Lara M. Simpson

Reduction of Stroke Incidence After Myocardial Infarction With Pravastatin The Cholesterol and Recurrent Events (CARE) Study

BACKGROUND The role of lipid modification in stroke prevention is controversial, although increasing evidence suggests that HMG-CoA reductase inhibition may reduce cerebrovascular events in patients with prevalent coronary artery disease. METHODS AND RESULTS To test the hypothesis that cholesterol reduction with pravastatin may reduce stroke incidence after myocardial infarction, we followed 4159 subjects with average total and LDL serum cholesterol levels (mean, 209 and 139 mg/dL, respectively) who had sustained an infarction an average of 10 months before study entry and who were randomized to pravastatin 40 mg/d or placebo in the Cholesterol and Recurrent Events (CARE) trial. Using prospectively defined criteria, we assessed the incidence of stroke, a prespecified secondary end point, and transient ischemic attack (TIA) over a median 5-year follow-up period. Patients were well matched for stroke risk factors and the use of antiplatelet agents (85% of subjects in each group). Compared with placebo, pravastatin lowered total serum cholesterol by 20%, LDL cholesterol by 32%, and triglycerides by 14% and raised HDL cholesterol by 5% over the course of the trial. A total of 128 strokes (52 on pravastatin, 76 on placebo) and 216 strokes or TIAs (92 on pravastatin, 124 on placebo) were observed, representing a 32% reduction (95% CI, 4% to 52%, P=0.03) in all-cause stroke and 27% reduction in stroke or TIA (95% CI, 4% to 44%, P=0.02). All categories of strokes were reduced, and treatment effect was similar when adjusted for age, sex, history of hypertension, cigarette smoking, diabetes, left ventricular ejection fraction, and baseline total, HDL, and LDL cholesterol and triglyceride levels. There was no increase in hemorrhagic stroke in patients on pravastatin compared with placebo (2 versus 6, respectively). CONCLUSIONS Pravastatin significantly reduced stroke and stroke or TIA incidence after myocardial infarction in patients with average serum cholesterol levels despite the high concurrent use of antiplatelet therapy.

Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure: the FOCUS-CCTRN trial.

CONTEXT Previous studies using autologous bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy have demonstrated safety and suggested efficacy. OBJECTIVE To determine if administration of BMCs through transendocardial injections improves myocardial perfusion, reduces left ventricular end-systolic volume (LVESV), or enhances maximal oxygen consumption in patients with coronary artery disease or LV dysfunction, and limiting heart failure or angina. DESIGN, SETTING, AND PATIENTS A phase 2 randomized double-blind, placebo-controlled trial of symptomatic patients (New York Heart Association classification II-III or Canadian Cardiovascular Society classification II-IV) with a left ventricular ejection fraction of 45% or less, a perfusion defect by single-photon emission tomography (SPECT), and coronary artery disease not amenable to revascularization who were receiving maximal medical therapy at 5 National Heart, Lung, and Blood Institute-sponsored Cardiovascular Cell Therapy Research Network (CCTRN) sites between April 29, 2009, and April 18, 2011. INTERVENTION Bone marrow aspiration (isolation of BMCs using a standardized automated system performed locally) and transendocardial injection of 100 million BMCs or placebo (ratio of 2 for BMC group to 1 for placebo group). MAIN OUTCOME MEASURES Co-primary end points assessed at 6 months: changes in LVESV assessed by echocardiography, maximal oxygen consumption, and reversibility on SPECT. Phenotypic and functional analyses of the cell product were performed by the CCTRN biorepository core laboratory. RESULTS Of 153 patients who provided consent, a total of 92 (82 men; average age: 63 years) were randomized (n = 61 in BMC group and n = 31 in placebo group). Changes in LVESV index (-0.9 mL/m(2) [95% CI, -6.1 to 4.3]; P = .73), maximal oxygen consumption (1.0 [95% CI, -0.42 to 2.34]; P = .17), and reversible defect (-1.2 [95% CI, -12.50 to 10.12]; P = .84) were not statistically significant. There were no differences found in any of the secondary outcomes, including percent myocardial defect, total defect size, fixed defect size, regional wall motion, and clinical improvement. CONCLUSION Among patients with chronic ischemic heart failure, transendocardial injection of autologous BMCs compared with placebo did not improve LVESV, maximal oxygen consumption, or reversibility on SPECT. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00824005.

