European Heart Journal Advance Access published online on February 8, 2007
European Heart Journal, doi:10.1093/eurheartj/ehl504
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Effect of hypertension on anticoagulated patients with atrial fibrillation
1 Haemostasis Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham B18 7QH, UK
2 AstraZeneca R&D Mölndal, SE-431 83 Mölndal, Sweden
Received 25 May 2006; revised 11 December 2006; accepted 12 January 2007.
* Corresponding author. Tel: +44 121 507 5080; fax: +44 121 554 4083. E-mail address: g.y.h.lip{at}bham.ac.uk
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Abstract |
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AIMS: To test the hypothesis that stroke and systemic embolic events (SEE) in the Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation (SPORTIF) III and V trials were related to blood pressure, and that differences in event rates (stroke and SEE, bleeding) could also be related to the degree of hypertension.
METHODS AND RESULTS: A cross-sectional, longitudinal analysis was conducted, using data from the SPORTIF III and V trials. Results showed an increasing rate of stroke and SEE with increasing quartiles of systolic blood pressure (SBP) in AF patients. For the top quartile of SBP compared with the lowest quartile, the hazard ratio (HR) for stroke and SEE was 1.83 (95% confidence intervals [CI]: 1.22–2.74), whereas mortality was lower in the top quartile (HR 0.64; 95% CI: 0.49–0.83). In the combined SPORTIF III and V cohort, the event rate for stroke/SEE increased markedly at mean SBP of >140 mmHg. There was no relationship between bleeding and quartiles of BP. The proportion of subjects with mean systolic BP 
140 mmHg was 35.8% (1220/3407) in SPORTIF III and 20.6% (807/3922) in SPORTIF V (P < 0.0001).
CONCLUSION: Hypertension contributes to increased stroke and SEE in AF. Event rates markedly increase at SBP levels of 140 mmHg. The higher stroke rates observed in SPORTIF III compared with SPORTIF V may be related to the greater proportion of subjects with SBP 140 mmHg during the trial.
Key Words: Hypertension • Atrial fibrillation • Stroke • Ximelagatran • Warfarin
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Introduction |
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Atrial fibrillation (AF) is the most common cardiac arrhythmia and is strongly associated with a substantial risk of stroke and thromboembolism. AF often coexists with advanced age and such cardiovascular conditions as hypertension, heart failure, coronary artery disease (CAD), and diabetes mellitus. Among subjects with AF-associated stroke in a community survey, hypertension was the most common comorbid condition.1 Hypertension is also the most frequently associated comorbidity among hospitalized patients with AF.2
Hypertension is an independent risk factor for stroke, with a direct correlation between increasing blood pressure (BP) and stroke risk that extends even into the normotensive range.3 Hypertension raises the risk of stroke in patients with AF, and the stroke risk in patients with both AF and hypertension is substantially higher than in those with either condition alone.4 In the aspirin arm of the Stroke Prevention in Atrial Fibrillation (SPAF)-III trial, even subjects with a history of hypertension (but who did not meet the stated ‘high risk’ criterion of SBP > 150 mmHg) had an increased risk of stroke in AF.5 Among patients with AF, hypertension is associated with adjusted annual thromboembolism rates of 4.0 and 2.4% per year in women and men, respectively.6 Furthermore, uncontrolled hypertension is an important risk factor for bleeding in anticoagulated subjects.7
Ximelagatran is the first oral direct thrombin inhibitor that was recently tested for stroke thromboprophylaxis in two large Phase III clinical trials, the Stroke Prevention using an ORal Thrombin Inhibitor in AF (SPORTIF) III and V trials.8,9 These trials found ximelagatran as effective as well-controlled warfarin in reducing the risk of stroke in moderate-to-high risk patients with AF, and rates of major bleeding on ximelagatran were slightly less than on warfarin. The most common risk factor in both trials was a history of hypertension (requiring anti-hypertensive treatment, but <180/100 mmHg at study randomization), which was present in 
70% of participants. Rates of the primary endpoint (stroke and systemic embolic events [SEE]) were 1.6%/year on ximelagatran in both trials, but the event rates on warfarin differed: 2.3%/year in SPORTIF III and 1.2%/year in SPORTIF V.8,9 In both trials, elevations of serum alanine aminotransferase (ALAT) beyond three times the upper limit of normal (ULN) were seen in 6% of patients treated with ximelagatran.
