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Hypertension and Outcomes Following Myocardial Infarction Effect of Antecedent Hypertension and Follow-Up Blood Pressure on Outcomes After High-Risk Myocardial Infarction Jens J. Thune, James Signorovitch, Lars Kober, Eric J. Velazquez, John J.V. McMurray, Robert M. Califf, Aldo P. Maggioni, Jean L. Rouleau, Jonathan Howlett, Steven Zelenkofske, Marc A. Pfeffer, Scott D. Solomon Downloaded from http://hyper.ahajournals.org/ by guest on May 6, 2017 Abstract—The influence of blood pressure on outcomes after high-risk myocardial infarction is not well characterized. We studied the relationship between blood pressure and the risk of cardiovascular events in 14 703 patients with heart failure, left ventricular systolic dysfunction, or both after acute myocardial infarction in the Valsartan in Myocardial Infarction Trial. We assessed the relationship between antecedent hypertension and outcomes and the association between elevated (systolic: ⬎140 mm Hg) or low blood pressure (systolic: ⬍100 mm Hg) in 2 of 3 follow-up visits during the first 6 months and subsequent cardiovascular events over a median 24.7 months of follow-up. Antecedent hypertension independently increased the risk of heart failure (hazard ratio [HR]: 1.19; 95% CI: 1.08 to 1.32), stroke (HR: 1.27; 95% CI: 1.02 to 1.58), cardiovascular death (HR: 1.11; 95% CI: 1.01 to 1.22), and the composite of death, myocardial infarction, heart failure, stroke, or cardiac arrest (HR: 1.13; 95% CI: 1.06 to 1.21). While low blood pressure in the postmyocardial infarction period was associated with increased risk of adverse events, patients with elevated blood pressure (n⫽1226) were at significantly higher risk of stroke (adjusted HR: 1.64; 95% CI: 1.17 to 2.29) and combined cardiovascular events (adjusted HR: 1.14; 95% CI: 1.00 to 1.31). Six months after a high-risk myocardial infarction, elevated systolic blood pressure, a potentially modifiable risk factor, is associated with an increased risk of subsequent stroke and cardiovascular events. Whether aggressive antihypertensive treatment can reduce this risk remains unknown. (Hypertension. 2008;51:48-54.) Key Words: myocardial infarction 䡲 heart failure, congestive 䡲 hypertension 䡲 hypotension 䡲 mortality H ypertension is an established risk factor for progression of cardiovascular disease,1 and antihypertensive treatment has been associated with reduced risk of myocardial infarction (MI), heart failure (HF), stroke, and cardiovascular death.2,3 While hypertension before MI is associated with greater left ventricular (LV) dilation4,5 and a higher risk of subsequent HF, stroke, and death,6 –12 a drop in blood pressure after MI is common.13,14 Thus, the influence of post-MI blood pressure on cardiovascular outcomes may be complex, particularly in patients with large infarctions. To better understand the relationship between blood pressure and risk in the post-MI patient, we performed a posthoc analysis of data from the VALsartan In Acute myocardial INfarction Trial (VALIANT) to assess the effect of antecedent hypertension and post-MI systolic blood pressure on subsequent adverse cardiovascular outcomes. Methods Patients VALIANT enrolled 14 703 patients with LV dysfunction (LV ejection fraction: ⬍35%), HF, or both who had systolic blood pressure ⬎100 mm Hg between 12 hours and 10 days after an acute MI. Patients were randomly assigned to receive valsartan (160 mg twice daily), captopril (50 mg 3 times a day), or both (80 mg of valsartan twice daily and 50 mg of captopril 3 times a day).15,16 All of the patients gave written informed consent, and the research protocol was approved by the appropriate institutional review boards. Assessment of Hypertension and Follow-Up Blood Pressure Information on antecedent hypertension and other baseline data were assessed at the randomization visit. Patients who reported a diagnosis of hypertension before randomization were considered to have hypertension antecedent to their MI. Blood pressure was recorded at each follow-up visit, with the second visit on discharge or day 14, whichever came first, and subsequent visits scheduled at 1, 3, 6, 9, Received May 11, 2007; first decision June 6, 2007; revision accepted October 23, 2007. From the Brigham and Women’s Hospital (J.J.T., J.S., M.A.P, S.D.S.), Boston, Mass; Rigshospitalet (L.K.), Copenhagen, Denmark; Duke Clinical Research Institute (E.J.V., R.M.C.), Duke University Medical Center, Durham, NC; Western Infirmary (J.J.V.M.), Glasgow, Scotland; ANMCO Research Center (A.P.M.), Florence, Italy; Montreal Heart Institute (J.L.R.), Montreal, Quebec, Canada; Queen Elizabeth II Health Sciences Centre (J.H.), Halifax, Nova Scotia, Canada; and Novartis Pharmaceuticals (S.Z.), East Hanover, NJ. Correspondence to Scott D. Solomon, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail [email protected] © 2007 American Heart Association, Inc. Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.107.093682 48 Thune et al Table 1. Pre-MI and Post-MI Hypertension and Outcomes 49 Baseline Demographics Demographics No Antecedent Hypertension (n⫽6126) Age, mean⫾SD, y* Antecedent Hypertension (n⫽8575) 62.9⫾12.4 Male, n (%)* 66.2⫾11.2 4790 (78.2) 5342 (62.3) White 5802 (94.7) 7944 (92.6) Black 92 (1.5) 315 (3.7) Asian 75 (1.2) 66 (0.8) Other 157 (2.6) 250 (2.9) Systolic* 114 (107, 123) 124 (112, 140) Diastolic* 70 (61, 78) 75 (68, 80) 28.5⫾5.7 Race, n (%)* Baseline BP, median (25th, 75th), mm Hg 2 BMI, mean⫾SD, kg/m * 27.0⫾4.6 eGFR, mean⫾SD, mL/min per 1.73 m2* 74.0⫾20.6 67.5⫾21.4 LVEF, mean⫾SD, % 35.5⫾10.3 35.7⫾10.3 Evidence or history of HF, n (%)* Downloaded from http://hyper.ahajournals.org/ by guest on May 6, 2017 4642 (75.8) 6984 (81.4) I 1912 (33.3) 2051 (26.5) II 2563 (44.6) 3293 (42.5) III 1087 (18.9) 2016 (26.0) IV 184 (3.2) 384 (5.0) Anterio, n (%)* 3642 (61.9) 4750 (57.8) Q-wave type, n (%)* 4233 (71.6) 5209 (63.0) Max CK (U/L), median (25th, 75th)* 1379 (608, 2902) NYHA class, n (%)* Qualifying MI 941 (472, 2012) History, n (%) MI* Unstable angina* Stable angina* 1372 (22.4) 2732 (31.9) 904 (14.8) 2225 (25.9) 1768 (28.9) 4072 (47.5) HF* 527 (8.6) 1646 (19.2) Stroke* 217 (3.5) 678 (7.9) PVD* 384 (6.3) 853 (9.9) Diabetes* 945 (15.4) 2455 (28.6) Atrial fibrillation* 277 (4.5) 682 (8.0) ACE inhibitor* 2173 (35.5) 3643 (42.5) -Blocker* Concomitant medication, n (%) 4292 (70.1) 6057 (70.7) Calcium-channel blocker* 322 (5.3) 939 (11.0) K-sparing diuretic† 500 (8.2) 830 (9.7) 2811 (45.9) 4587 (53.5) Other diuretic* BP indicates blood pressure; LVEF, LV ejection fraction; PVD, peripheral vascular disease; ACE, angiotensin-converting enzyme. *P⬍0.001. †P⬍0.01. and 12 months after randomization and every 4 months thereafter. Because blood pressure was assessed primarily for safety, no recommendations for blood pressure measuring or number of times to measure blood pressures at each visit were provided, although if ⬎1 blood pressure result was measured, investigators were asked to report the lowest. No specific instructions were given to investigators on how to treat blood pressure. Patients who completed ⱖ2 visits after discharge and 1 visit between 4 and 8 months and were free of clinical events were considered for the analyses as 6-month event-free survivors. Patients with a systolic blood pressure ⬎140 mm Hg on 2 of the visits at 1, 3, and 6 months were considered to have an elevated blood pressure. Patients with a systolic blood pressure ⬍100 mm Hg on 2 of the visits at 1, 3, and 6 months were considered to have low blood pressure. The remaining patients were considered to have normal blood pressure. The same cutoffs were used for all of the patients irrespective of comorbidities, such as diabetes or renal impairment. Statistical Analysis All of the major cardiovascular end points, including death, MI, stroke, resuscitated cardiac arrest, and hospitalization for HF, were adjudicated by an independent clinical events committee, and deaths 50 Hypertension January 2008 Table 2. Effect of History of Hypertension on Outcomes Events/1000 Patient Years Outcomes (No. of Events) No History of Hypertension History of Hypertension HR (95% CI) Adjusted HR (95% CI)* All-cause mortality (2878) 77 115 1.47 (1.36 to 1.59) 1.08 (0.99 to 1.18) CV death (2484) 65 100 1.52 (1.40 to 1.62) 1.11 (1.01 to 1.22) Fatal and nonfatal stroke (463) 12 20 1.70 (1.39 to 2.07) 1.27 (1.02 to 1.58) Fatal and nonfatal MI (1740) 53 75 1.36 (1.24 to 1.50) 1.02 (0.91 to 1.14) Sudden death/resuscitated cardiac arrest (1073) 29 43 1.42 (1.26 to 1.62) 1.09 (0.94 to 1.25) 65 118 1.72 (1.58 to 1.88) 1.19 (1.08 to 1.32) 146 235 1.53 (1.44 to 1.66) 1.13 (1.06 to 1.21) HF (2388) CV death, MI, HF, stroke, or sudden