Previous longitudinal cohort studies have suggested an association between baseline depressive symptoms and incident hypertension. We assessed this possible association using data from the Multi-ethnic Study of Atherosclerosis, a population-based prospective cohort study of 6,814 US adults from 4 different racial/ethnic groups. Baseline users of antihypertensive medications and participants lost to follow-up were excluded leaving 3914 participants. Patients with baseline depressive symptoms (n=622) were defined using a high score on the Center for Epidemiologic Studies Depression Scale (≥ 16) or the use of an antidepressant medication. Hypertension was defined as systolic blood pressure ≥ 140, diastolic blood pressure ≥90 or new use of antihypertensive medications plus physician diagnosis. Estimates were adjusted for known risk factors including: age, sex, baseline blood pressure, diabetes, and body mass index. Untreated blood pressure was estimated using an imputation approach. A total of 477 participants developed hypertension. Using relative risk regression, patients with baseline depressive symptoms did not have an increased risk of incident hypertension (Relative Risk = 1.02; 95% Confidence Interval (CI):0.99 to 1.05) although an association between tricyclic antidepressants and hypertension (Relative Risk 1.20; 95% CI:1.05 to 1.37) was observed in sub-group analysis. Depression, even after adjustment for covariates, was associated with small changes in systolic (+2.4 mmHG; 95% CI: 0.2 to 4.7) and diastolic (+0.8 mmHG; 95% CI: −0.6 to 2.3) blood pressure. Depressive symptoms may be associated with slight increases in blood pressure in this multi-ethnic cohort but it is premature to conclude much without longer studies in other populations.
Multi-Ethnic Study of Atherosclerosis; depression; hypertension; blood pressure; imputation; censored normal regression
There is evidence that the utilization of antidepressant medications (ADM) may vary between different ethnic groups in the United States population.
The Multi-Ethnic Study of Atherosclerosis is a population-based prospective cohort study of 6,814 US adults from 4 different ethnic groups. After excluding baseline users of ADM, we examined the relation between baseline depression and new use of ADM for 4 different ethnicities: African-Americans (n=1,822), Asians (n=784) Caucasians (n=2,300), and Hispanics (n=1,405). Estimates of the association of ethnicity and ADM use were adjusted for age, study site, gender, Center for Epidemiologic Studies Depression Scale (CES-D), alcohol use, smoking, blood pressure, diabetes, education, and exercise. Non-random loss to follow-up was present and estimates were adjusted using inverse probability of censoring weighting (IPCW).
Of the four ethnicities, Caucasian participants had the highest rate of ADM use (12%) compared with African-American (4%), Asian (2%) and Hispanic (6%) participants. After adjustment, non-Caucasian ethnicity was associated with reduced ADM use: African-American (HR: 0.42; 95% Confidence Interval (CI):0.31– 0.58), Asian (HR: 0.14; 95%CI: 0.08–0.26) and Hispanic (HR: 0.47; 95%CI: 0.31–0.65). Applying IPCW to correct for non-random loss to follow-up among the study participants weakened but did not eliminate these associations: African-American (HR: 0.48; 95%CI: 0.30–0.57), Asian (HR: 0.23; 95% CI: 0.13–0.37) and Hispanic (HR: 0.58; 95%CI: 0.47–0.67).
Non-Caucasian ethnicity is associated with lower rates of new ADM use. After IPCW adjustment, the observed ethnicity differences in ADM use are smaller although still statistically significant.
Inverse probability of censoring weighting; ethnicity; antidepressants; drug utilization; Multi-Ethnic Study of Atherosclerosis; non-random loss to follow-up
Three types of non-steroidal anti-inflammatory drugs (NSAIDs) can be obtained both over the counter (OTC) and by prescription in the United States. OTC NSAID use is not recorded in prescription claims databases; this might lead to differential misclassification of NSAID exposure status in studies that use computerized pharmacy databases to study NSAID use.
To evaluate characteristics of OTC versus prescription NSAID users
This analysis is set within the Multi-Ethnic Study of Atherosclerosis (MESA) study; a prospective cohort study of 6,814 adults from 4 ethnic groups (European descent, Asian, African-American and Hispanic) with a mean age of 62 years. The cohort was restricted to those who initiated NSAID use (aspirin, ibuprofen or naproxen) during follow-up. We compared information about age, sex, ethnicity, body mass index, smoking, diabetes, medication use, education, income, health insurance status and exercisebetween groups.
OTC NSAID use was prevalent at baseline (25% Aspirin, 9% Ibuprofen, 2% Naproxen). Compared to prescribed NSAID use, OTC NSAID use was lower for users of non-European descent for all classes: aspirin (p<0.0001), ibuprofen (p<0.0001) and naproxen (p=0.0094). For aspirin, differences were seen for male gender (Relative Risk (RR):0.92; 95%(Confidence interval) CI:0.86–0.98), use of lipid lowering drugs (RR:0.88; 95% CI: 0.80–0.96), low income (RR:0.89; 95%CI:0.81–0.97), and participants one standard deviation above average in intentional exercise (RR:1.03; 95%CI:1.01–1.05).