Effect of Intracoronary Delivery of Autologous Bone Marrow Mononuclear Cells 2 to 3 Weeks Following Acute Myocardial Infarction on Left Ventricular Function The LateTIME Randomized Trial

CONTEXT Clinical trial results suggest that intracoronary delivery of autologous bone marrow mononuclear cells (BMCs) may improve left ventricular (LV) function when administered within the first week following myocardial infarction (MI). However, because a substantial number of patients may not present for early cell delivery, the efficacy of autologous BMC delivery 2 to 3 weeks post-MI warrants investigation. OBJECTIVE To determine if intracoronary delivery of autologous BMCs improves global and regional LV function when delivered 2 to 3 weeks following first MI. DESIGN, SETTING, AND PATIENTS A randomized, double-blind, placebo-controlled trial (LateTIME) of the National Heart, Lung, and Blood Institute-sponsored Cardiovascular Cell Therapy Research Network of 87 patients with significant LV dysfunction (LV ejection fraction [LVEF] ≤45%) following successful primary percutaneous coronary intervention (PCI) between July 8, 2008, and February 28, 2011. INTERVENTIONS Intracoronary infusion of 150 × 10(6) autologous BMCs (total nucleated cells) or placebo (BMC:placebo, 2:1) was performed within 12 hours of bone marrow aspiration after local automated cell processing. MAIN OUTCOME MEASURES Changes in global (LVEF) and regional (wall motion) LV function in the infarct and border zone between baseline and 6 months, measured by cardiac magnetic resonance imaging. Secondary end points included changes in LV volumes and infarct size. RESULTS A total of 87 patients were randomized (mean [SD] age, 57 [11] years; 83% men). Harvesting, processing, and intracoronary delivery of BMCs in this setting was feasible. Change between baseline and 6 months in the BMC group vs placebo for mean LVEF (48.7% to 49.2% vs 45.3% to 48.8%; between-group mean difference, -3.00; 95% CI, -7.05 to 0.95), wall motion in the infarct zone (6.2 to 6.5 mm vs 4.9 to 5.9 mm; between-group mean difference, -0.70; 95% CI, -2.78 to 1.34), and wall motion in the border zone (16.0 to 16.6 mm vs 16.1 to 19.3 mm; between-group mean difference, -2.60; 95% CI, -6.03 to 0.77) were not statistically significant. No significant change in LV volumes and infarct volumes was observed; both groups decreased by a similar amount at 6 months vs baseline. CONCLUSION Among patients with MI and LV dysfunction following reperfusion with PCI, intracoronary infusion of autologous BMCs vs intracoronary placebo infusion, 2 to 3 weeks after PCI, did not improve global or regional function at 6 months. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00684060.

Heart Failure With Preserved and Reduced Left Ventricular Ejection Fraction in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial

Background— Heart failure (HF) developing in hypertensive patients may occur with preserved or reduced left ventricular ejection fraction (PEF [≥50%] or REF [<50%]). In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), 42 418 high-risk hypertensive patients were randomized to chlorthalidone, amlodipine, lisinopril, or doxazosin, providing an opportunity to compare these treatments with regard to occurrence of hospitalized HFPEF or HFREF. Methods and Results— HF diagnostic criteria were prespecified in the ALLHAT protocol. EF estimated by contrast ventriculography, echocardiography, or radionuclide study was available in 910 of 1367 patients (66.6%) with hospitalized events meeting ALLHAT criteria. Cox regression models adjusted for baseline characteristics were used to examine treatment differences for HF (overall and by PEF and REF). HF case fatality rates were examined. Of those with EF data, 44.4% had HFPEF and 55.6% had HFREF. Chlorthalidone reduced the risk of HFPEF compared with amlodipine, lisinopril, or doxazosin; the hazard ratios were 0.69 (95% confidence interval [CI], 0.53 to 0.91; P=0.009), 0.74 (95% CI, 0.56 to 0.97; P=0.032), and 0.53 (95% CI, 0.38 to 0.73; P<0.001), respectively. Chlorthalidone reduced the risk of HFREF compared with amlodipine or doxazosin; the hazard ratios were 0.74 (95% CI, 0.59 to 0.94; P=0.013) and 0.61 (95% CI, 0.47 to 0.79; P<0.001), respectively. Chlorthalidone was similar to lisinopril with regard to incidence of HFREF (hazard ratio, 1.07; 95% CI, 0.82 to 1.40; P=0.596). After HF onset, death occurred in 29.2% of participants (chlorthalidone/amlodipine/lisinopril) with new-onset HFPEF versus 41.9% in those with HFREF (P<0.001; median follow-up, 1.74 years); and in the chlorthalidone/doxazosin comparison that was terminated early, 20.0% of HFPEF and 26.0% of HFREF patients died (P=0.185; median follow-up, 1.55 years). Conclusions— In ALLHAT, with adjudicated outcomes, chlorthalidone significantly reduced the occurrence of new-onset hospitalized HFPEF and HFREF compared with amlodipine and doxazosin. Chlorthalidone also reduced the incidence of new-onset HFPEF compared with lisinopril. Among high-risk hypertensive men and women, HFPEF has a better prognosis than HFREF.

