-1.19)

0.93 (0.85-1.02)

⁎ Among patients with SBP b115 mm Hg. SBP ≥115 mm Hg, all patients had equivalent risk.

this group, decreasing screening SBP was associated with an increased risk of death among patients with an SBP b115 mm Hg. In patients with a screening SBP ≥115 mm Hg, all patients had an equivalent risk of all-cause mortality.

Rivaroxaban versus warfarin in patients by hypertension bracket The relative effect of rivaroxaban compared with warfarin on the primary efficacy outcome was similar in patients with controlled and uncontrolled hypertension (P interaction = .69). No differences in treatment effect were detected between patients with controlled versus uncontrolled hypertension for any of the secondary end points (Figure 3).

Discussion In this analysis of N12,000 patients with hypertension in the ROCKET AF trial, there are 4 major findings. First, one-third of patients in this contemporary clinical trial of AF had uncontrolled screening SBP. Second, screening SBP was associated with a higher risk of stroke or systemic embolism, stroke, and ischemic stroke but not bleeding risk. Third, there was a trend toward higher risk of stroke or systemic embolism with uncontrolled screening SBP. Finally, there was no evidence of differential efficacy or safety in patients treated with rivaroxaban versus warfarin according to screening SBP bracket. Hypertension is widely considered to be an etiologic factor in multiple cardiovascular diseases. Rapsomaniki et al 3 recently demonstrated that for every 20–mm Hg/10–mm Hg increase in SBP, the HRs for developing cardiovascular complications were highest for intracerebral hemorrhage

(HR 1.44, 95% CI 1.32-1.58), subarachnoid hemorrhage (HR 1.43, 95% CI 1.25-1.63), stable angina (HR 1.41, 95% CI 1.36-1.46), and ischemic stroke (HR 1.35, 95% CI 1.28-1.42). Given that ischemic stroke and intracranial hemorrhage represent 2 of the most important clinical end points among patients with AF warranting anticoagulation, the association between SBP control or hypertension bracket and outcomes warrants scrutiny. Despite the role of hypertension in stroke and intracranial hemorrhage, and the presence of JNC 7 and ESC antihypertensive targets, the implications of the quality of SBP control have only been assessed in 3 previous studies of anticoagulated patients with AF. 12–14 A previous analysis of the Stroke Prevention Using an Oral Thrombin Inhibitor in Atrial Fibrillation (SPORTIF) III and V data in patients anticoagulated with a vitamin K antagonist suggested an increase in stroke risk with an inflection point at an SBP N140 mm Hg during follow-up. 12 Whereas the previous analysis of the SPORTIF III and V trials used mean follow-up SBP, the present analysis has extended the relationship between SBP and stroke to a single measure of SBP and to those treated with the factor Xa inhibitor rivaroxaban. Importantly, we have also shown a linear relationship between SBP and the hazard of stroke below 140 mm Hg which is consistent with the relationship seen between SBP and stroke in the general population and was not demonstrated in the post hoc analysis of the SPORTIF III and V trials. Although it is conceivable that the discrepancy between our findings and the previous SPORTIF analysis may be due to increased baseline stroke risk in the present analysis, our findings did not vary by CHA2DS2-VASc score (P interaction = .66).

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Figure 3

A, Efficacy end points classified by hypertension bracket and treatment assignment. B, Safety end points classified by hypertension bracket and treatment assignment.

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A subsequent analysis of the relationship between SBP and hazard of stroke was performed among patients randomized to warfarin or dabigatran in the RE-LY trial. 14 Unlike the aforementioned SPORTIF analysis, the RE-LY analysis focused on the hazard of stroke as a function of the presence or absence of a diagnosis of hypertension at study entry. This categorical analysis did not reveal a relationship between a diagnosis of hypertension and stroke risk in the anticoagulated RE-LY population. Similarly, a recently published analysis among those randomized to warfarin or apixaban in the ARISTOTLE trial focused on the relationship between hypertension, defined as SBP ≥140 mm Hg and/or DPB) ≥90 mm Hg, and stroke. 13 Despite previous studies failing to show a relationship between DBP and hazard of stroke among anticoagulated patients with AF, 12,14 these investigators combined systolic and diastolic hypertension and found a relationship between time-dependent average follow-up hypertension, but not baseline hypertension, and stroke. In light of previous studies demonstrating a relationship between SBP and stroke in both anticoagulated and nonanticoagulated patients with AF, the present study focused solely on SBP and is the only study to demonstrate (1) a statistically and clinically significant relationship between a single SBP and stroke risk and (2) a linear relationship between continuous SBP and stroke at all SBPs. Indeed, the linear relationship between SBP and stroke is without a clear cut point and may explain why we did not find a relationship between hypertension bracket and stroke. It is also indicative that current guideline-defined hypertension brackets may not capture the full extent of the relationship between SBP and stroke in anticoagulated patients with AF. Although the linear relationship between SBP and stroke risk is distinct from evidence that pharmacotherapy with antihypertensives will lower stroke risk in anticoagulated patients with AF, it suggests that progressively lower SBPs lower stroke risk in these patients. This recapitulates similar findings in a meta-analysis of the relationship between SBP and stroke risk among patients without AF. 20 Previous cohort studies have indicated that, among those without preexisting cardiovascular disease, the risks associated with increasing blood pressure vary according to age and the particular cardiovascular outcome. 3,21 In contrast to ischemic stroke, the relationship between SBP and hemorrhagic stroke has been less well studied in part because hemorrhagic strokes are combined with either ischemic stroke or intracerebral hemorrhage. Although we did not find a statistically significant variation in hemorrhagic stroke rates as a function of screening SBP, analysis of the event curves indicates that whereas overall stroke and systemic embolism rates separate modestly 6 months postrandomization, hemorrhagic stroke rate curves separate extensively, particularly in patients with an SBP N160 mm Hg. Although subject to verification in larger data sets, this suggests that