death or resuscitated cardiac arrest (4833) CV indicates cardiovascular. *Adjusted for age, sex, BMI, eGFR, previous MI, previous HF, previous stroke, baseline diabetes, peripheral vascular disease, and NYHA class. Downloaded from http://hyper.ahajournals.org/ by guest on May 6, 2017 were classified as cardiovascular or noncardiovascular. Only the first occurrence of each nonfatal event was adjudicated and used for analyses. End points were counted from the time of randomization for analyses of antecedent hypertension (median follow-up: 750 days; range: 0 to 1432 days; total: 29 242 patient years) and from time of the 6-month visit for analyses of post-MI systolic blood pressure (median follow-up: 605 days; range: 0 to 1251 days; total: 17 751 patient years). Baseline variables were compared using the Wilcoxon nonparametric test. The relationships between hypertension before and blood pressure 1 to 6 months after MI and cardiovascular outcomes were assessed by univariate and multivariable (adjusted for age, sex, body mass index [BMI], estimated glomerular filtration rate [eGFR], previous MI, previous HF, previous stroke, baseline diabetes, peripheral vascular disease, randomization arm [intention-to-treat], and New York Heart Association [NYHA] class) proportional hazards regression of time to first event. In addition, analyses of the association between post-MI blood pressure and outcomes were adjusted for antecedent hypertension, and we assessed for statistical interaction. Supportive analyses of the nature of the relationship between the average systolic blood pressure across the 1-, 3-, and 6-month visits as a continuous variable and subsequent outcomes were performed by allowing for increasingly complex relationships (linear, quadratic, cubic, and splined) and reporting the simplest relationship that significantly improved model fit compared with the preceding one, adjusting for baseline covariates. To further test the robustness of our analyses, we performed a Cox analysis with high or low systolic blood pressure as a time-dependent variable censored 30 days before first event. Results Antecedent Hypertension At the time of enrollment, 8575 patients (58.3%) reported antecedent hypertension, and 7609 (88.7%) of these reported receiving medical treatment for hypertension (no information on 2 patients). Patients with antecedent hypertension were older, more often female, had higher blood pressure at baseline, higher BMI, lower eGFR, lower peak creatinine kinase, higher prevalence of previous cardiac disease and risk factors, and were more likely to receive antihypertensive medication (Table 1). Patients with antecedent hypertension had higher average systolic blood pressures across the follow-up visits at 1, 3, and 6 months compared with patients who did not report antecedent hypertension (difference in medians: 9 mm Hg; P⬍0.0001). Antecedent hypertension was associated with a statistically significant increased risk of stroke, HF hospitalization, cardiovascular death, and a combined cardiovascular outcome of cardiovascular death, MI, HF hospitalization, stroke, or sudden death or resuscitated cardiac arrest in multivariable analyses (Table 2). Antecedent hypertension did not affect the risk of developing renal impairment (P⫽0.3) or hyperkaliemia (P⫽0.4). Post-MI Blood Pressure Of the 10 532 patients who had not experienced a cardiovascular event by the 6-month follow-up visit and had adequate follow-up information, 1522 (14.5%) had elevated systolic blood pressure, and 602 (5.7%) had low blood pressure 1 to 6 months post-MI. Patients with elevated systolic blood pressure post-MI were older, more often female, had lower eGFR, lower peak creatinine kinase, and had a higher prevalence of cardiovascular risk factors and previous HF (Table 3). Patients with elevated systolic blood pressure were more likely to receive the target dose of the study drug compared with patients with normal systolic blood pressure. Compared with patients with normal systolic blood pressure, patients with elevated systolic blood pressure were at significantly higher risk of stroke and a combined cardiovascular outcome of cardiovascular death, MI, HF hospitalization, stroke, or sudden death or resuscitated cardiac arrest (Table 4). Adding information about LV ejection fraction to the model (n⫽8220) did not substantially