OTC NSAID use is prevalent in an older multi-ethnic population and OTC users differ from prescription NSAID users. Caution should be exercised when using prescribed NSAIDs as a proxy for NSAID use.
Aspirin; over the counter drug use; ethnicity; Multi-Ethnic Study of Atherosclerosis
Background. Yangxue Qingnao granule (YQG) combined with antihypertensive drugs, a new integrative medicine therapy, has been widely used for essential hypertension (EH) in China. This study aims to assess the current clinical evidence of YQG combined with antihypertensive drugs for EH. Methods. Randomized controlled trials(RCTs) published between 1996 and 2012 on YQG combined with antihypertensive drugs versus antihypertensive drugs in treating EH were retrieved from six major electronic databases, including The Cochrane Library, PubMed, Chinese National Knowledge Infrastructure, Chinese Scientific Journal Database, Chinese Biomedical Literature Database, and Wanfang Data. Meta-analysis was performed on the overall effects on blood pressure. Results. Twelve randomized trials were included. Methodological quality of the trials was evaluated as generally low. Meta-analysis showed that YQG combined with antihypertensive drugs demonstrated potential effect for lowing either SBP (MD: −7.31 [−11.75, −2.87]; P = 0.001) or DBP (MD: −5.21 [−8.19, −2.24]; P = 0.0006) compared to antihypertensive drugs alone. Conclusions. It indicated that YQG combined with antihypertensive drugs is more effective than antihypertensive drugs alone in treating EH. However, more RCTs of larger scale, multicentre/country, longer follow-up periods, and higher quality are required to verify the efficacy of integrative medicine therapy over all antihypertensive therapies.
Hypertension is extremely prevalent in patients with diabetes. Limited data exist on whether patterns of antihypertensive use in this population are consistent with evidence-based practice guidelines.
To evaluate utilization patterns of antihypertensive agents and blood pressure (BP) control among diabetic patients with hypertension.
Retrospective cohort study.
In all, 9,975 patients with diabetes and hypertension as of March 2001 from an outpatient medical center of the Department of Veterans Affairs.
Proportions of use of 6 different antihypertensive drug classes were compared for all patients receiving 1, 2, 3, or 4 or more drugs, and separately among patients with and without coronary artery disease (CAD). Blood pressure control (<130/85 mmHg) was compared for untreated patients, those on monotherapy, and patients on multi-drug regimens.
Over 60% of patients were receiving angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blocker (ARB), followed by diuretics (38.1%), calcium channel blockers (35.3%) and β-blockers (28.5%) with 19.1% of patients untreated. Patients on monotherapy were mostly receiving ACEI/ARB (59.5%). The majority (70.7%) of treated patients were on multidrug regimens. In patients with CAD, β-blocker and ACEI/ARB use was higher, and 70.5% of patients on single-drug regimens received either ACEI/ARB or β-blockers. The proportions of patients not on medications, on monotherapy, or multidrug regimens achieving BP control were 23.4%, 27.4%, and 24.9%, respectively.
Patterns of anti-hypertensive therapy were generally consistent with evidence-based practice guidelines. Areas of improvement include increasing ACEI/ARB and diuretic use, decreasing the number of untreated patients, and increasing the proportion of patients with controlled BP in this population.
hypertension control; diabetes; multidrug regimens; prescribing patterns; evidence base
The prevalence of hypertension is higher among African-Americans than whites. However, inconsistent findings have been reported on the incidence of hypertension among middle-aged and older African-Americans and whites and limited data are available on the incidence of hypertension among Hispanics and Asians in the US. Therefore, this study investigated the age-specific incidence of hypertension by ethnicity for 3,146 participants from the Multi-Ethnic Study of Atherosclerosis. Participants, age 45–84 years at baseline, were followed for a median of 4.8 years for incident hypertension, defined as systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥ 90 mmHg, or the initiation of antihypertensive medications. The crude incidence rate of hypertension, per 1,000 person-years, was 56.8 for whites, 84.9 for African-Americans, 65.7 for Hispanics, and 52.2 for Chinese. After adjustment for age, gender, and study site, the incidence rate ratio (IRR) for hypertension was increased for African-Americans age 45–54 (IRR=2.05, 95% CI=1.47, 2.85), 55–64 (IRR=1.63, 95% CI=1.20, 2.23), and 65–74 years (IRR=1.67, 95% CI=1.21, 2.30) compared with whites, but not for those 75–84 years of age (IRR=0.97, 95% CI=0.56, 1.66). Additional adjustment for health characteristics attenuated these associations. Hispanic participants also had a higher incidence of hypertension compared with whites; however, hypertension incidence did not differ for Chinese and white participants. In summary, hypertension incidence was higher for African-Americans compared with whites between 45 and 74 years of age but not after age 75 years. Public health prevention programs tailored to middle-age and older adults are needed to eliminate ethnic disparities in incident hypertension.
hypertension; race/ethnicity; epidemiology; incidence
Moxibustion is a traditional East Asian medical therapy that uses the heat generated by burning herbal preparations containing Artemisia vulgaris to stimulate acupuncture points. The aim of this review was to evaluate previously published clinical evidence for the use of moxibustion as a treatment for hypertension.