SBP may be an important driver of hemorrhagic stroke risk in anticoagulated patients with AF. Analysis of screening SBP as a continuous variable did not reveal a statistically significant relationship between screening SBP and major bleeding, NMCR bleeding, hemorrhagic stroke, or intracranial hemorrhage. Although previous clinical practice data indicate that patients with hypertension usually require close monitoring of anticoagulation and optimal blood pressure control to diminish the risk of bleeding complications, 22 only the analysis of patients randomized to warfarin or the direct thrombin inhibitor dabigatran confirmed this. 14 Neither the present analysis of patients randomized to warfarin or the factor Xa inhibitor rivaroxaban nor previous analyses of patients randomized to the factor Xa inhibitor apixaban 13 or the direct thrombin inhibitor ximelagatran 12 have confirmed this finding. Furthermore, a previous analysis of the ROCKET AF cohort indicated that increasing DBP, but not SBP, was significantly associated with increasing risk of intracranial hemorrhage. 23 Although our current analysis suggests that lower screening SBP is associated with a lower risk of stroke, some previous reports assessing the relationship between blood pressure and cardiovascular outcomes have demonstrated a “j-curve” with increasing adverse events at lower SBPs. 24 In the present report, significance testing seemed to indicate that increasing hypertension bracket was associated with decreasing all-cause death. However, given that the confidence intervals cross 1, this is a at best a weak finding in the present analysis and likely represents a statistical aberration rather than confirmation of a “j-curve.” Taken together, the present analysis implies that SBP control may be an important factor in controlling the residual ischemic and hemorrhagic stroke risk in patients with AF on anticoagulation. Yet, up to one-third of the patients in the present analysis may not be controlled to JNC 7– and ESC-recommended SBP targets. 5,6 In this setting, our finding that the relationship between screening SBP and outcomes is independent of anticoagulant type may have implications for clinical practice. Should the relationship demonstrated in the present analysis be replicated across other studies of anticoagulants, clinicians and guideline documents may need to refocus attention on antihypertensive therapy as a measure to universally reduce residual stroke risk among anticoagulated patients.

Limitations There are multiple limitations to a subgroup analysis of a large, randomized controlled trial. First, as a post hoc analysis, the findings must be considered hypothesis generating. Second, our use of a single screening SBP to classify patients is subject to error and does not take into account accumulated cardiovascular risk that is a function of the magnitude of blood pressure derangement and the length of time that derangement exists. Although we have attempted to address this deficiency by

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examining association of cardiovascular outcomes and SBP as a function of history of hypertension status, future analyses of the impact of hypertension in AF will need to take into account serial blood pressure measurements. Third, blood pressure was measured in ROCKET AF using individual site sphygmomanometers, and standardization of devices was not required, although device variety is likely reflective of real-world practice. Additionally, blood pressure was measured after 5 minutes in a semirecumbent position, which diverges from American Heart Association 25 and ESC recommendations. 6 Finally, ROCKET AF enrolled patients at high screening risk for stroke and systemic embolism, with N93% of patients having a CHADS2 score ≥3, and the results may not be generalizable to all patients with AF.

Conclusions In this large, randomized controlled trial, a single SBP was significantly linearly related to the risk of stroke, and stroke or systemic embolism, in anticoagulated patients with AF and high stroke risk. Furthermore, the relationship between screening SBP and outcomes was independent of treatment anticoagulant. Up to one-third of trial participants had uncontrolled blood pressure at screening.

Funding sources This work and the ROCKET AF trial were supported by Janssen Research & Development and Bayer HealthCare. The Duke Clinical Research Institute coordinated the trial, managed the database, and undertook the primary analysis independent of the sponsors. The authors had complete access to the data and were responsible for writing and submitting the manuscript for publication.

Acknowledgments The authors would like to thank Morgan deBlecourt and Elizabeth Cook for editorial assistance.

Disclosures S. Vemulapalli: research grant; Boston Scientific. Honoraria; Medtronic. A. S. Hellkamp: none. W. S. Jones: none. J. P. Piccini: research grant; ARCA Biopharma, GE Healthcare, Johnson & Johnson, ResMed. Consultant/ Advisory Board; Johnson & Johnson, Forest Laboratories, Spectranetics, Medtronic. K. W. Mahaffey: Consultant/Advisory Board; AstraZeneca, Bayer, Bristol-Myers Squibb, Forest, Johnson & Johnson, WebMD. R. C. Becker: Consultant/Advisory Board; Bayer, Janssen, Daiichi Sankyo, Portola, Regado Biosciences, Boehringer Ingelheim.

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G. J. Hankey: honoraria; Bayer, Medscape (Heart.org). S. D. Berkowitz: employment; Bayer. C. C. Nessel: employment; Janssen Research & Development. G. Breithardt: honoraria; Bayer HealthCare, BMS/Pfizer. Consultant/Advisory Board; Bayer HealthCare, BMS/ Pfizer, Sanofi Aventis. D. E. Singer: research grant; Johnson & Johnson, Bristol-Myers Squibb. Consultant/Advisory Board; Bayer HealthCare, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Johnson & Johnson, Merck, Pfizer. K. A. A. Fox: research grant; Eli Lilly. Consultant/ Advisory Board; Boehringer Ingelheim, Sanofi Aventis, AstraZeneca, Johnson & Johnson/Bayer. M. R. Patel: research grant; Johnson & Johnson, AstraZeneca. Consultant/Advisory Board; Bayer, Janssen, AstraZeneca, Genzyme.

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