Clinical Events in High-Risk Hypertensive Patients Randomly Assigned to Calcium Channel Blocker Versus Angiotensin-Converting Enzyme Inhibitor in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial

The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) provides a unique opportunity to compare the long-term relative safety and efficacy of angiotensin-converting enzyme inhibitor and calcium channel blocker–initiated therapy in older hypertensive individuals. Patients were randomized to amlodipine (n=9048) or lisinopril (n=9054). The primary outcome was combined fatal coronary heart disease or nonfatal myocardial infarction, analyzed by intention-to-treat. Secondary outcomes included all-cause mortality, stroke, combined cardiovascular disease (CVD), end-stage renal disease (ESRD), cancer, and gastrointestinal bleeding. Mean follow-up was 4.9 years. Blood pressure control was similar in nonblacks, but not in blacks. No significant differences were found between treatment groups for the primary outcome, all-cause mortality, ESRD, or cancer. Stroke rates were higher on lisinopril in blacks (RR=1.51, 95% CI 1.22 to 1.86) but not in nonblacks (RR=1.07, 95% CI 0.89 to 1.28), and in women (RR=1.45, 95% CI 1.17 to 1.79), but not in men (RR=1.10, 95% CI 0.92 to 1.31). Rates of combined CVD were higher (RR=1.06, 95% CI 1.00 to 1.12) because of higher rates for strokes, peripheral arterial disease, and angina, which were partly offset by lower rates for heart failure (RR=0.87, 95% CI 0.78 to 0.96) on lisinopril compared with amlodipine. Gastrointestinal bleeds and angioedema were higher on lisinopril. Patients with and without baseline coronary heart disease showed similar outcome patterns. We conclude that in hypertensive patients, the risks for coronary events are similar, but for stroke, combined CVD, gastrointestinal bleeding, and angioedema are higher and for heart failure are lower for lisinopril-based compared with amlodipine-based therapy. Some, but not all, of these differences may be explained by less effective blood pressure control in the lisinopril arm.

Glycated Hemoglobin Measurement and Prediction of Cardiovascular Disease

IMPORTANCE The value of measuring levels of glycated hemoglobin (HbA1c) for the prediction of first cardiovascular events is uncertain. OBJECTIVE To determine whether adding information on HbA1c values to conventional cardiovascular risk factors is associated with improvement in prediction of cardiovascular disease (CVD) risk. DESIGN, SETTING, AND PARTICIPANTS Analysis of individual-participant data available from 73 prospective studies involving 294,998 participants without a known history of diabetes mellitus or CVD at the baseline assessment. MAIN OUTCOMES AND MEASURES Measures of risk discrimination for CVD outcomes (eg, C-index) and reclassification (eg, net reclassification improvement) of participants across predicted 10-year risk categories of low (<5%), intermediate (5% to <7.5%), and high (≥ 7.5%) risk. RESULTS During a median follow-up of 9.9 (interquartile range, 7.6-13.2) years, 20,840 incident fatal and nonfatal CVD outcomes (13,237 coronary heart disease and 7603 stroke outcomes) were recorded. In analyses adjusted for several conventional cardiovascular risk factors, there was an approximately J-shaped association between HbA1c values and CVD risk. The association between HbA1c values and CVD risk changed only slightly after adjustment for total cholesterol and triglyceride concentrations or estimated glomerular filtration rate, but this association attenuated somewhat after adjustment for concentrations of high-density lipoprotein cholesterol and C-reactive protein. The C-index for a CVD risk prediction model containing conventional cardiovascular risk factors alone was 0.7434 (95% CI, 0.7350 to 0.7517). The addition of information on HbA1c was associated with a C-index change of 0.0018 (0.0003 to 0.0033) and a net reclassification improvement of 0.42 (-0.63 to 1.48) for the categories of predicted 10-year CVD risk. The improvement provided by HbA1c assessment in prediction of CVD risk was equal to or better than estimated improvements for measurement of fasting, random, or postload plasma glucose levels. CONCLUSIONS AND RELEVANCE In a study of individuals without known CVD or diabetes, additional assessment of HbA1c values in the context of CVD risk assessment provided little incremental benefit for prediction of CVD risk.