We searched 15 databases without language restrictions from their respective dates of inception until March 2010. We included randomized controlled trials (RCTs) comparing moxibustion to either antihypertensive drugs or no treatment. The risk of bias was assessed for each RCT.
During the course of our search, we identified 519 relevant articles. A total of 4 RCTs met all the inclusion criteria, two of which failed to report favorable effects of moxibustion on blood pressure (BP) compared to the control (antihypertensive drug treatment alone). However, a third RCT showed significant effects of moxibustion as an adjunct treatment to antihypertensive drug therapy for lowering BP compared to antihypertensive drug therapy alone. The fourth RCT included in this review addressed the immediate BP-lowering effects of moxibustion compared to no treatment. None of the included RCTs reported the sequence generation, allocation concealment and evaluator blinding.
There is insufficient evidence to suggest that moxibustion is an effective treatment for hypertension. Rigorously designed trials are warranted to answer the many remaining questions.
This paper re-evaluates the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) considering information from new clinical trials, meta-analyses, and recent ALLHAT analyses, especially those regarding heart failure and the association of drug treatment with new-onset diabetes (NOD) and its cardiovascular disease (CVD) consequences.
Subgroup and explanatory analyses from a long-term 4-arm double-blind randomized antihypertensive treatment trial in diverse North American settings.
Chlorthalidone was superior to 1) doxazosin in preventing combined CVD (CCVD) (RR=1.20, 95% CI 1.13-1.27), especially HF (RR=1.80, CI 1.40-2.22) and stroke (RR=1.26, CI 1.10-1.46); 2) lisinopril, in preventing CCVD (RR=1.10, CI 1.05-1.16), including stroke (in Black persons only) and HF (RR=1.20, CI 1.09-1.34); and 3) amlodipine, in preventing HF, overall (by 28%) and in hospitalized/fatal cases (by 26%). Central independent blinded re-review of HF hospitalizations confirmed each comparison. Results were consistent by age, sex, race (except for stroke and CCVD), diabetic status, metabolic syndrome status, and renal function level. Neither amlodipine nor lisinopril was superior to chlorthalidone in preventing end-stage renal disease overall, by diabetes status or by renal function level. In the chorthalidone arm, NOD was not significantly associated with CCVD (RR=0.96, CI 0.88-2.42).
Evidence from subsequent analyses of ALLHAT and other clinical outcome trials confirm that neither α-blockers, ACE-inhibitors nor calcium channel blockers surpass thiazide-type diuretics (at appropriate dosage) as initial therapy for reduction of cardiovascular or renal risk. Thiazides are superior in preventing heart failure, and new-onset diabetes associated with thiazides does not increase CVD outcomes.
Strategies are needed to improve the translation of clinical trial results into practice. We assessed the impact of the ALLHAT/JNC7 Dissemination Project’s academic detailing component on thiazide-type diuretic prescribing (ALLHAT indicates Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial: JNC7 indicates the Seventh Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure).
We used two national databases available from IMS Health: a physician survey of medications reported for hypertension and a pharmacy dispensing database on antihypertensive medications. At a county level, we correlated medication data with Dissemination Project intensity. Practices before the Dissemination Project in 2004 were compared to those after its completion in 2007. We also examined 2000–2008 national trends.
Academic detailing reached 18,524 physicians in 1698 venues via 147 investigator-educators. We noted an association between ALLHAT/JNC7 academic detailing activities and increased prescribing of thiazide-type diuretics. Physician survey data showed that the percentage of hypertension visits where the physician recorded where a thiazide-type diuretic was noted increased the most in counties with the greatest activities (8.6%, from 37.9% to 46.5%) compared to counties with moderate-level (2% change), low-level (−2%) and no activities (2%, p for trend <0.05). Pharmacy dispensing data showed that thiazide-type diuretic prescribing increased by 8.7% in counties with Dissemination Project activities compared to 3.9% in those without activities (p<0.001). Nationally, thiazide-type diuretic use did not increase between 2004 and 2008.
The ALLHAT/JNC7 Dissemination Project was associated with a small effect on thiazide-type diuretic use consistent with its small dose and the potential of external factors to diminish its impact. Academic detailing may increase physicians’ implementation of clinical trial results thereby making prescribing more consistent with evidence.
Antihypertensive medications are widely prescribed by doctors and heavily promoted by the pharmaceutical industry. Despite strong evidence of the effectiveness and cost-effectiveness of thiazide diuretics, trends in both promotion and prescription of antihypertensive drugs favour newer, less cost-effective agents. Observational evidence shows correlations between exposure to pharmaceutical promotion and less ideal prescribing. Our study therefore aimed to determine whether print advertisements for antihypertensive medications promote quality prescribing in hypertension.
