Antihypertensive And Lipid-Lowering Treatment To Prevent Heart Attack Trial Research Articles

Mortality and Morbidity Among Individuals With Hypertension Receiving a Diuretic, ACE Inhibitor, or Calcium Channel Blocker

The long-term relative risk of antihypertensive treatments with regard to mortality and morbidity is not well understood. To determine the long-term posttrial risk of primary and secondary outcomes among trial participants who were randomized to either a thiazide-type diuretic, calcium channel blocker (CCB), or angiotensin-converting enzyme (ACE) inhibitor with up to 23 years of follow-up. This prespecified secondary analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a multicenter randomized, double-blind, active-controlled clinical trial, followed up with participants aged 55 years or older with a diagnosis of hypertension and at least 1 other coronary heart disease risk factor for up to 23 years, from February 23, 1994, to December 31, 2017. Trial participants were linked with administrative databases for posttrial mortality (N = 32 804) and morbidity outcomes (n = 22 754). Statistical analysis was performed from January 2022 to October 2023. Participants were randomly assigned to receive a thiazide-type diuretic (n = 15 002), a CCB (n = 8898), or an ACE inhibitor (n = 8904) for planned in-trial follow-up of approximately 4 to 8 years and posttrial passive follow-up for up to 23 years. The primary end point was mortality due to cardiovascular disease (CVD). Secondary outcomes included all-cause mortality, combined fatal and nonfatal (morbidity) CVD, and both mortality and morbidity for coronary heart disease, stroke, heart failure, end-stage renal disease, and cancer. A total of 32 804 participants (mean [SD] age, 66.9 [7.7] years; 17 411 men [53.1%]; and 11 772 Black participants [35.9%]) were followed up for all-cause mortality and a subgroup of 22 754 participants (mean [SD] age, 68.7 [7.2] years; 12 772 women [56.1%]; and 8199 Black participants [36.0%]) were followed up for fatal or nonfatal CVD through 2017 (mean [SD] follow-up, 13.7 [6.7] years; maximum follow-up, 23.9 years). Cardiovascular disease mortality rates per 100 persons were 23.7, 21.6, and 23.8 in the diuretic, CCB, and ACE inhibitor groups, respectively, at 23 years after randomization (adjusted hazard ratio [AHR], 0.97 [95% CI, 0.89-1.05] for CCB vs diuretic; AHR, 1.06 [95% CI, 0.97-1.15] for ACE inhibitor vs diuretic). The long-term risks of most secondary outcomes were similar among the 3 groups. Compared with the diuretic group, the ACE inhibitor group had a 19% increased risk of stroke mortality (AHR, 1.19 [95% CI, 1.03-1.37]) and an 11% increased risk of combined fatal and nonfatal hospitalized stroke (AHR, 1.11 [95% CI, 1.03-1.20]). In this secondary analysis of a randomized clinical trial in an adult population with hypertension and coronary heart disease risk factors, CVD mortality was similar between all 3 groups. ACE inhibitors increased the risk of stroke outcomes by 11% compared with diuretics, and this effect persisted well beyond the trial period. ClinicalTrials.gov Identifier: NCT00000542.

The 18-year risk of cancer, angioedema, insomnia, depression, and erectile dysfunction in association with antihypertensive drugs: post-trial analyses from ALLHAT-Medicare linked data.

This study aimed to determine the 18-year risk of cancer, angioedema, insomnia, depression, and erectile dysfunction in association with antihypertensive drug use. This is a post-trial passive follow-up study of Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) participants between 1994 and 1998 that was conducted by linking their follow-up data with Medicare claims data until 2017 of subjects who were free of outcomes at baseline on 1 January 1999. The main outcomes were the occurrence of cancer (among n = 17,332), angioedema (among n = 17,340), insomnia (among n = 17,340), depression (among n = 17,330), and erectile dysfunction (among n = 7,444 men) over 18 years of follow-up. The 18-year cumulative incidence rate of cancer other than non-melanoma skin cancer from Medicare inpatient claims was 23.9% for chlorthalidone, 23.4% for amlodipine, and 25.3% for lisinopril. There were no statistically significant differences in the 18-year risk of cancer, depression, and erectile dysfunction among the three drugs based on the adjusted hazard ratios. The adjusted 18-year risk of angioedema was elevated in those receiving lisinopril than in those receiving amlodipine (hazard ratio: 1.63, 95% CI: 1.14-2.33) or in those receiving chlorthalidone (1.33, 1.00-1.79), whereas the adjusted 18-year risk of insomnia was statistically significantly decreased in those receiving lisinopril than in those receiving amlodipine (0.90, 0.81-1.00). The 18-year risk of angioedema was significantly higher in patients receiving lisinopril than in those receiving amlodipine or chlorthalidone; the risk of insomnia was significantly lower in patients receiving lisinopril than in those receiving amlodipine; and the risk of cancer, depression, and erectile dysfunction (in men) was not statistically significantly different among the three drug groups.