change these results. Elevated systolic blood pressure was most associated with the adverse cardiovascular outcome in patients who received a statin (P for interaction⫽0.0001) and in patients not using long-lasting nitrates (P for interaction⫽0.001). Patients with low systolic blood pressure between 1 and 6 months after MI were at a higher risk of HF, cardiovascular death, all-cause death, and the combined cardiovascular outcome. Patients with low systolic blood pressure were more likely to experience renal impairment (adjusted hazard ratio [HR]: 1.43; 95% CI: 1.01 to 2.04; P⫽0.047). Adding information about LV ejection fraction to the model attenuated the Thune et al Table 3. Pre-MI and Post-MI Hypertension and Outcomes Demographics of 6-Month Event-Free Survivors Demographics Age, mean⫾SD, y Male, n (%) Low BP (n⫽602) Normal BP (n⫽8408) 59.6⫾12.5* 63.6⫾11.7 487 (80.8)* 6178 (73.5) Elevated BP (n⫽1522) 68.8⫾9.9* 827 (54.3)* Race, n (%)‡ White 558 (92.7) 7912 (94.1) 1431 (94.0) Black 10 (1.7) 181 (2.2) 56 (3.7) Asian 13 (2.2) 89 (1.1) 4 (0.3) Other 21 (3.5) 226 (2.7) 31 (2.0) BP at randomization, median (25th, 75th) Systolic 110 (104, 118)* 120 (110, 130) 135 (120, 150)* Diastolic 70 (60, 73)* 70 (65, 80) 80 (70, 82)* Systolic 95 (92, 99)* 121 (113, 130) 151 (146, 160)* Diastolic 62 (59, 67)* 73 (68, 80) Average BP at 1 to 6 mo, median (25th, 75th) Antecedent hypertension at baseline, n (%) 179 (29.7)* 4568 (54.3) 84 (78, 90)* 1229 (80.7)* Downloaded from http://hyper.ahajournals.org/ by guest on May 6, 2017 BMI, mean⫾SD, kg/m2 26.8⫾4.1* 27.9⫾5.0 eGFR, mean⫾SD, mL/min/1.73 m2 75.3⫾20.7† 73.1⫾20.6 65.4⫾20.8* LVEF, mean⫾SD, % 34.5⫾10.2† 36.3⫾10.2 37.7⫾11.0† Evidence or history of HF, n (%) 434 (72.1)† 6368 (75.7) 28.6⫾5.3* 1272 (83.6)* NYHA class at 6 mo, n (%)‡ I 332 (56.2) 4295 (51.6) 674 (44.8) II 205 (34.7) 3326 (40.0) 652 (43.4) III 51 (8.6) 662 (8.0) 171 (11.4) IV 3 (0.5) 36 (0.4) 6 (0.4) Qualifying MI Anterior, n (%) 411 (70.9)* 4854 (59.8) 786 (53.7)* Q-wave, n (%) 456 (78.4)* 5710 (70.1) 845 (57.4)* 1191 (561, 2538) 748 (414, 1468)* Max CK, median (25th, 75th) 1878 (756, 3754)* History, n (%) MI 142 (23.6) 2073 (24.7) 382 (25.1) Unstable angina 100 (16.6) 1691 (20.1) 323 (21.2) Stable angina 690 (45.3)* 164 (27.2)* 3090 (36.8) Previous HF 48 (8.0)* 967 (11.5) 234 (15.4)† Stroke 23 (3.8) 403 (4.8) 104 (6.8)† PVD 39 (6.5) 601 (7.1) 128 (8.4) Diabetes 74 (12.3)* 1666 (19.8) 419 (27.5)* Atrial fibrillation 30 (5.0) 419 (5.0) 109 (7.2)† 413 (68.6)† 6185 (73.6) 1117 (73.4) Medications at 6 mo, n (%)  -Blocker Calcium-channel blocker 28 (4.7)† 745 (8.9) 357 (23.5)* K-sparing diuretic 64 (10.6) 745 (8.9) 159 (10.4) Other diuretic 197 (32.7)† 3163 (37.6) 743 (48.8)* Statin 355 (59.0)† 4396 (52.3) 690 (45.3)* Drug titration level at 6 mo, n (%)‡ 30 (5.3) 312 (3.9) 76 (5.4) 1 to 3 0 (no study drug) 419 (74.0) 2903 (36.3) 174 (12.4) 4 (target dose) 117 (20.7) 4777 (59.8) 1155 (82.2) BP indicates blood pressure; LVEF, LV ejection fraction; PVD, peripheral vascular disease. *P⬍0.001 vs normal. †P⬍0.01 vs normal. ‡P⬍0.001 for difference between categorical variables. 51 52 Table 4. Hypertension January 2008 Risk Associated With Blood Pressure Status 6 Months Post-MI Events/1000 Patient Years, Follow-Up BP Low BP Compared With Normal High BP Compared With Normal Outcome (No. of Events) Low (n⫽602) Normal (n⫽8408) High (n⫽1522) HR (95% CI) Adjusted HR (95% CI)* HR (95% CI) Adjusted HR (95% CI)* All-cause mortality (936) 63 51 68 1.23 (0.95 to 1.58) 1.46 (1.11 to 1.91) 1.33 (1.13 to 1.57) 1.04 (0.87 to 1.24) CV death (720) 48 39 52 1.24 (0.93 to 1.66) 1.48 (1.09 to 2.01) 1.33 (1.10 to 1.61) 1.02 (0.83 to 1.24) Fatal and nonfatal stroke (198) 6 10 22 0.60 (0.26 to 1.35) 0.81 (0.35 to 1.85) 2.19 (1.60 to 2.99) 1.64 (1.17 to 2.29) Fatal and nonfatal MI (509) 23 29 41 0.80 (0.52 to 1.21) 1.05 (0.69 to 1.61) 1.40 (1.13 to 1.75) 1.13 (0.89 to 1.43) Sudden death/resuscitated cardiac arrest (364) 24 20 27 1.24 (0.82 to 1.87) 1.38 (0.90 to 2.13) 1.39 (1.06 to 1.80) 1.17 (0.88 to 1.54) Downloaded from http://hyper.ahajournals.org/ by guest on May 6, 2017 HF (704) 42 39 61 1.06 (0.77 to 1.45) 1.49 (1.07 to 2.09) 1.53 (1.27 to 1.84) 1.07 (0.88 to 1.30) CV death, MI, HF, stroke, or sudden death/resuscitated cardiac arrest (1591) 92 91 137 1.03 (0.83 to 1.27) 1.32 (1.06 to 1.66) 1.50 (1.33 to 1.70) 1.14 (1.00 to 