We performed a cross-sectional study of 113 advertisements for antihypertensive drugs from 4 general practice-oriented Australian medical publications in 2004. Advertisements were evaluated using a quality checklist based on a review of hypertension management guidelines. Main outcome measures included: frequency with which antihypertensive classes were advertised, promotion of thiazide class drugs as first line agents, use of statistical claims in advertisements, mention of harms and prices in the advertisements, promotion of assessment and treatment of cardiovascular risk, promotion of lifestyle modification, and targeting of particular patient subgroups.
Thiazides were the most frequently advertised drug class (48.7% of advertisements), but were largely promoted in combination preparations. The only thiazide advertised as a single agent was the most expensive, indapamide. No advertisement specifically promoted any thiazide as a better first-line drug. Statistics in the advertisements tended to be expressed in relative rather than absolute terms. Drug costs were often reported, but without cost comparisons between drugs. Adverse effects were usually reported but largely confined to the advertisements' small print. Other than mentioning drug interactions with alcohol and salt, no advertisements promoted lifestyle modification. Few advertisements (2.7%) promoted the assessment of cardiovascular risk.
Print advertisements for antihypertensive medications in Australia provide some, but not all, of the key messages required for guideline-concordant care. These results have implications for the regulation of drug advertising and the continuing education of doctors.
Antihypertensive drugs with favorable metabolic effects on glucose and lipid levels are advocated for first-line therapy in hypertensive patients with metabolic/cardiometabolic syndrome (MetS). We compared outcomes by race in black and nonblack hypertensive individuals with and without MetS treated with a thiazide-type diuretic (chlorthalidone), a calcium channel blocker (amlodipine besylate), an α-blocker (doxazosin mesylate), or an angiotensin-converting enzyme inhibitor (lisinopril).
A post hoc subgroup analysis from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized, double-blind, active-controlled hypertension treatment trial in 42 418 participants. We defined MetS as hypertension plus at least 2 of the following: fasting serum glucose level of at least 100 mg/dL, body mass index (calculated as weight in kilograms divided by height in meters squared) of at least 30 kg/m2, fasting triglyceride levels of at least 150 mg/dL, and high-density lipoprotein cholesterol levels of less than 40 mg/dL in men (or less than 50 mg/dL in women).
Significantly higher rates of heart failure were consistent across all treatment comparisons in those with MetS. Relative risks (RRs) were 1.50 (95% confidence interval [CI], 1.18–1.90), 1.49 (95% CI, 1.17–1.90), and 1.88 (95% CI, 1.42–2.47) in black participants and 1.25 (95% CI, 1.06–1.47), 1.20 (95% CI, 1.01–1.41), and 1.82 (95% CI, 1.51–2.19) in nonblack participants for amlodipine, lisinopril, and doxazosin comparisons with chlorthalidone, respectively. Higher rates for combined cardiovascular disease were observed with lisinopril-chlorthalidone (RR, 1.24 [95% CI, 1.09–1.40] and 1.10 [95% CI, 1.02–1.19], respectively) and doxazosin-chlorthalidone comparisons (RR, 1.37 [95% CI, 1.19–1.58] and 1.18 [95% CI, 1.08– 1.30], respectively), in black and nonblack participants with MetS. Higher rates of stroke were seen in black participants only (RR, 1.37 [95% CI, 1.07–1.76] for the lisinopril-chlorthalidone comparison; RR, 1.49 [95% CI, 1.09–2.03] for the doxazosin-chlorthalidone comparison). Black patients with MetS also had higher rates of end-stage renal disease (RR, 1.70 1 [95% CI, 1.13– 2.55]) with lisinopril compared with chlorthalidone.
The ALLHAT findings fail to do not support the preference of for calcium channel blockers, α-blockers, or angiotensin-converting enzyme inhibitors compared with thiazide-type diuretics in patients with the MetS, despite their more favorable metabolic profiles. This was particularly true for black participants.
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 pre-specified in the ALLHAT protocol. EF estimated by contrast ventriculography, echocardiography or radionuclide study was available in 910 (66.6%) of 1367 patients 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 [HRs] and 95% CIs were 0.69 (0.53-0.91; p=0.009), 0.74 (0.56-0.97; p=0.032), and 0.53 (0.38-0.73; p<0.001), respectively. Chlorthalidone reduced the risk of HFREF compared with amlodipine or doxazosin; HRs were 0.74 (0.59-0.94; p=0.013) and 0.61 (0.47-0.79; p<0.001), respectively. Chlorthalidone was similar to lisinopril with regard to incidence of HFREF; HR=1.07 (0.82-1.40; p=0.596). Following 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 terminated early chlorthalidone/doxazosin comparison 20.0% (HFPEF) versus 26.0% (HFREF), p=0.185 (median follow-up 1.55 years).
In the ALLHAT trial, using 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.
antihypertensive therapy; hypertension, detection and control; diuretics; angiotensin-converting enzyme inhibitors; calcium channel blockers; heart failure; ejection fraction
To describe the prospective relationship of retinal vessel diameters with risk of hypertension in a multiethnic population-based cohort.