Manifestations of Liver Impairment and the Effects of MH-76, a Non-Quinazoline α1-Adrenoceptor Antagonist, and Prazosin on Liver Tissue in Fructose-Induced Metabolic Syndrome.

Excessive fructose consumption may lead to metabolic syndrome, metabolic dysfunction-associated fatty liver disease (MAFLD) and hypertension. α1-adrenoceptors antagonists are antihypertensive agents that exert mild beneficial effects on the metabolic profile in hypertensive patients. However, they are no longer used as a first-line therapy for hypertension based on Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) outcomes. Later studies have shown that quinazoline-based α1-adrenolytics (prazosin, doxazosin) induce apoptosis; however, this effect was independent of α1-adrenoceptor blockade and was associated with the presence of quinazoline moiety. Recent studies showed that α1-adrenoceptors antagonists may reduce mortality in COVID-19 patients due to anti-inflammatory properties. MH-76 (1-[3-(2,6-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride)) is a non-quinazoline α1-adrenoceptor antagonist which, in fructose-fed rats, exerted anti-inflammatory, antihypertensive properties and reduced insulin resistance and visceral adiposity. In this study, we aimed to evaluate the effect of fructose consumption and treatment with α1-adrenoceptor antagonists of different classes (MH-76 and prazosin) on liver tissue of fructose-fed rats. Livers were collected from four groups (Control, Fructose, Fructose + MH-76 and Fructose + Prazosin) and subjected to biochemical and histopathological studies. Both α1-adrenolytics reduced macrovesicular steatosis and triglycerides content of liver tissue and improved its antioxidant capacity. Treatment with MH-76, contrary to prazosin, reduced leucocytes infiltration as well as decreased elevated IL-6 and leptin concentrations. Moreover, the MH-76 hepatotoxicity in hepatoma HepG2 cells was less than that of prazosin. The use of α1-adrenolytics with anti-inflammatory properties may be an interesting option for treatment of hypertension with metabolic complications.

Pharmacoepidemiologic study of association between apparent treatment resistant hypertension, cardiovascular disease and interaction effect by sex and age

A limited number of studies have been conducted to test the magnitudes of the association between apparent treatment resistant hypertension (aTRH) and risk of cardiovascular disease (CVD). To investigate the association between aTRH and risk of CVD and examine whether sex and age modify this association. We applied an observational analysis study design using data from the United States Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). ALLHAT recruited participants (n = 25516) from 625 primary care settings throughout the United States, Canada, Puerto Rico, and United States Virgin Islands, aged 55 and older with hypertension and at least one additional risk factor for heart disease. aTRH was assessed from the year 2 visit. CVD event was defined as one of the following from the year 2 follow-up visit: Fatal or non-fatal myocardial infarction, coronary revascularization, angina, stroke, heart failure, or peripheral artery disease. Cox proportional hazards regression was used to examine the effect of aTRH on CVD risk. Potential modifications of sex and age on this association were examined on the multiplicative scale by interaction term and additive scale by joint effects and relative excess risk for interaction. Of the total study participants (n = 25516), 5030 experienced a CVD event during a mean of 4.7 years follow-up. aTRH was associated with a 30% increase in risk of CVD compared to non-aTRH [hazards ratio (HR) = 1.3, 95%CI: 1.19-1.42]. Sex and age modified this relationship on both multiplicative and additive scales independently. Stratified by sex, aTRH was associated with a 64% increase in risk of CVD (HR = 1.64, 95%CI: 1.43-1.88) in women, and a 13% increase in risk of CVD (HR = 1.13, 95%CI: 1.01-1.27) in men. Stratified by age, aTRH had a stronger impact on the risk of CVD in participants aged < 65 (HR = 1.53, 95%CI: 1.32-1.77) than it did in those aged ≥ 65 (HR = 1.18, 95%CI: 1.05-1.32). Significant two-way interactions of sex and aTRH, and age and aTRH on risk of CVD were observed (P < 0.05). The observed joint effect of aTRH and ages ≥ 65 years (HR = 1.85, 95%CI: 1.22-2.48) in males was less than what was expected for both additive and multiplicative models (HR = 4.10, 95%CI: 3.63-4.57 and 4.88, 95%CI: 3.66-6.31), although three-way interaction of sex, age, and aTRH on the risk of CVD and coronary heart disease did not reach a statistical significance (P > 0.05). aTRH was significantly associated with an increased risk of CVD and this association was modified by both sex and age. Further studies are warranted to test these mechanisms.