On 14 February 2006, ximelagatran was withdrawn due to concerns about liver safety but recent interest into the value of hypertension control in AF merits an analysis of the large, combined SPORTIF trial dataset to ascertain the impact of hypertension and BP control in a large, anticoagulated AF population at moderate-to-high risk of stroke and vascular events. We therefore hypothesized that the rate of stroke and SEE during anticoagulation can be related to the degree of hypertension, and that differences in various event rates between the SPORTIF III and V trials (stroke and SEE, bleeding) could also be related to hypertension.
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Patients and methods |
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The design and final results of the SPORTIF III and V clinical trials have been published.8,9 In brief, both trials were designed as non-inferiority Phase III trials comparing ximelagatran with warfarin in subjects with non-valvular AF at moderate-to-high risk of thromboembolism, with a pooled analysis of the results of both trials pre-specified. SPORTIF V was a double-blind trial conducted in North America, while SPORTIF III was performed open label in 23 countries outside of North America. Inclusion criteria for both trials were similar and included age
18 years, persistent or paroxysmal AF, and at least one of the following risk factors for stroke: hypertension (defined as high BP requiring anti-hypertensive treatment, but which was below 180/100 mmHg on randomization); age 75 years; previous stroke; transient ischaemic attack (TIA) or SEE; left ventricular (LV) dysfunction (ejection fraction <40% or symptomatic heart failure); age 65 years and CAD; and age 65 years and diabetes mellitus. Endpoints were evaluated in a blinded manner by a Central Events Adjudication Committee. To assess the relationship between hypertension and clinical outcomes of interest, patients were categorized into quartiles, according to mean systolic BP (SBP), during the entire follow-up period. For SPORTIF III, the median follow-up was 17.9 months per patient (range 0–26 months); for SPORTIF V, the median follow-up was 20.1 months (range 0–31 months); and for the pooled analysis, the median follow-up was 18.6 months per patient (range 0–31 months). BP was measured at baseline, 1, 3, and 6 months and every 6 months thereafter, and the mean BP for each patient was based, on average, on 6.5 measurements (SD 1.5). Illustration of efficacy results as a function of BP data is complicated by the continuous nature of the BP variable. Rather than categorizing BP data according to typically used intervals, we opted to illustrate unprejudiced relationships through reporting efficacy results vs. a continuously ‘moving average’ of BP data.
The duration of exposure differed between patients according to the time of enrolment, since the study closure period was the same for all patients. Analyses of clinical outcomes were made for all stroke (ischaemic and haemorrhagic) and SEE (the primary endpoint), major bleeding, all-cause mortality, and ALAT elevations (>3 x ULN).
Statistical analysis
Categorical data were evaluated with Fisher's exact test or the 
2 test for more than two categories and continuous data using Student's t-test. All tests were performed as two-sided, adopting a 5% significance level. No adjustments for multiple testing has been done, all results reported are explorative in nature. Annualized event rates formed the basis for analyses, assuming constant event rates over time. Patients were categorized into quartiles according to their overall mean SBP-levels. Comparisons between quartiles have been conducted assuming that neither study drug nor length of follow-up influenced SBP levels, thus making it appropriate to use each patient's mean SBP level during the study as an explanatory variable. Unless otherwise stated, all analyses were performed following pooling of the two studies. With one exception, the analyses were conducted without allowing for a study factor—this was deliberate, since there were systematic differences in SBP-control in the two studies, resulting from more aggressive anti-hypertensive treatment in the study centres based in North America (SPORTIF V). Thus, the ‘study centre’ factor is intrinsically confounded with SBP-control.
All randomized patients were included in the intention-to-treat (ITT) population. An on-treatment (OT) analysis accounted for time until the therapy was interrupted for up to 30 consecutive days (or up to 60 days for cardioversion) or 60 days cumulatively. Analyses confined to stroke, SEE, and death were analysed according to ITT. Assessment of major bleeding used the OT approach. No censoring was made of any ALAT elevations. Hazard ratios (HR) between treatments were obtained through Cox regression modelling. Moving averages of event rates over time are given as a function of BP, together with smoothing splines to illustrate unprejudiced relationships. All analyses were performed in SAS (Version 8.2; SAS Institute, Inc., Cary, NC, USA). More detailed descriptions of the statistical analyses used in the SPORTIF III and V trials have been published previously.8,9
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Results |
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The mean BP and patient characteristics at study entry are summarized in Tables 1 and 2. The patients in the higher BP quartile were more likely to have more stroke risk factors (P = 0.012 for
2 vs. >2 risk factors) as well as higher mean body mass index (BMI) (P = 0.0036).