The Multi-Ethnic Study of Atherosclerosis is a population-based study of subclinical cardiovascular disease among white, African–American, Hispanic, and Chinese American adults aged 45–84 years. Retinal vessel diameters were measured using a standardized imaging software at the second examination (considered baseline in this analysis) and summarized as the central retinal artery/vein equivalent. Presence of retinopathy and retinal focal arteriolar narrowing and arteriovenous nicking was assessed by trained graders. Incidence of hypertension was defined among participants at risk as systolic blood pressure at least 140 mmHg, diastolic blood pressure at least 90 mmHg, or use of an antihypertensive medication.
Of the initial 6237 participants at baseline, 2583 were at risk of hypertension. After 3.2±0.5 years of follow-up, 448 (17.3%) participants developed hypertension. After adjusting for age, sex, race/ethnicity, the average of mean arterial blood pressure in the first and second examination, and other vascular risk factors, persons with narrower retinal arteriolar diameter and wider venular diameter at baseline were more likely to develop hypertension [odds ratio per SD decrease in central retinal artery equivalent 1.20, 95% confidence intervals 1.02, 1.42; and odds ratio per SD increase in central retinal vein equivalent 1.18, 95% confidence interval 1.02, 1.37]. Persons with focal arteriolar narrowing were also more likely to develop hypertension (odds ratio 1.80, 95% confidence interval 1.09, 2.97).
Findings from this multiethnic population confirm that narrower retinal arteriolar diameter and wider venular diameter are associated with the development of hypertension independent of traditional risk factors.
hypertension; microcirculation; retinal vessel diameter; retinopathy; the Multi-Ethnic Study of Atherosclerosis
Antihypertensive drugs have been linked to new-onset diabetes (NOD); however, data on the effect of these drugs on the development of NOD in hypertensive patients has not been well determined in a clinical setting. The aim was to investigate the association between antihypertensive drugs and NOD in Taiwan. We conducted a retrospective study of hypertensive Taiwanese patients receiving antihypertensive drugs treatment between January 2006 and December 2011. Clinical information and laboratory parameters were collected by reviewing the medical records. We estimated the odds ratios (ORs) of NOD associated with antihypertensive drug use; nondiabetic subjects served as the reference group. A total of 120 NOD cases were identified in 1001 hypertensive patients during the study period. The risk of NOD after adjusting sex, age, baseline characteristics, and lipid profiles was higher among users of thiazide diuretics (OR, 1.65; 95% confidence interval (CI), 1.12–2.45) and nondihydropyridine (non-DHP) calcium channel blockers (CCBs) (OR, 1.96; 95% CI, 1.01–3.75) than among nonusers. Other antihypertensive drug classes were not associated with risk of NOD. Our results show that patients with hypertension who take thiazide diuretics and non-DHP CCBs are at higher risk of developing NOD than those who take other classes of antihypertensive drugs in Taiwan.
To determine whether changes in serum glucose, serum potassium, and plasma insulin levels are correlated in a cohort of hypertensive patients.
Prespecified subgroup analysis of results from a prospective, multicenter, randomized, open-label, parallel-group study.
Primary care clinics at three tertiary care medical centers.
Community-based ambulatory population of 202 patients (age range 17–65 yrs) with a new diagnosis of hypertension, untreated hypertension, or known hypertension, who were previously treated with fewer than three antihypertensive drugs and had no evidence of cardiovascular disease or diabetes mellitus.
Monotherapy with oral hydrochlorothiazide 12.5 or 25 mg/day for 9 weeks.
Measurements and Main Results
Fasting serum glucose, serum potassium, and plasma insulin levels were obtained at baseline (before hydrochlorothiazide therapy was started) and after 9 weeks of therapy. Significant elevations were noted in fasting serum glucose (mean ± SD 3.42 ± 10.38 mg/dl, p<0.0001) and plasma insulin (2.35 ± 9.47 μIU/ml, p<0.0001) levels, and a significant reduction in serum potassium level (0.30 ± 0.44 mEq/L, p<0.0001) was noted. No significant correlation was observed between changes in fasting serum glucose and potassium levels (r = 0.022, 95% confidence interval (CI) −0.120–0.164, p=0.757) or between changes in serum potassium and plasma insulin levels (r = −0.112, 95% CI −0.256–0.037, p=0.140). Changes in serum glucose levels did not differ significantly between patients maintaining serum potassium levels of 4.0 mEq/L or greater and those with levels below 4.0 mEq/L.
Changes in serum potassium and serum glucose levels were not correlated in individuals receiving hydrochlorothiazide monotherapy; thus maintenance of normal potassium levels may not attenuate the risk of thiazide diuretic–induced hyperglycemia.
thiazide diuretics; hyperglycemia; hypokalemia; thiazide-induced hyperglycemia; hydrochlorothiazide.
C-reactive protein is a predictor of adverse cardiovascular outcomes. The effect of antihypertensive therapy on C-reactive protein levels is largely unknown.