Abstract 27: Genetic Risk of Blood Pressure on Antihypertensive Efficacy and Apparent Treatment Resistant Hypertension in Participants of the Genetics of Hypertension Associated Treatments (GenHAT) Study

Background: Polygenic risk scores (PRS) have shown promise in complementing existing clinical risk factors and improving early diagnosis of cardiovascular disease. Recently, several studies have developed PRS for blood pressure traits; however, few have examined to what extent these PRS predict antihypertensive (AHT) efficacy. Hypothesis: We hypothesize that applying a systolic blood pressure (SBP) PRS developed and trained in multi-ancestral observational studies will predict response to chlorthalidone (CHL), as well as non-response to AHT treatment (apparent treatment resistant hypertension, aTRH), among African Americans (AA). Methods: We applied an optimized multi-ancestry PRS generated in a pooled Trans-Omics for Precision Medicine (TOPMed) cohort of &gt;21,000 adults for SBP (PRS SBP ) to 4,297 AA Genetics of Hypertension Associated Treatment (GenHAT) participants randomized to CHL as part of the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) with genome wide association study data. We then used linear regression to test the association of PRS SBP quintiles with CHL response (6 month BP - baseline BP) adjusting for age, sex, genetic ancestry, and baseline SBP. For the analysis of aTRH, cases were defined as individuals (a) treated with 3 different AHT classes, with average BP ≥140/90 mmHg at year 3 follow-up or (b) ≥4 AHT classes regardless of BP (cases, n=286). Treated controls were defined as individuals with BP &lt;140/90 mmHg and on trial drug monotherapy at year 3 (n=2,391). Logistic regression models adjusting for age, sex, and genetic ancestry were used to calculate the odds ratio for aTRH comparing the highest and lowest quintile (Q5 and Q1, respectively). Results: The PRS SBP was associated with reduced SBP response in Q5 (-5.01 [-6.15, -3.87] mmHg) versus Q1 (-8.24 [-9.39, -7.09] mmHg) and Q2 (-7.25 [-8.39, -6.11] mmHg). In regard to aTRH, Q5 was nominally associated with higher odds of aTRH compared to Q1 (1.48 [1.00, 2.20]). Conclusions: We found that a general SBP PRS was associated with BP response in AAs from GenHAT. On average, a greater SBP reduction was found in participants at low genetic risk (Q1 or Q2) compared to the high risk (Q5) taking the same AHT. Similarly, when compared to participants in the bottom 20% of the distribution, those in the top 20% had increased odds of aTRH. Additional work using the PRS SBP in other ancestral populations, as well as developing novel AHT class treatment response PRS, is warranted and in progress to determine whether we can identify individuals who would benefit the most from specific AHT classes.