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Pre-specified stroke risk factors and mean SBP for patients in SPORTIF III, V, and the pooled analysis, stratified according to high vs. low BP values, are summarized in Table 3. The prevalence of prior stroke or TIA was higher in groups with higher SBP (P = 0.02). As expected, those with high BP were older, but the prevalence of LV dysfunction (LV ejection fraction <40% or clinical heart failure) was lower (both P < 0.0001) in patients with hypertension. In the pooled cohort, fewer subjects with known CAD had high BP (P < 0.0001). Anti-hypertensive medication at entry by quartiles of mean SBP is shown in Table 4. Neither study drug nor length of follow-up significantly influenced SBP levels (Table 5).
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For patients categorized by mean SBP, diastolic blood pressure (DBP), and pulse pressure, selected outcome variables are summarized in Tables 6–11.
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The increasing stroke rate with increasing quartiles of SBP (Figure 1) is less apparent for DBP. The highest mortality rate occurred in patients in the lowest quartiles of SBP and DBP. When compared by quartiles of SBP, the HR between the SPORTIF III and V trials was not significantly different from unity (Table 8). The top quartile of SBP was associated with a greater risk of stroke and SEE than the lowest quartile (HR 1.83; 95% CI: 1.22–2.74), whereas mortality was lower in the top quartile (HR 0.64; CI: 0.49–0.83). There was a similar relationship between stroke/SEE and pulse pressure, and a trend for major bleeding (Table 9). The increased mortality in the lower quartile for SBP was not seen for pulse pressure.
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We assessed whether LV dysfunction was a confounder in explaining the mortality pattern in relation to SBP control. The increased mortality rate in the lowest SBP quartile was largely driven by a larger proportion of patients with heart failure who had a higher mortality rate (see Supplementary material online, Figure S1). Addition of CAD into the analysis did not alter this observation (data not shown). Among the patients with neither of the baseline risk factors (i.e. LV dysfunction/CAD/Stroke/TIA/age
75 years, <20% of the total cohort) mortality rate was about equally low in all SBP quartiles: 1.62, 1.30, 1.53, and 1.55%/year, respectively. There was an increased event rate for haemorrhagic stroke with increasing quartiles of BP (P-value for Q1 + 2 vs. Q3 + 4 is 0.013). The total number of such events being 1 (0.04%/year), 2 (0.07%/year), 5 (0.17%/year), and 9 (0.32%/year) in the four SBP-quartiles, respectively, with similar trends for both study drugs. There was no relationship between major bleeding, major plus minor bleeding or ALAT elevations to quartiles of BP (Tables 10 and 11). Relationships between SBP-control and bleeding rates were fairly similar between the warfarin and ximelagatran (data not shown).
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Figure 2 shows the cumulative stroke/SEE rate in SPORTIF III and V combined, with patients categorized by quartiles of mean SBP over the course of the studies.
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Smoothed curves around moving average rates of stroke/SEE, major bleed, and mortality, in SPORTIF III and V combined, pooled over study drugs, according to mean SBP are provided in Supplementary material online, Figure S2.
The greatest cumulative event rates occurred in association with the highest quartile of SBP, while the Kaplan–Meier curves for Q1 and Q2 are almost identical and the curve for Q3 shows a slight increase in the cumulative event rate after 12 months. The increasing event rate with increasing quartiles of BP was similar in the warfarin and ximelagatran treatment groups in the whole cohort (see Supplementary material online, Table S1) and in the individual studies (Table 11). HRs are given for comparison between the two studies for each quartile (Table 11). Differences in rates of stroke/SEE between SPORTIF III and V for each quartile of BP did not reach statistical significance. Sensitivity analyses show that the relationships seen between SBP quartiles and the outcomes analysed remained largely unaffected when allowing for relevant risk factors (e.g. age, gender, and previous stroke/TIA) (see Supplementary material online, Table S2).