Visit-to-Visit Variability of Blood Pressure and Coronary Heart Disease, Stroke, Heart Failure, and Mortality: A Cohort Study

Context It is not clear whether variability in a patients outpatient blood pressure (BP) measurements has prognostic importance. Contribution Patients with greater visit-to-visit variability in BP readings had an increased risk for cardiovascular events and mortality, which was independent of their overall degree of BP control. Implication Further studies are warranted to assess whether reducing visit-to-visit BP variations will alter the risk for adverse cardiovascular outcomes. The prognostic value of blood pressure (BP) is mainly based on measurements obtained in a clinical setting, typically from a few visits (1). Until recently, variability of BP across outpatient visits was dismissed as random fluctuation around a patients true underlying BP (2, 3). Although some studies have reported associations between higher visit-to-visit variability (VVV) of systolic BP (SBP) and an increased risk for stroke and coronary heart disease (CHD), other analyses have failed to show such associations (410). The method applied in estimating VVV of BP varied widely across previous studies. In addition, studies have used as few as 3 visits and as many as 56 visits to estimate the VVV of BP, and the time between visits has ranged from 2 days to as long as 4 years (5, 11, 12). These factors not only influence VVV of BP but could also affect the strength of its association with cardiovascular disease (CVD) outcomes (4, 13). To address the inconsistent findings from previous studies, we did a secondary data analysis of ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) to examine whether VVV of BP is associated with CVD and mortality events. ALLHAT provides the opportunity to evaluate the association between VVV of BP and major clinical outcomes in a large and diverse population with hypertension in which visits were conducted at set time intervals, BP was measured by following a standardized protocol, and outcomes were evaluated over several years of follow-up. Methods Study Design We did a cohort study as a secondary analysis using data from ALLHAT. Figure 1 shows the timeline for assessment of VVV of BP and outcome events within ALLHAT. The primary exposure of interest, VVV of SBP, was ascertained at the 7 study visits conducted between 6 and 28 months after randomization. We studied 4 outcomes: fatal CHD or nonfatal myocardial infarction (MI), all-cause mortality, stroke, and heart failure. Participants were followed from their 28-month visit until the occurrence of an outcome event or the end of active ALLHAT follow-up (October 2001 to March 2002). Participants who had an event before their 28-month visit were excluded from all analyses. Figure 1. Study design evaluating the association between VVV of BP and cardiovascular outcomes and all-cause mortality in ALLHAT. ALLHAT = Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; BP = blood pressure; DBP = diastolic blood pressure; SBP = systolic blood pressure; VVV = visit-to-visit variability. * Participants were followed for a mean of 2.7 to 2.9 y (maximum, 5.7 y) depending on the outcome after assessment of VVV of BP. ALLHAT was a multicenter, double-blind, randomized clinical trial sponsored by the National Heart, Lung, and Blood Institute of the National Institutes of Health. A complete description of the rationale and design of ALLHAT has been previously published (14). In brief, ALLHAT was designed to determine whether treatment initiated with a calcium-channel blocker (amlodipine), angiotensin-converting enzyme inhibitor (lisinopril), or -blocker (doxazosin)each compared with treatment initiated with a diuretic (chlorthalidone)would lower major cardiovascular outcomes. The primary end point was incidence of fatal CHD or nonfatal MI. A total of 42418 hypertensive adults aged 55 years or older with 1 or more additional risk factor for CVD were enrolled at 623 clinical sites across the United States, Canada, Puerto Rico, and the U.S. Virgin Islands between February 1994 and January 1998. The doxazosin treatment group was discontinued in 2000 because of the small chance of finding a benefit on CHD outcomes and an increased risk for CVD than in the chlorthalidone group (15). The main results comparing participants randomly assigned to chlorthalidone, amlodipine, or lisinopril were published in December 2002 (16). The trial was approved by local institutional review boards, and all participants provided written informed consent. Our current analysis was approved by the Institutional Review Board at the University of Alabama at Birmingham. Study Visits, BP Measurements, and Calculation of VVV of BP To calculate intraindividual VVV of SBP and diastolic BP (DBP), we used data from 7 follow-up visits that occurred 6, 9, 12, 16, 20, 24, and 28 months after randomization. We chose to begin the assessment period at the 6-month follow-up visit to avoid confounding by the initial reduction in BP that occurred between randomization and