We undertook a cross-sectional study of CRP levels among participants with primary hypertension on single-agent anti-hypertensive therapy in the community-based biracial Genetic Epidemiology Network of Arteriopathy cohort. Linear regression models were used to assess the association of anti-hypertensive medication class with log-transformed C-reactive protein after adjustment for age, gender, ethnicity, body mass index, smoking, diabetes, HMG-Co-A reductase inhibitor use, achieved blood pressure control (<140/90 mmHg), serum creatinine and urine albumin-to-creatinine ratios.
There were 662 participants in the cohort taking single-agent therapy for hypertension. Median C-reactive protein levels differed across participants: 0.40 mg/dL for those on diuretics, 0.34 mg/dL on calcium channel blockers, 0.25 mg/dL on beta blockers and 0.27 mg/dL on renin-angiotensin-aldosterone system inhibitors (p<0.001). With multivariable adjustment, the group on renin-angiotensin-aldosterone system inhibitors had a 20% lower mean CRP on average than the group on diuretics (p=0.044), differences between other medication classes were not apparent. Heart rate had a strong association with C-reactive protein (p < 0.001).
Antihypertensive medication class may influence inflammation, particularly in patients on RAAS inhibitors.
antihypertensive therapy; C-reactive protein; diuretics; inflammation; RAAS inhibitors; sibships
Many studies document racial variation, gender differences, and socioeconomic status (SES) patterning in cardiovascular disease (CVD) risk factors but few studies have investigated heterogeneity in SES differences by race/ethnicity or gender. Using data from the Multi-Ethnic Study of Atherosclerosis (N = 6,814) and stratified regression models, we investigated race/ethnic differences in the SES patterning of diabetes, hypertension, smoking, and body mass index (BMI). Inverse socioeconomic gradients in hypertension, diabetes, smoking, and BMI were observed in White and Black women but associations were weaker or absent in Hispanic and Chinese women (except in the case of diabetes for Hispanic women). Even greater heterogeneity in social patterning of risk factors was observed in men. In White men all four risk factors were inversely associated with socioeconomic position, although often associations were only present or were stronger for education than for income. The inverse socioeconomic patterning was much less consistent in men of other races/ethnic groups, and higher SES was associated with higher BMI in non-White men. These findings have implications for understanding the causes of social patterning, for the analysis of SES adjusted race/ethnic differences, and for the targeting of interventions.
Cardiovascular disease; risk factors; socioeconomic status; race; ethnicity
Studying the effects of medications on endpoints in an observational setting is an important yet challenging problem due to confounding by indication. The purpose of this study is to describe methodology for estimating such effects while including prevalent medication users. These techniques are illustrated in models relating statin use to cardiovascular disease (CVD) in a large multi-ethnic cohort study.
The Multi-Ethnic Study of Atherosclerosis (MESA) includes 6814 participants aged 45-84 years free of CVD. Confounding by indication was mitigated using a two step approach: First, the untreated values of cholesterol were treated as missing data and the values imputed as a function of the observed treated value, dose and type of medication, and participant characteristics. Second, we construct a propensity-score modeling the probability of medication initiation as a function of measured covariates and estimated pre-treatment cholesterol value. The effect of statins on CVD endpoints were assessed using weighted Cox proportional hazard models using inverse probability weights based on the propensity score.
Based on a meta-analysis of randomized controlled trials (RCT) statins are associated with a reduced risk of CVD (relative risk ratio = 0.73, 95% CI: 0.70, 0.77). In an unweighted Cox model adjusting for traditional risk factors we observed little association of statins with CVD (hazard ratio (HR) = 0.97, 95% CI: 0.60, 1.59). Using weights based on a propensity model for statins that did not include the estimated pre-treatment cholesterol we observed a slight protective association (HR = 0.92, 95% CI: 0.54-1.57). Results were similar using a new-user design where prevalent users of statins are excluded (HR = 0.91, 95% CI: 0.45-1.80). Using weights based on a propensity model with estimated pre-treatment cholesterol the effects of statins (HR = 0.74, 95% CI: 0.38, 1.42) were consistent with the RCT literature.
The imputation of pre-treated cholesterol levels for participants on medication at baseline in conjunction with a propensity score yielded estimates that were consistent with the RCT literature. These techniques could be useful in any example where inclusion of participants exposed at baseline in the analysis is desirable, and reasonable estimates of pre-exposure biomarker values can be estimated.
Multiple imputation; Confounding by indication; Propensity score; Inverse probability of treatment weights; Statins
Diabetes mellitus and hypertension commonly coexist, but the nature of this link is not well understood. The authors tested whether diabetes and higher concentrations of fasting serum glucose and insulin are associated with increased risk of developing incident hypertension in the community-based Multi-Ethnic Study of Atherosclerosis. At baseline, 3,513 participants were free of hypertension, defined as systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or use of antihypertensive medications to treat high blood pressure. Of these, 965 participants (27%) developed incident hypertension over 4.7 years’ median follow-up between 2002 and 2007. Compared with participants with normal baseline fasting glucose, those with impaired fasting glucose and diabetes had adjusted relative risks of hypertension of 1.16 (95% confidence interval (CI): 0.96, 1.40) and 1.41 (95% CI: 1.17, 1.71), respectively (P = 0.0015). The adjusted relative risk of incident hypertension was 1.08 (95% CI: 1.04, 1.13) for each mmol/L higher glucose (P < 0.0001) and 1.15 (95% CI: 1.05, 1.25) for each doubling of insulin (P = 0.0016). Further adjustment for serum cystatin C, urinary albumin/creatinine ratio, and arterial elasticity measured by tonometry substantially reduced the magnitudes of these associations. In conclusion, diabetes and higher concentrations of glucose and insulin may contribute to the development of hypertension, in part through kidney disease and arterial stiffness.