A ‘moving average’ for rates of stroke/SEE in the pooled cohort for both study drugs, according to mean SBP and DBP, is shown in Figure 3A and B, respectively.
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The data suggest that the rate of primary events rate increases markedly at mean SBP 140 mmHg. The corresponding relationship was not apparent for DBP. The proportion of subjects with mean SBP
140 mmHg was 35.8% (1220/3407) in SPORTIF III and 20.6% (807/3922) in SPORTIF V (P < 0.0001). Major bleeding rates in the four SBP quartiles were 2.43, 2.02, 2.05, and 2.23%/year, respectively. Corresponding rates by pulse pressure quartiles were 1.95, 1.78, 2.29, and 2.72%/year. |
Discussion |
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This is the most extensive analysis of the cumulative effects of BP on stroke and SEE in patients with AF currently available, involving serial measurements in anticoagulated patients over more than 11 000 patient-years (PY). The data clearly show that rates of stroke and SEE increase substantially at mean SBP levels of
140 mmHg, and the event rates were highest in participants with the highest average SBP readings. The higher proportion of subjects with average SBP 140 mmHg in the SPORTIF III trial may account for the higher event rates than in SPORTIF V, where hypertension was better controlled. The data further suggest that event rates markedly increase at SBP levels over 140 mmHg, and that control of hypertension to lower SBP is associated with a uniformly lower thromboembolic risk. Although hypertension raises the risk of stroke in patients with AF, this analysis suggests controlled hypertension (mean SBP <140 mmHg) is associated with a low stroke risk compared with patients with poorly controlled hypertension, in which the risk markedly increases with higher BP. The present analysis also supports SBP as being a more powerful determinant of stroke risk as compared with DBP among the AF patients. Hypertension is an important risk factor in most stratification schemes used to identify patients with AF who require anticoagulation10 and maintains predictive power for the development of ischaemic events, even in patients with AF receiving anticoagulant therapy.11
Hypertension is also a risk factor for bleeding complications of anticoagulation, including intracranial haemorrhage (OR 2.69; 95% CI: 1.04–6.97).7,12,13 Bleeding can also be related to the duration and intensity of anticoagulant therapy.13 We were not able to confirm a relationship between quartiles of SBP and rates of major or major plus minor bleeding in the SPORTIF cohorts, but this may be a reflection of the optimization of risk factor management and close monitoring associated with a clinical trial setting. Clinical practice usually advocates that patients with hypertension require especially close monitoring of anticoagulation and optimum control of BP13 during chronic anticoagulant therapy.
Of interest is our observation that mortality was highest in the lowest quartile of BP. There has been a long-standing debate on the existence of a J-curve in relation to the relationship between BP and mortality,14 especially among the elderly. The present post hoc analysis of the SPORTIF trials adds to this debate, but only among an AF population. Further observations on the existence of a J-curve in larger, non-trial AF populations would be needed to address this issue.
A major limitation of this study was its reliance upon post hoc analysis of the SPORTIF III and V clinical trial dataset. The ‘selection phenomenon’ for trial inclusion may partly account for the unusual distribution of risk factors; for example, hypertension is a risk factor for LV dysfunction, heart failure, and CAD, but patients with hypertension had a lower prevalence of LV dysfunction. Patients were also not randomized on the basis of severity of antecedent hypertension or quality of BP control during the trials, and hypertension management was left to the discretion of the patients' personal physicians. Apart from the differences in BP control between SPORTIF III and V, there were also geographical differences within the SPORTIF III trial cohort, with patients in some countries achieving better BP control than others. The relatively small numbers of patients in these subsets, however, preclude meaningful analyses in relation to outcomes. The SPORTIF V study was conducted exclusively in North America, where secondary prevention strategies (including control of hypertension) were more systematically applied than in the array of countries involved in the SPORTIF III study, and other therapies (e.g. lipid-lowering medications) were more often given concurrently. Hence, relationships between SBP-control and events may intrinsically be confounded with other differential effects between the two studies. These correlations between study and SBP-control caused us to exclude study (that is, SPORTIF III or V) as a factor in most analyses.
In conclusion, hypertension contributes to increased rates of stroke and SEE in AF. Event rates markedly increased at SBP levels of 140 mmHg, and control of hypertension to lower levels was associated with uniformly lower rates of stroke and SEE. The higher stroke rates in SPORTIF III may have been related to the greater proportion of subjects with inadequate BP control.