this visit (SBP, 6 to 10 mm Hg; DBP, approximately 5 mm Hg) due to early medication titration. To increase the precision of estimates, we calculated VVV of BP for participants with BP measurements at 5, 6, or 7 visits conducted between month 6 and 28 after randomization. The VVV of BP was imputed for participants who attended fewer than 5 visits between months 6 and 28. To maximize follow-up time, we did not extend the assessment past the 28-month follow-up visit. At each follow-up visit, BP was measured twice by a trained observer by means of a standardized technique (17). Using the average BP at each visit, we defined VVV of BP by the intraindividual SD across visits. Average real variability (ARV) and SD independent of the mean (SDIM) were calculated as alternative metrics for VVV of BP (Appendix Figure) (18). The VVV of DBP was also calculated in secondary analyses. Appendix Figure. Formulas used to calculate VVV of BP metrics. ARV = average real variability; BP = blood pressure; SDIM = SD independent of the mean; VVV = visit-to-visit variability. Outcome Ascertainment We studied 4 outcomes, including fatal CHD or nonfatal MI, all-cause mortality, stroke, and heart failure. The event ascertainment process is detailed elsewhere (14, 16). Participants were followed from the end of the assessment period to the date of each outcome, their date of death, or the end of active ALLHAT follow-up (1 October 2001 through 31 March 2002). Covariate Information Covariates used for adjustment were selected a priori on the basis of their potential role as confounders. Baseline (before randomization) variables included age, sex, race/ethnicity, education, current cigarette smoking status, body mass index, use of aspirin, high-density lipoprotein cholesterol level less than 0.91 mmol/L (<35 mg/dL) (at 2 occasions in the 5 years before ALLHAT enrollment), total cholesterol level, estimated glomerular filtration rate (eGFR), diabetes, history of MI or stroke, documentation of other atherosclerotic CVD, history of revascularization, atrial fibrillation by electrocardiography, left ventricular hypertrophy (LVH), the presence of ST depression and T-wave inversion, and use of antihypertensive medication before ALLHAT randomization. The eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation (19). Data collected at visits conducted 6 to 28 months after randomization were used to calculate mean SBP and DBP; pulse pressure; the use of antihypertensive medications beyond the randomization drug; changes in antihypertensive medication regimen (adding, stopping, or changing antihypertensive medications); use of statins; and low adherence, which is defined as a report of a participant receiving less than 80% of the randomization drug at any visit between months 6 and 28. Participants who reported taking 80% or more of their randomization drug at every visit between months 6 and 28 were considered to have high adherence. Statistical Analysis Because of limited follow-up available after the assessment period for participants randomly assigned to receive doxazosin, we restricted our analyses to the 33357 ALLHAT participants randomly assigned to receive chlorthalidone, amlodipine, or lisinopril. We excluded 7543 participants who had CVD events or died before the 28-month visit. We imputed VVV of BP for participants with fewer than 5 visits and BP measurements between months 6 and 28 of follow-up. In addition, missing data for covariates were imputed (Appendix Table 1). Imputation was performed with 10 data sets using chained equations. Appendix Table 1. Percentage of Missing Data for Participants Included in the Current Analyses Characteristics of participants included in the current analyses were calculated after participants were stratified into a quintile of SD of SBP. The KaplanMeier method was used to calculate the cumulative incidence of each outcome by quintile of SD of SBP. Cox proportional hazards regression was used to calculate multivariable-adjusted hazard ratios (HRs) for each outcome associated with a quintile of SD of SBP, with the lowest quintile serving as the reference. Four nested models were constructed. Model 1 included adjustment for age, race/ethnicity, sex, region of residence, and antihypertensive randomization assignment. Model 2 includes the variables in model 1 and additional adjustment for education, smoking status, body mass index, use of aspirin, low high-density lipoprotein cholesterol level, total cholesterol level, eGFR, diabetes, history of MI or stroke, history of other atherosclerotic CVD, history of coronary revascularization, atrial fibrillation by electrocardiography, major ST depression or T-wave inversion, LVH, use of antihypertensive medications before ALLHAT randomization, and statin use during the assessment period (months 6 through 28 of follow-up). Model 3 includes the variables in model 2 and additional adjustment for mean pulse pressure, medic

The effect of statin therapy on heart failure events: a collaborative meta-analysis of unpublished data from major randomized trials