Abstract 15208: Association Between Electrocardiographic St-t Wave Abnormalities and Stroke Risk in the Allhat Trial

Background: The presence of electrocardiographic (ECG) ST-T wave abnormalities has previously been shown to be associated with increased risk of coronary artery disease but their association with stroke incidence is unclear.Objective: We sought to investigate the relationship between ST-T wave abnormalities and stroke incidence in the ALLHAT trial. Methods: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is a randomized double-blinded clinical trial (n=33,357) conducted from 1994 through 2002, examining whether treatment with a calcium channel blocker or an angiotensin-converting enzyme inhibitor lowers incidence of CHD or CVD events compared to treatment with a diuretic. Major ST depression or T wave inversion on any ECG in the past 2 years were included in the study. One of the secondary outcomes included in the study was incident stroke. Hazard ratios (relative risks [RRs]) and 95% confidence intervals (CIs) were obtained using Cox proportional hazards regression model. All statistical analyses were performed using STATA 12 (Stata Corp., College Station, TX, USA). Results: Study participants were predominantly middle-aged, male, white, with prevalence of ST-T wave abnormality being 10.35% (N=3,420). Presence of ST-T wave abnormalities were not associated with a higher risk of stroke [hazard ratio 0.47 (95% CI, 0.91-1.22)] in unadjusted analyses. This relationship was not significant even after adjustment for prevalent cardiovascular disease (CABG, ASCVD) [0.51(95% CI, 0.91- 1.22)], cardiovascular risk factors (age, sex, diabetes, systolic blood pressure, diastolic blood pressure, cholesterol, BMI) [0.15 (95% CI, 0.96-1.31)] as well as randomized treatment groups in ALLHAT [0.15 (95% CI, 0.96-1.31)]. Conclusion: Presence of major ST-T wave abnormality does not predict incident stroke in the the ALLHAT trial, more observations from contemporary studies need to be elucidated.

Abstract 13384: Choice of Antihypertensive Agent in Isolated Systolic Hypertension and Isolated Diastolic Hypertension: A Secondary Analysis of the Allhat Trial

Introduction: Although isolated systolic hypertension (ISH) and isolated diastolic hypertension (IDH) exhibit differing pathophysiology and phenotypes, it is unclear whether specific antihypertensive agents are preferred for each condition. Methods: Using data from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), we set out to determine whether certain antihypertensive agents had differential effects on clinical outcomes in patients with ISH or IDH. We defined ISH as SBP ≥140mmHg and DBP &lt;90mmHg, and we defined IDH as SBP &lt;140mmHg and DBP ≥90mmHg. We used risk-adjusted cox regression to evaluate the primary outcome (a composite of all-cause mortality, combined CHD, or stroke) by antihypertensive agent in cohorts of patients with ISH or IDH. We also evaluated achievement of normotension using risk-adjusted logistic regression. Results: We identified 12,845 patients with ISH and 1,259 patients with IDH. The adjusted hazard of the primary outcome was similar across antihypertensive agents for both ISH (aHR=1.01, 95% CI 0.94-1.09 for amlodipine vs chlorthalidone, and aHR=1.03, 95% CI 0.95-1.10 for lisinopril vs chlorthalidone) and IDH (aHR=1.06, 95% CI 0.80-1.41 for amlodipine vs chlorthalidone, and aHR=1.11, 95% CI 0.84-1.47 for lisinopril vs chlorthalidone) (Figure). There were no significant differences across antihypertensive agents in the achievement of normotension at six years for ISH (OR=1.01, 95% CI 0.89-1.15 for amlodipine vs chlorthalidone; and OR=0.97, 95% CI 0.85-1.10 for lisinopril vs chlorthalidone) or IDH (aOR=0.92, 95% CI 0.59-1.42 for amlodipine vs chlorthalidone; and aOR=0.77, 95% CI 0.49-1.21 for lisinopril vs chlorthalidone). Conclusions: In this large cohort of patients, clinical events were similar across antihypertensive agents for both ISH or IDH. These results lend credence to the flexible treatment recommendations in current hypertension guidelines.

Jeremiah Stamler, MD (1919-2022).

Jeremiah Stamler, MD (1919-2022).