diabetes mellitus; glucose; hypertension; insulin; kidney; nephrology
Nonsteroidal anti-inflammatory drugs (NSAIDs) may disrupt control of blood pressure in hypertensive patients and increase their risk of morbidity, mortality, and the costs of care. The objective of this study was to examine the association between incident use of NSAIDs and blood pressure in patients with hypertension.
We conducted a retrospective cohort study of adult hypertensive patients to determine the effects of their first prescription for NSAID on systolic blood pressure and antihypertensive drug intensification. Data were collected from an electronic medical record serving an academic general medicine practice in Indianapolis, Indiana, USA. Using propensity scores to minimize bias, we matched a cohort of 1,340 users of NSAIDs with 1,340 users of acetaminophen. Propensity score models included covariates likely to affect blood pressure or the use of NSAIDs. The study outcomes were the mean systolic blood pressure measurement after starting NSAIDs and changes in antihypertensive therapy.
Compared to patients using acetaminophen, NSAID users had a 2 mmHg increase in systolic blood pressure (95% CI, 0.7 to 3.3). Ibuprofen was associated with a 3 mmHg increase in systolic blood pressure compared to naproxen (95% CI, 0.5 to 4.6), and a 5 mmHg increase compared to celecoxib (95% CI, 0.4 to 10). The systolic blood pressure increase was 3 mmHg in a subgroup of patients concomitantly prescribed angiotensin converting enzyme inhibitors or calcium channel blockers and 6 mmHg among those prescribed a beta-adrenergic blocker. Blood pressure changes in patients prescribed diuretics or multiple antihypertensives were not statistically significant.
Compared to acetaminophen, incident use of NSAIDs, particularly ibuprofen, is associated with a small increase in systolic blood pressure in hypertensive patients. Effects in patients prescribed diuretics or multiple antihypertensives are negligible.
NSAIDs; Hypertension; Blood pressure; Propensity score
Doxazosin and its role as an antihypertensive agent have come under recent scrutiny as a result of the early termination of that treatment arm in ALLHAT. It is unclear why the cardiovascular (CV) event rate in this randomized, controlled trial (RCT), especially heart failure, is higher in those treated with a doxazosin-based regimen than with a chlorthalidone based-regimen. There has been little work in the past to summarize information on peripheral alpha-1 antagonists that may be helpful in evaluating the results of this randomized controlled trial.
Using Medline and the Cochrane databases, we performed a comprehensive review of the literature on the use of peripheral alpha-1 antagonists as antihypertensive agents, focusing on available information that could explain the excess cardiovascular events observed in the Antihypertensive and Lipid-Lowering Treatment to prevent Heart Attack Trial (ALLHAT).
Minimal data were available concerning the effects of peripheral alpha-1 antagonists on CV endpoints. A multitude of short-term studies-ranging from small observational studies to short-term moderate-sized RCTs – focused on safety, efficacy, and tolerability, and some studies investigated the physiologic effects of these agents. These previously reported studies reveal associations with weight gain, fluid retention, and neurohormonal changes among various populations of those treated with peripheral alpha-1 antagonists.
These findings suggest several possible mechanisms by which doxazosin may be inferior to low-dose diuretics as antihypertensive therapy for the prevention of heart failure.
To assess the importance of the obesity epidemic on cardiovascular disease (CVD) risk, we determined the prevalence of obesity and the relationship of obesity to CVD risk factors and subclinical vascular disease.
The Multi-Ethnic Study of Atherosclerosis is an observational cohort study involving 6814 persons aged 45 to 84 years who were free of clinical CVD at baseline (2000–2002). The study assessed the association between body size and CVD risk factors, medication use, and subclinical vascular disease (coronary artery calcium, carotid artery intimal medial thickness, and left ventricular mass).
A large proportion of white, African American, and Hispanic participants were overweight (60% to 85%) and obese (30% to 50%), while fewer Chinese American participants were overweight (33%) or obese (5%). Hypertension and diabetes were more prevalent in obese participants despite a much higher use of antihy-pertensive and/or antidiabetic medications. Obesity was associated with a greater risk of coronary artery calcium (17%), internal carotid artery intimal medial thickness greater than 80th percentile (32%), common carotid artery intimal medial thickness greater than 80th percentile (45%), and left ventricular mass greater than 80th percentile (2.7-fold greater) compared with normal body size. These associations persisted after adjustment for traditional CVD risk factors.