1.31) BP indicates blood pressure; CV, cardiovascular; HF, hospitalization for heart failure. *Adjusted for age, sex, BMI, eGFR, previous MI, previous HF, previous stroke, baseline diabetes, peripheral vascular disease, history of hypertension, and NYHA class at 6 months. relationship between low systolic blood pressure and the risk of hospitalization for HF (adjusted HR: 1.35; 95% CI: 0.92 to 1.96; P⫽0.12) and combined cardiovascular events (adjusted HR: 1.26; 95% CI: 0.98 to 1.61; P⫽0.07). There was no interaction between antecedent hypertension and the effect of elevated or low systolic blood pressure at 6 months (for all end points P⬎0.2). Assessing the relationship between the average systolic blood pressure across the 1-, 3-, and 6-month visits as a continuous variable and the risk of subsequent cardiovascular events demonstrated a linear relationship between increasing systolic blood pressure and stroke (P for linear term⫽0.003) and a quadratic relationship between systolic blood pressure and the risk of all-cause death (P for quadratic term⫽0.0003; nadir: 135 mm Hg), cardiovascular death (P⫽0.002; nadir: 135 mm Hg), sudden death or resuscitated cardiac arrest (P⫽0.02; nadir: 127 mm Hg), and combined cardiovascular events (P⫽0.004; nadir: 131 mm Hg; Figure). The average systolic blood pressure across the 1-, 3-, and 6-month visits was not associated with the risk of recurrent MI (P for linear, quadratic, cubic, or splined, all ⬎0.2), whereas the relationship with the risk of hospitalization for HF was complex (P for cubic fit⫽0.002). A time-dependent Cox analysis also demonstrated that both post-MI systolic blood pressure ⬎140 mm Hg (adjusted HR: 1.11; 95% CI: 1.01 to 1.21; P⫽0.03) and systolic blood pressure ⬍100 mm Hg (adjusted HR: 1.38; 95% CI: 1.21 to 1.59; P⬍0.0001) were significantly associated with the combined outcome. Classification of patients based on diastolic blood pressure demonstrated trends similar to those seen for systolic blood pressure, but the relationships were not significant because of the lower number of patients with consistent diastolic blood pressure ⬍60 mm Hg (n⫽301) or ⬎90 mm Hg (n⫽302). Discussion We observed that antecedent hypertension at the time of MI is strongly associated with adverse cardiovascular outcomes in patients with LV dysfunction, HF, or both receiving contemporary therapy, including inhibitors of the renin-an- Figure. Adjusted HR as a function of average blood pressure across the 1-, 3-, and 6-month visits relative to hazard at 130 mm Hg. The red lines are 95% CI. For each end point, the simplest model not significantly improved by a more complex model is shown. Thune et al Downloaded from http://hyper.ahajournals.org/ by guest on May 6, 2017 giotensin system. Moreover, in this well-treated cohort, in which nearly all of the patients, by design, received an renin-angiotensin system inhibitor, 68% received a -blocker, and 84% received ⱖ1 antihypertensive drug in addition to study drug; ⬇15% of post-MI patients who survived to 6 months had elevated systolic blood pressure on 2 of 3 visits, and these patients were at increased risk for subsequent stroke and combined cardiovascular events compared with patients with normal blood pressure. The effect of hypertension on the risk of adverse CV events has been well documented in patients without MI,17 and our results confirm previous findings that antecedent hypertension increases the risk of HF, stroke, and death after MI.6 – 8,18 –21 Other studies have also examined the relationship between post-MI blood pressure and outcomes. A U-shaped relationship between diastolic blood pressure and death from coronary heart disease was observed in patients with a previous MI from the Framingham Heart Study cohort,22 whereas a linear increase in the risk of reinfarction and coronary heart disease death was seen with increasing systolic blood pressure.23 However, an analysis of the Coronary Drug Project found no relation between diastolic or systolic blood pressure after MI and adverse cardiovascular outcomes when adjusting for other clinical variables.24 Low diastolic or systolic blood pressure was associated with adverse outcome early after MI in the Multiple Risk Factor Intervention Trial, whereas high blood pressure was worse for long-term outcome.11 In 2677 community-based post-MI patients, the risk of stroke