Chlortalidone

Chlortalidone

PO-713-04 PROGNOSTIC EFFECTS OF ELECTROCARDIOGRAPHIC ST-T WAVE ABNORMALITIES IN THE ALLHAT (ANTIHYPERTENSIVE AND LIPID-LOWERING TREATMENT TO PREVENT HEART ATTACK TRIAL)

Major electrocardiographic (ECG) ST-T wave abnormalities are widely seen in clinical practice, but the longitudinal significance in cardiovascular risk assessment within a contemporary hypertension treatment cohort remains unknown. We sought to investigate the relationship between ST-T wave abnormalities and the primary outcome (fatal coronary heart disease or nonfatal myocardial infarction) in the ALLHAT trial. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is a randomized double-blinded clinical trial (n=33,357) conducted during 1994- 2002, examining whether treatment with a calcium channel blocker or an angiotensin-converting enzyme inhibitor lowers incidence of CHD or CVD events compared to treatment with a diuretic. 33,357 participants aged 55 years or older with hypertension and at least 1 other CHD risk factor were included and followed up for 4-8 years. Major ST depression or T wave inversion on any ECG in past 2 years were included in the study. The primary outcome was combined fatal CHD or nonfatal myocardial infarction. Hazard ratios (relative risks [RRs]) and 95% confidence intervals (CIs) were obtained from the Cox proportional hazards regression model. Cumulative event rates were calculated using the Kaplan-Meier method. All statistical analyses were performed using STATA 12 (Stata Corp., College Station, TX, USA). Study participants were predominantly middle-aged, male, white, with prevalence of ST-T wave abnormality being 10.35% (N=3,420). Moreover, ST-T changes were associated with a higher risk of fatal CHD or nonfatal MI [hazard ratio 1.17 (95% CI, 1.05-1.29)] in unadjusted analyses. This relationship remained statistically significant after adjustment for prevalent cardiovascular disease (stroke, CABG, ASCVD) [1.15 (95% CI, 1.04- 1.28)], cardiovascular risk factors (age, sex, diabetes, systolic blood pressure, diastolic blood pressure, cholesterol, BMI) [1.21 (95% CI, 1.09-1.34)] as well as randomized treatment groups in ALLHAT [1.21 (95% CI, 1.09-1.34)]. Presence of major ST-T wave abnormality was significantly associated with fatal CHD or nonfatal MI, underscoring the potential prognostic value of these ECG findings in overall cardiovascular risk.

Effects of Posttrial Antihypertensive Drugs on Morbidity and Mortality: Findings from 15-Year Passive Follow-Up after ALLHAT Ended.

Background Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) ended in 2002, but it is important to study its long-term outcomes during the posttrial period by incorporating posttrial antihypertensive medication uses in the analysis. Purposes The primary aim is to explore the patterns of antihypertensive medication use during the posttrial period from Medicare Part-D data over the 11-year period from 2007 to 2017. The secondary aim is to examine the potential effects of these posttrial antihypertensive medications on the observed mortality and morbidity benefits. Methods This is a posttrial passive follow-up study of ALLHAT participants in 567 US centers in 1994–1998 with the last date of active in-trial follow-up on March 31, 2002, by linking with their Medicare and National Death Index data through 2017 among 8,007 subjects receiving antihypertensive drugs (3,637 for chlorthalidone, 2,189 for amlodipine, and 2,181 for lisinopril). Outcomes included posttrial antihypertensive drug use, all-cause mortality, and cardiovascular disease (CVD) mortality. Results Of 8007 subjects, 3,637 participants were initially randomized to diuretic (chlorthalidone). The majority (67.9%) of them still received diuretics in 2007, and 52.7%, 47.2%, and 44.0% received β-blockers, angiotensin-converting enzyme (ACE) inhibitors, and calcium channel blockers (CCBs), respectively. Compared to participants who received diuretic-based antihypertensives, those who received CCB had a nonsignificantly higher risk of all-cause mortality (1.17, 0.99–1.37), whereas those who received ACE/ARB (angiotensin receptor blockers) had a significantly higher risk of all-cause mortality (1.26, 1.09–1.45). For the combined fatal or nonfatal hospitalized events, the risk of CVD was significantly higher in patients receiving CCB (1.30, 1.04–1.61) and ACE/ARB (1.49, 1.22–1.81) as compared to patients receiving diuretics. Conclusion After the conclusion of the ALLHAT, almost all patients switched to combination antihypertensive therapies, independently by the original drug class, and the combination therapies (mostly based on diuretics) reduced the incidence of major cardiovascular outcomes and mortality.