These data confirm the epidemic of obesity in most but not all racial and ethnic groups. The observed low prevalence of obesity in Chinese American participants indicates that high rates of obesity should not be considered inevitable. These findings may be viewed as indicators of potential future increases in vascular disease burden and health care costs associated with the obesity epidemic.
Background. Tianma Gouteng Yin (TGY) is widely used for essential hypertension (EH) as adjunctive treatment. Many randomized clinical trials (RCTs) of TGY for EH have been published. However, it has not been evaluated to justify their clinical use and recommendation based on TCM zheng classification. Objectives. To assess the current clinical evidence of TGY as adjunctive treatment for EH with liver yang hyperactivity syndrome (LYHS) and liver-kidney yin deficiency syndrome (LKYDS). Search Strategy. 7 electronic databases were searched until November 20, 2012. Inclusion Criteria. RCTs testing TGY combined with antihypertensive drugs versus antihypertensive drugs were included. Data Extraction and Analyses. Study selection, data extraction, quality assessment, and data analyses were conducted according to the Cochrane standards. Results. 22 RCTs were included. Methodological quality was generally low. Except diuretics treatment group, blood pressure was improved in the other 5 subgroups; zheng was improved in angiotensin converting enzyme inhibitors (ACEIs), calcium channel blockers (CCBs), and “CCB + ACEI” treatment groups. The safety of TGY is still uncertain. Conclusions. No confirmed conclusion about the effectiveness and safety of TGY as adjunctive treatment for EH with LYHS and LKYDS could be made. More rigorous trials are needed to confirm the results.
The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is a randomized, double-blind, active-controlled trial designed to compare the rate of coronary heart disease events in high-risk hypertensive participants initially randomized to a diuretic (chlorthalidone) versus each of three alternative antihypertensive drugs: alpha-adrenergic blocker (doxazosin), ACE-inhibitor (lisinopril), and calcium-channel blocker (amlodipine). Combined cardiovascular disease risk was significantly increased in the doxazosin arm compared to the chlorthalidone arm (RR 1.25; 95% CI, 1.17–1.33; P < .001), with a doubling of heart failure (fatal, hospitalized, or non-hospitalized but treated) (RR 2.04; 95% CI, 1.79–2.32; P < .001). Questions about heart failure diagnostic criteria led to steps to validate these events further.
Methods and Results
Baseline characteristics (age, race, sex, blood pressure) did not differ significantly between treatment groups (P < .05) for participants with heart failure events. Post-event pharmacologic management was similar in both groups and generally conformed to accepted heart failure therapy. Central review of a small sample of cases showed high adherence to ALLHAT heart failure criteria. Of 105 participants with quantitative ejection fraction measurements provided, (67% by echocardiogram, 31% by catheterization), 29/46 (63%) from the chlorthalidone group and 41/59 (70%) from the doxazosin group were at or below 40%. Two-year heart failure case-fatalities (22% and 19% in the doxazosin and chlorthalidone groups, respectively) were as expected and did not differ significantly (RR 0.96; 95% CI, 0.67–1.38; P = 0.83).
Results of the validation process supported findings of increased heart failure in the ALLHAT doxazosin treatment arm compared to the chlorthalidone treatment arm.
heart failure; alpha-blocker; diuretic; clinical trial
Hypertension is a major risk factor for the development of stroke. It is well known that lowering blood pressure decreases the risk of stroke in people with moderate to severe hypertension. However, the specific effects of calcium channel blockers (CCBs) against stroke in patients with hypertension as compared to no treatment and other antihypertensive drug classes are not known.
Methods and Findings
This systematic review and meta-analysis of randomized controlled trials (RCTs) evaluated CCBs effect on stroke in patients with hypertension in studies of CCBs versus placebo, angiotensin-converting-enzyme inhibitors (ACEIs), β-adrenergic blockers, and diuretics. The PUBMED, MEDLINE, EMBASE, OVID, CNKI, MEDCH, and WANFANG databases were searched for trials published in English or Chinese during the period January 1, 1996 to July 31, 2012. A total of 177 reports were collected, among them 31 RCTs with 273,543 participants (including 130,466 experimental subjects and 143,077 controls) met the inclusion criteria. In these trials a total of 9,550 stroke events (4,145 in experimental group and 5,405 in control group) were reported. CCBs significantly decreased the incidence of stroke compared with placebo (OR = 0.68, 95% CI 0.61–0.75, p<1×10−5), β-adrenergic blockers combined with diuretics (OR = 0.89, 95% CI 0.83–0.95, p = 7×10−5) and β-adrenergic blockers (OR = 0.79, 95% CI 0.72–0.87, p<1×10−5), statistically significant difference was not found between CCBs and ACEIs (OR = 0.92, 95% CI 0.8–1.02, p = 0.12) or diuretics (OR = 0.95, 95% CI 0.84–1.07, p = 0.39).
In a pooled analysis of data of 31 RCTs measuring the effect of CCBs on stroke, CCBs reduced stroke more than placebo and β-adrenergic blockers, but were not different than ACEIs and diuretics. More head to head RCTs are warranted.