was increased with higher diastolic and systolic blood pressure after MI, whereas reinfarction and all-cause death were associated with low diastolic blood pressure only.25 Finally, the International Verapamil-Trandolapril Study, in which a third of the patients had a previous MI, and ⬇5% had HF, noted a quadratic relationship between blood pressure and the rate of death, MI, or stroke.26 Although decreased blood pressure after MI may be associated with reduced LV function, and our data demonstrate higher morbidity and mortality in patients with low blood pressure after MI, we and others have found that elevated blood pressure in medium- and long-term survivors of MI re-emerges as a potent risk factor for new cardiovascular events. Although a number of mechanisms may underlie the increased risk associated with post-MI hypertension, we have shown previously that patients with a previous history of hypertension are at the greatest risk for adverse LV remodeling post-MI, which itself is associated with an increased likelihood of adverse outcomes.4 Similarly, LV hypertrophy, a consequence of hypertension, is itself an independent predictor of both adverse remodeling and clinical outcomes post-MI.5,9 Unfortunately, few data on patients with high-risk MI are available from the large, randomized, placebocontrolled hypertension trials, which either specifically excluded patients with HF or included too few patients with a previous MI to perform adequate subgroup analyses.27–30 Thus, whether aggressive blood pressure treatment in the post-MI population would reduce the risk of stroke or other cardiovascular events remains unknown. Our finding that elevated blood pressure at follow-up was associated with adverse cardiovascular outcome in high-risk, Pre-MI and Post-MI Hypertension and Outcomes 53 post-MI patients contrasts with large studies of patients with acute or stable HF. In these studies, increasing blood pressure has generally been associated with improved prognosis, even for patients with blood pressure in the normal and high range.31–35 This finding may be explained in part by the fact that 44% of the patients in VALIANT were in NYHA class 1 at the 6-month follow-up visit, and only 11% were in class 3 or 4. Thus, whereas cardiac function may be the main determinant of outcome in the HF population, in post-MI patients without overt HF, elevated blood pressure may be more common and may reflect an increased risk of ischemic events. Some important limitations of this analysis should be noted. Patients who survived to the 6-month follow-up visit were not representative of the baseline cohort, and these differences may reflect significant survivor bias, potentially limiting the generalizability of our findings to early post-MI patients. We cannot exclude the possibility that some patients not considered hypertensive at 6 months might have lower blood pressure secondary to worsening LV function. The interpretation of the effect of diastolic blood pressure on outcomes is complicated by the potential for increased pulse pressure because of increased conduit vessel stiffness. Finally, because VALIANT was not a hypertension trial, there was no strict definition of antecedent hypertension, and blood pressure was measured during the trial in an ambulatory setting with no strict protocol. Nevertheless, this limitation likely attenuated the true relationship between post-MI hypertension and outcome. Perspectives Both low and elevated systolic blood pressure after a highrisk MI are associated with an increased risk for adverse cardiovascular events. Elevated systolic blood pressure, a potentially modifiable risk factor, is associated with a profound increase in the risk of stroke. Whether more aggressive treatment of elevated blood pressure in patients with a previous MI can reduce adverse outcomes remains unknown. Source of Funding VALIANT was sponsored by Novartis Pharmaceuticals. Disclosures E.J.V., J.J.V.M., R.M.C., J.H., M.A.P., and S.D.S. report having received research funding from Novartis Pharmaceuticals. E.J.V., J.L.R., J.H., M.A.P., and S.D.S. report having served as consultants for or having received honorariums from Novartis Pharmaceuticals. References 1. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ, and the National High Blood Pressure Education Program Coordinating Committee. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42:1206 –1252. 2. Ogden LG, He J, Lydick E, Whelton PK. Long-term absolute benefit of lowering blood pressure in hypertensive patients according to the JNC VI risk stratification. Hypertension. 2000;35:539 –543. 3. Gueyffier F, Boutitie F, Boissel JP, Pocock S, Coope J, Cutler J, Ekbom T, Fagard R, Friedman L, Perry M, Prineas R, Schron E. Effect of antihypertensive drug treatment on cardiovascular outcomes in women and men. A meta-analysis of individual patient data from randomized, controlled trials. Ann Intern Med. 1997;126:761–767. 54 Hypertension January 2008 Downloaded from http://hyper.ahajournals.org/ by guest on May 6, 2017 4. Kenchaiah S, Pfeffer MA, St John Sutton M, Plappert T, Rouleau JL, Lamas GA, Sasson Z, Parker JO, Geltman EM, Solomon SD. Effect of antecedent systemic hypertension on subsequent left ventricular dilation after acute myocardial infarction (from the Survival and Ventricular Enlargement trial). Am J Cardiol. 2004;94:1– 8. 5. Jilaihawi H, Greaves S, Rouleau JL, Pfeffer MA, Solomon SD. Healing and Early Afterload Reducing Therapy Trial Investigators. Left ventricular hypertrophy and the risk of subsequent left ventricular remodeling following myocardial infarction. Am J Cardiol. 2003;91:723–726. 6. Lewis EF, Moye LA, Rouleau JL, Sacks FM, Arnold JM, Warnica JW, Flaker GC, Braunwald E, Pfeffer MA. Predictors of late development of heart failure in stable survivors of myocardial infarction: the CARE study. J Am Coll Cardiol. 2003;42:1446 –1453. 7. Richards AM, Nicholls MG, Troughton RW, Lainchbury JG, Elliott J, Frampton C, Espiner EA, Crozier IG, Yandle TG, Turner J. Antecedent hypertension and heart failure after myocardial infarction. J Am Coll Cardiol. 2002;39:1182–1188. 8. Witt BJ, Ballman KV, Brown RD Jr, Meverden RA, Jacobsen SJ, Roger VL. The incidence of stroke after myocardial infarction: a meta-analysis. Am J Med. 2006;119:354.e1–354.e9. 9. Kesari S, Janardhanan R, Pfeffer MA, Skali H, Anavekar NS, McMurray JJV, Velazquez EJ, Kober L, Arnold JMO, Warnica JW, Ghali JK, Solomon SD. Baseline left ventricular wall thickness after myocardial infarction predicts death or heart failure: findings from the Valsartan in Acute Myocardial Infarction Trial (VALIANT). Circulation. 2005;112: II-526 (abstract). 10. Kenchaiah S, Davis BR, Braunwald E, Rouleau JL, Dagenais GR, Sussex B, Steingart RM, Brown EJ Jr, Lamas GA, Gordon D, Bernstein V, Pfeffer MA. Antecedent hypertension and the effect of captopril on the risk of adverse cardiovascular outcomes after acute myocardial infarction with left ventricular systolic dysfunction: insights from the Survival and Ventricular Enlargement Trial. Am Heart J. 2004;148:356 –364. 11. Flack JM, Neaton J, Grimm R Jr, Shih J, Cutler J, Ensrud K, MacMahon S. Blood pressure and mortality among men with prior myocardial infarction. Circulation. 1995;92:2437–2445. 12. Fresco C, Avanzini F, Bosi S, Franzosi MG, Maggioni AP, Santoro L, Bellanti G. Prognostic value of a history of hypertension in 11,483 patients with acute myocardial infarction treated with thrombolysis. GISSI-2 Investigators. Gruppo Italiano per lo Studio della, Sopravvivena nell’Infarto Miocardico. J Hypertens. 1996;14:743–750. 13. Kannel WB, Sorlie P, Castelli WP, McGee D. Blood pressure and survival after myocardial infarction: the Framingham Study. Am J Cardiol. 1980;45:326 –330. 14. Fletcher PJ, Pfeffer JM, Pfeffer MA, Braunwald E. Effects of hypertension on cardiac performance in rats with myocardial infarction. Am J Cardiol. 1982;50:488 – 496. 15. Pfeffer MA, McMurray JJ, Velazquez EJ, Rouleau JL, Kober L, Maggioni AP, Solomon SD, Swedberg K, Van de Werf F, White H, Leimberger JD, Henis M, Edwards S, Zelenkofske S, Sellers MA, Califf RM. the Valsartan in Acute Myocardial Infarction Trial Investigators. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003; 349:1893–1906. 16. Pfeffer MA, McMurray J, Leizorovicz A, Maggioni AP, Rouleau JL, Van de Werf F, Henis M, Neuhart E, Gallo P, Edwards S, Sellers MA, Velazquez E, Califf R. Valsartan in Acute Myocardial Infarction Trial (VALIANT): rationale and design. Am Heart J. 2000;140:727–750. 17. MacMahon S, Peto R, Cutler J, Collins R, Sorlie P, Neaton J, Abbott R, Godwin J, Dyer A, Stamler J. Blood pressure, stroke, and coronary heart disease. Part 1, Prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet. 1990;335:765–774. 