A Novel Hypertension Management Algorithm Guided by Hemodynamic Data

A Novel Hypertension Management Algorithm Guided by Hemodynamic Data

Risk of hospitalized and non-hospitalized gastrointestinal bleeding in ALLHAT trial participants receiving diuretic, ACE-inhibitor, or calcium-channel blocker.

This post-trial data linkage analysis was to utilize the data of Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) participants linked with their Medicare data to examine the risk of hospitalized and non-hospitalized gastrointestinal (GI) bleeding associated with antihypertensives. ALLHAT was a multicenter, randomized, double-blind, active-controlled trial conducted in a total of 42,418 participants aged ≥55 years with hypertension in 623 North American centers. Data for ALLHAT participants who were aged at ≥65 have been linked with their Medicare claims data. A total of 16,676 patients (4,480 for lisinopril, 4,537 for amlodipine, and 7,659 for chlorthalidone) with complete Medicare claims data were available for the final analysis. The cumulative incidences through March 31, 2002 of hospitalized GI bleeding were 5.4%, 5.8% and 5.4% for amlodipine, lisinopril, and chlorthalidone arms, respectively, but were not statistically significant among the 3 arms after adjusting for confounders in Cox regression models. The cumulative incidences of non-hospitalized GI bleeding were also similar across the 3 arms (12.0%, 12.2% and 12.0% for amlodipine, lisinopril, and chlorthalidone, respectively). The increased risk of GI bleeding by age was statistically significant after adjusting for confounders (HR = 1.04 per year, 95% CI: 1.03-1.05). Smokers also had a significantly higher risk of having hospitalized GI bleeding (1.45, 1.19-1.76). Hispanics, those who used aspirin or atenolol in-trial, had diabetes, more education, and a history of stroke had a significantly lower risk of having GI bleeding than their counterparts. Other factors such as gender, history of CHD, prior antihypertensive use, use of estrogen in women, and obesity did not have significant effects on the risk of GI bleeding. There were no statistically significant differences on the risk of hospitalized or non-hospitalized GI bleeding among the 3 ALLHAT trial arms (amlodipine, lisinopril, and chlorthalidone) during the entire in-trial follow-up.

Contributions of Systolic and Diastolic Blood Pressures to Cardiovascular Outcomes in the ALLHAT Study

BackgroundSBP and DBP have important associations with cardiovascular events, but are seldom considered simultaneously. ObjectivesThis study sought to simultaneously analyze systolic blood pressure (SBP) and diastolic blood pressure (DBP) measurements on the associated risk of a primary composite outcome of all-cause mortality, myocardial infarction (MI), congestive heart failure (CHF), or stroke. MethodsThis study analyzed ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) data, which randomized adults to chlorthalidone, amlodipine, or lisinopril. The authors evaluated the simultaneous association of repeated SBP and DBP measurements on the primary composite outcome, and each outcome using proportional hazards regression. The authors report hazard ratios using a “heat map” to represent high and low risk according to SBP and DBP combinations. ResultsDuring a median follow-up of 4.4 years (interquartile range: 3.6-5.4 years), 33,357 participants experienced 2,636 MIs, 866 CHF events, 936 strokes, and 3,700 deaths; 8,138 patients (24.4%) had at least 1 event. For the composite outcome, all-cause mortality, MI, and CHF, a U-shaped association was observed with SBP and DBP, but the SBP and DBP associated with the lowest hazards differed for each outcome. For example, SBP/DBP of 140-155/70-80 mm Hg was associated with the lowest HR for all-cause mortality, compared with 110-120/85-90 mm Hg for MI and 125-135/70-75 mm Hg for CHF. In contrast, the association of SBP and stroke was linear. ConclusionsThe risk pattern of SBP and DBP differs by clinical outcomes, and the SBP and DBP associated with the lowest risk. Our results suggest individualization of blood pressure targets may depend in part on the cardiovascular event for which the patient is most at risk.

Lowering Nighttime Blood Pressure With Bedtime Dosing of Antihypertensive Medications: Controversies in Hypertension - Con Side of the Argument.

Lowering Nighttime Blood Pressure With Bedtime Dosing of Antihypertensive Medications: Controversies in Hypertension - Con Side of the Argument.