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Supplementary material |
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Supplementary material is available at European Heart Journal online.
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Acknowledgements |
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The SPORTIF III and V investigators are listed in references Olsson8 and SPORTIF Executive Committee for the SPORTIF V Investigators,9 respectively.
Conflict of interest: G.Y.H.L. has received funding for research, educational symposia, consultancy, and lecturing from different manufacturers of drugs used for the treatment of hypertension, AF, and thrombosis, including AstraZeneca, who manufacture ximelagatran. L.F. and M.G. are employees of AstraZeneca.
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References |
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- Tsang TS, Petty GW, Barnes ME, O'Fallon WM, Bailey KR, Wiebers DO, Sicks JD, Christianson TJ, Seward JB, Gersh BJ. (2003) The prevalence of atrial fibrillation in incident stroke cases and matched population controls in Rochester, Minnesota: changes over three decades. J Am Coll Cardiol 42:93–100.
[Abstract/Free Full Text] - Wattigney WA, Mensah GA, Croft JB. (2003) Increasing trends in hospitalisation for atrial fibrillation in the United States, 1985 through 1999: implications for primary prevention. Circulation 108:711–716.
- Wang JG, Staessen JA, Franklin SS, Fagard R, Gueyffier F. (2005) Systolic and diastolic blood pressure lowering as determinants of cardiovascular outcome. Hypertension 45:907–913.
[Abstract/Free Full Text] - Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. (2001) Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 285:2864–2870.
[Abstract/Free Full Text] - Zabalgoitia M, Halperin JL, Pearce LA, Blackshear JL, Asinger RW, Hart RG. (1998) Transesophageal echocardiographic correlates of clinical risk of thromboembolism in nonvalvular atrial fibrillation. Stroke Prevention in Atrial Fibrillation III Investigators. J Am Coll Cardiol 31:1622–1626.
[Abstract/Free Full Text] - Fang MC, Singer DE, Chang Y, Hylek EM, Henault LE, Jensvold NG, Go AS. (2005) Gender differences in the risk of ischaemic stroke and peripheral embolism in atrial fibrillation: the AnTicoagulation and Risk factors In Atrial fibrillation (ATRIA) study. Circulation 112:1687–1691.
- Hart RG, Tonarelli SB, Pearce LA. (2005) Avoiding central nervous system bleeding during antithrombotic therapy: recent data and ideas. Stroke 36:1588–1593.
[Abstract/Free Full Text] - Olsson SB. Executive Steering Committee on behalf of the SPORTIF III Investigators. (2003) Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet 362:1691–1698.[CrossRef][Web of Science][Medline]
- SPORTIF Executive Committee for the SPORTIF V Investigators. (2005) Ximelagatran versus warfarin for stroke prevention in patients with nonvalvular atrial fibrillation. JAMA 293:690–698.
[Abstract/Free Full Text] - Lip GY and Boos C. (2006) Antithrombotic therapy for atrial fibrillation. Heart 92:155–156.
[Abstract/Free Full Text] - Poli D, Antonucci E, Cecchi E, Marcucci R, Liotta AA, Cellai AP, Lenti M, Gensini GF, Abbate R, Prisco D. (2005) Culprit factors for the failure of well-conducted warfarin therapy to prevent ischaemic events in patients with atrial fibrillation: the role of homocysteine. Stroke 36:2159–2163.
[Abstract/Free Full Text] - Huber J, Stollberger C, Finsterer J, Schneider B, Langer T. (2003) Quality of blood pressure control and risk of cerebral bleeding in patients with oral anticoagulation. Acta Med Austriaca 30:6–9.[CrossRef][Web of Science][Medline]
- Berwaerts J and Webster J. (2000) Analysis of risk factors involved in oral-anticoagulant-related intracranial haemorrhages. QJM 93:513–521.
[Abstract/Free Full Text] - Boutitie F, Gueyffier F, Pocock S, Fagard R, Boissel JP. INDANA Project Steering Committee. (2002) INdividual Data ANalysis of Antihypertensive intervention. J-shaped relationship between blood pressure and mortality in hypertensive patients: new insights from a meta-analysis of individual-patient data. Ann Intern Med 136:438–448.
[Abstract/Free Full Text] - Cockcroft DW and Gault MH. (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16:31–41.[Web of Science][Medline]
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