18. Gustafsson F, Kober L, Torp-Pedersen C, Hildebrandt P, Ottesen MM, Sonne B, Carlsen J. Long-term prognosis after acute myocardial 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. infarction in patients with a history of arterial hypertension. TRACE study group. Eur Heart J. 1998;19:588 –594. Staessen JA, Gasowski J, Wang JG, Thijs L, Den Hond E, Boissel JP, Coope J, Ekbom T, Gueyffier F, Liu L, Kerlikowske K, Pocock S, Fagard RH. Risks of untreated and treated isolated systolic hypertension in the elderly: meta-analysis of outcome trials. Lancet. 2000;355:865– 872. Lloyd-Jones DM, Larson MG, Leip EP, Beiser A, D’Agostino RB, Kannel WB, Murabito JM, Vasan RS, Benjamin EJ, Levy D. Lifetime risk for developing congestive heart failure: the Framingham Heart Study. Circulation. 2002;106:3068 –3072. Society of Actuaries. Build and Blood Pressure Study. Chicago, IL: Society of Actuaries; 1959. D’Agostino RB, Belanger AJ, Kannel WB, Cruickshank JM. Relation of low diastolic blood pressure to coronary heart disease death in presence of myocardial infarction: the Framingham Study. BMJ. 1991;303: 385–389. Wong ND, Cupples LA, Ostfeld AM, Levy D, Kannel WB. Risk factors for long-term coronary prognosis after initial myocardial infarction: the Framingham Study. Am J Epidemiol. 1989;130:469 – 480. Schlant RC, Forman S, Stamler J, Canner PL. The natural history of coronary heart disease: prognostic factors after recovery from myocardial infarction in 2789 men. The 5-year findings of the coronary drug project. Circulation. 1982;66:401– 414. Kaplan RC, Heckbert SR, Furberg CD, Psaty BM. Predictors of subsequent coronary events, stroke, and death among survivors of first hospitalized myocardial infarction. J Clin Epidemiol. 2002;55:654 – 664. Messerli FH, Mancia G, Conti CR, Hewkin AC, Kupfer S, Champion A, Kolloch R, Benetos A, Pepine CJ. Dogma disputed: can aggressively lowering blood pressure in hypertensive patients with coronary artery disease be dangerous? Ann Intern Med. 2006;144:884 – 893. Dahlof B, Lindholm LH, Hansson L, Schersten B, Ekbom T, Wester PO. Morbidity and mortality in the Swedish Trial in Old Patients With Hypertension (STOP-Hypertension). Lancet. 1991;338:1281–1285. Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhager WH, Bulpitt CJ, de Leeuw PW, Dollery CT, Fletcher AE, Forette F, Leonetti G, Nachev C, O’Brien ET, Rosenfeld J, Rodicio JL, Tuomilehto J, Zanchetti A. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet. 1997; 350:757–764. Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, Menard J, Rahn KH, Wedel H, Westerling S. Effects of intensive bloodpressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet. 1998;351:1755–1762. Wang JG, Staessen JA, Gong L, Liu L. Chinese trial on isolated systolic hypertension in the elderly. Systolic Hypertension in China (Syst-China) Collaborative Group. Arch Intern Med. 2000;160:211–220. Ghali JK, Kadakia S, Bhatt A, Cooper R, Liao Y. Survival of heart failure patients with preserved versus impaired systolic function: the prognostic implication of blood pressure. Am Heart J. 1992;123:993–997. Lee TT, Chen J, Cohen DJ, Tsao L. The association between blood pressure and mortality in patients with heart failure. Am Heart J. 2006; 151:76 – 83. Lee DS, Austin PC, Rouleau JL, Liu PP, Naimark D, Tu JV. Predicting mortality among patients hospitalized for heart failure: derivation and validation of a clinical model. JAMA. 2003;290:2581–2587. Levy WC, Mozaffarian DM, Linker DT, Sutradhar SC, Anker SD, Cropp AB, Anand I, Maggioni A, Burton P, Sullivan MD, Pitt B, Poole-Wilson PA, Mann DL, Packer M. The Seattle Heart Failure Model: prediction of survival in heart failure. Circulation. 2006;113:1424 –1433. Pocock SJ, Wang D, Pfeffer MA, Yusuf S, McMurray JJ, Swedberg KB, Ostergren J, Michelson EL, Pieper KS, Granger CB. Predictors of mortality and morbidity in patients with chronic heart failure. Eur Heart J. 2006;27:65–75. Effect of Antecedent Hypertension and Follow-Up Blood Pressure on Outcomes After High-Risk Myocardial Infarction Jens J. Thune, James Signorovitch, Lars Kober, Eric J. Velazquez, John J.V. McMurray, Robert M. Califf, Aldo P. Maggioni, Jean L. Rouleau, Jonathan Howlett, Steven Zelenkofske, Marc A. Pfeffer and Scott D. 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