MH-76, a Novel Non-Quinazoline α1-Adrenoceptor Antagonist, but Not Prazosin Reduces Inflammation and Improves Insulin Signaling in Adipose Tissue of Fructose-Fed Rats

Background: Quinazoline α1-adrenoceptors antagonists have been shown to exert moderately favorable effects on the metabolic profile in hypertensive patients. However, based on AntiHypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) results, they are no longer recommended as a first line therapy of hypertension. Recent studies have shown that quinazoline-based α1-adrenoceptors antagonists (prazosin, doxazosin) induce the apoptosis and necrosis, which may be responsible for ALLHAT outcomes; however, these effects were proven to be independent of α1-adrenoceptor blockade and were associated with the presence of quinazoline moiety. MH-76 (1-[3-(2,6-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride)) is a non-quinazoline α1-adrenoceptor antagonist which, in fructose-fed rats, exerted antihypertensive effect, and, contrary to prazosin, reduced insulin resistance and abdominal adiposity. In this study we aimed to further investigate and compare the effects of MH-76 and prazosin on inflammation in adipose tissue of fructose-fed rats. Methods: Abdominal adipose tissue was collected from four groups of fructose-fed rats (Control, Fructose, Fructose + MH-76 and Fructose + Prazosin) and subjected to biochemical, histopathological and immunohistochemical studies. Moreover, selected tissue distribution studies were performed. Results: Treatment with MH-76 but not with prazosin improved endothelial integrity, reduced adipose tissue inflammation and infiltration by immune cells, resulting in lowering leptin, MCP-1, IL-6, TNF-α and PAI-1 levels. In adipose tissue from Fructose + MH-76 animals, a higher amount of eosinophils accompanied with higher IL-4 concentration was observed. Treatment with MH-76 but not with prazosin markedly reduced phosphorylation of IRS-1 at Ser307. Conclusion: MH-76 may improve insulin signaling in adipose tissue by reducing the pro-inflammatory cytokine production and inhibiting the inflammatory cells recruitment. In contrast, in adipose tissue from animals treated with prazosin, the inflammatory effect was clearly enhanced.

Association of Sustained Blood Pressure Control with Lower Risk for High-Cost Multimorbidities Among Medicare Beneficiaries in ALLHAT.

Clustering of chronic conditions is associated with high healthcare costs. Sustaining blood pressure (BP) control could be a strategy to prevent high-cost multimorbidity clusters. To determine the association between sustained systolic BP (SBP) control and incident multimorbidity cluster dyads and triads. Cohort study of Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) linked to Medicare claims. ALLHAT included adults with hypertension and ≥1 coronary heart disease risk factor. This analysis was restricted to 5234 participants with ≥ 8 SBP measurements during a 48-month BP assessment period. SBP control was defined as <140 mm Hg at <50%, 50 to <75%, 75 to <100%, and 100% of study visits during the BP assessment period. High-cost multimorbidity clusters included dyads (stroke/chronic kidney disease [CKD], stroke/chronic obstructive pulmonary disease [COPD], stroke/heart failure [HF], stroke/asthma, COPD/CKD) and triads (stroke/CKD/asthma, stroke/CKD/COPD, stroke/CKD/depression, stroke/CKD/HF, stroke/HF/asthma) identified during follow-up. Incident dyads occurred in 1334 (26%) participants and triads occurred in 481 (9%) participants over a median follow-up of 9.2 years. Among participants with SBP control at <50%, 50 to <75%, 75 to <100%, and 100% of visits, 32%, 23%, 23%, and 19% of participants developed high-cost dyads, respectively, and 13%, 9%, 8%, and 5% of participants developed high-cost triads, respectively. Compared to those with sustained BP control at <50% of visits, adjusted HRs (95% CI) for incident dyads were 0.66 (0.57, 0.75), 0.67 (0.59, 0.77), and 0.51 (0.42, 0.62) for SBP control at 50 to <75%, 75 to <100%, and 100% of visits, respectively. The corresponding HRs (95% CI) for incident triads were 0.69 (0.55, 0.85), 0.56 (0.44, 0.71), and 0.32 (0.22, 0.47). Among Medicare beneficiaries in ALLHAT, sustained SBP was associated with a lower risk of developing high-cost multimorbidity dyads and triads.