Aims The effect of statins on risk of heart failure (HF) hospitalization and HF death remains uncertain. We aimed to establish whether statins reduce major HF events. Methods and results We searched Medline, EMBASE, and the Cochrane Central Register of Controlled Trials for randomized controlled endpoint statin trials from 1994 to 2014. Collaborating trialists provided unpublished data from adverse event reports. We included primary- and secondary-prevention statin trials with >1000 participants followed for >1 year. Outcomes consisted of first non-fatal HF hospitalization, HF death and a composite of first non-fatal HF hospitalization or HF death. HF events occurring <30 days after within-trial myocardial infarction (MI) were excluded. We calculated risk ratios (RR) with fixed-effects meta-analyses. In up to 17 trials with 132 538 participants conducted over 4.3 [weighted standard deviation (SD) 1.4] years, statin therapy reduced LDL-cholesterol by 0.97 mmol/L (weighted SD 0.38 mmol/L). Statins reduced the numbers of patients experiencing non-fatal HF hospitalization (1344/66 238 vs. 1498/66 330; RR 0.90, 95% confidence interval, CI 0.84–0.97) and the composite HF outcome (1234/57 734 vs. 1344/57 836; RR 0.92, 95% CI 0.85–0.99) but not HF death (213/57 734 vs. 220/57 836; RR 0.97, 95% CI 0.80–1.17). The effect of statins on first non-fatal HF hospitalization was similar whether this was preceded by MI (RR 0.87, 95% CI 0.68–1.11) or not (RR 0.91, 95% CI 0.84–0.98). Conclusion In primary- and secondary-prevention trials, statins modestly reduced the risks of non-fatal HF hospitalization and a composite of non-fatal HF hospitalization and HF death with no demonstrable difference in risk reduction between those who suffered an MI or not.

Long-Term Follow-Up of Participants With Heart Failure in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

Background— In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized, double-blind, practice-based, active-control, comparative effectiveness trial in high-risk hypertensive participants, risk of new-onset heart failure (HF) was higher in the amlodipine (2.5–10 mg/d) and lisinopril (10–40 mg/d) arms compared with the chlorthalidone (12.5–25 mg/d) arm. Similar to other studies, mortality rates following new-onset HF were very high (≥50% at 5 years), and were similar across randomized treatment arms. After the randomized phase of the trial ended in 2002, outcomes were determined from administrative databases. Methods and Results— With the use of national databases, posttrial follow-up mortality through 2006 was obtained on participants who developed new-onset HF during the randomized (in-trial) phase of ALLHAT. Mean follow-up for the entire period was 8.9 years. Of 1761 participants with incident HF in-trial, 1348 died. Post-HF all-cause mortality was similar across treatment groups, with adjusted hazard ratios (95% confidence intervals) of 0.95 (0.81–1.12) and 1.05 (0.89–1.25), respectively, for amlodipine and lisinopril compared with chlorthalidone, and 10-year adjusted rates of 86%, 87%, and 83%, respectively. All-cause mortality rates were also similar among those with reduced ejection fractions (84%) and preserved ejection fractions (81%), with no significant differences by randomized treatment arm. Conclusions— Once HF develops, risk of death is high and consistent across randomized treatment groups. Measures to prevent the development of HF, especially blood pressure control, must be a priority if mortality associated with the development of HF is to be addressed. Clinical Trial Registration— http://www.clinicaltrials.gov. Unique identifier: NCT00000542.

Effect of Chlorthalidone, Amlodipine, and Lisinopril on Visit-to-Visit Variability of Blood Pressure: Results From the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial

Few randomized trials have compared visit‐to‐visit variability (VVV) of systolic blood pressure (SBP) across drug classes. The authors compared VVV of SBP among 24,004 participants randomized to chlorthalidone, amlodipine, or lisinopril in the Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). VVV of SBP was calculated across 5 to 7 visits occurring 6 to 28 months following randomization. The standard deviation (SD) of SBP was 10.6 (SD=5.0), 10.5 (SD=4.9), and 12.2 (SD=5.8) for participants randomized to chlorthalidone, amlodipine, and lisinopril, respectively. After multivariable adjustment including mean SBP across visits and compared with participants randomized to chlorthalidone, participants randomized to amlodipine had a 0.36 (standard error [SE]: 0.07) lower SD of SBP and participants randomized to lisinopril had a 0.77 (SE=0.08) higher SD of SBP. Results were consistent using other VVV of SBP metrics. These data suggest chlorthalidone and amlodipine are associated with lower VVV of SBP than lisinopril.