Cardiac α1A-adrenergic receptors: emerging protective roles in cardiovascular diseases.

α1-Adrenergic receptors (ARs) are catecholamine-activated G protein-coupled receptors (GPCRs) that are expressed in mouse and human myocardium and vasculature, and play essential roles in the regulation of cardiovascular physiology. Though α1-ARs are less abundant in the heart than β1-ARs, activation of cardiac α1-ARs results in important biologic processes such as hypertrophy, positive inotropy, ischemic preconditioning, and protection from cell death. Data from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) indicate that nonselectively blocking α1-ARs is associated with a twofold increase in adverse cardiac events, including heart failure and angina, suggesting that α1-AR activation might also be cardioprotective in humans. Mounting evidence implicates the α1A-AR subtype in these adaptive effects, including prevention and reversal of heart failure in animal models by α1A agonists. In this review, we summarize recent advances in our understanding of cardiac α1A-ARs.

Worsening Kidney Function Is the Major Mechanism of Heart Failure in Hypertension: The ALLHAT Study

ObjectivesThe authors aimed to quantify the extent to which the effect of antihypertensive drugs on incident heart failure (HF) is mediated by their effect on kidney function. BackgroundThe authors hypothesized that the dynamic change in kidney function is the mechanism behind differences in the rate of incident HF in ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) participants randomized to lisinopril and chlorthalidone, in comparison with those randomized to amlodipine and doxazosin. MethodsCausal mediation analysis of ALLHAT data (1994 to 2002) included participants with available baseline and 24- to 48-month estimated glomerular filtration rate (eGFR) (N = 27,918; mean age 66 ± 7.4 years; 32.4% Black, 56.3% men). Change in eGFR was the mediator. Incident symptomatic HF was the primary outcome. Hospitalized/fatal HF was the secondary outcome. Linear regression (for mediator) and logistic regression (for outcome) analyses were adjusted for demographics, cardiovascular disease, and risk factors. ResultsThere were 1,769 incident HF events, including 1,359 hospitalized/fatal HF events. In fully adjusted causal mediation analysis, the relative change in eGFR mediated 18% of the effect of chlorthalidone, and 33% of lisinopril on incident symptomatic HF, and 25% of the effect of chlorthalidone, and 41% of lisinopril on hospitalized/fatal HF. In participants with diabetes, the relative change in eGFR mediated nearly 50% of the effect of lisinopril on incident symptomatic HF, whereas in diabetes-free participants, only 17%. ConclusionsOn the risk difference scale, change in eGFR accounts for up to 50% of the mechanism by which antihypertensive medications affect HF. (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial [ALLHAT]; NCT00000542).

Glucose Variability and Diabetic Complications: Is It Time to Treat?

Increasing evidence is supporting the role of glucose variability (GV) in the development of diabetic complications, particularly cardiovascular (CV) ones (1). Many observational studies (1) and post hoc analyses of trials, such as ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation) (2), DEVOTE (Trial Comparing Cardiovascular Safety of Insulin Degludec Versus Insulin Glargine in Subjects With Type 2 Diabetes at High Risk of Cardiovascular Events) (3), VADT (Veterans Affairs Diabetes Trial) (4), ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) (5), and EMPAREG OUTCOME (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) (6), confirm that in type 2 diabetes long-term GV, in terms of fasting glucose and/or HbA1c variability, is correlated with an increased risk of both CV and microvascular complications. In this issue of Diabetes Care , a post hoc analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial adds a further important piece of evidence on this topic (7). This analysis shows that HbA1c variability is a strong predictor of the total mortality in people with type 2 diabetes and a previous CV event or high risk for CV disease (7). It is worth mentioning that, with abundant measurements in the ACCORD trial, it has been possible for the first time to compare GV effects between the standard and intensive treatment arms. As is well known, increased mortality from all causes was reported in the intensive treatment arm of ACCORD, leading to the premature discontinuation of the study (8). In this post hoc analysis it emerges that HbA1c variability, together with a higher mean HbA1c level, is involved in the increased total mortality, particularly in the intensive treatment arm (7). The authors suggest …