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1.  Impact of the ALLHAT/JNC7 Dissemination Project on Thiazide-type Diuretic Use 
Archives of internal medicine  2010;170(10):851-858.
Background
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).
Methods
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.
Results
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.
Conclusions
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.
doi:10.1001/archinternmed.2010.130
PMCID: PMC2989728  PMID: 20498411
2.  Antihypertensive Pharmacogenetic Effect of Fibrinogen-beta Variant -455 G>A on Cardiovascular Disease, End-Stage Renal Disease and Mortality: The GenHAT Study 
Pharmacogenetics and genomics  2009;19(6):415-421.
Objective
The FGB gene codes for fibrinogen-beta, a polypeptide of the coagulation factor fibrinogen, which is positively associated with cardiovascular diseases. Studies show ACE inhibitors lower plasma fibrinogen concentrations, whereas diuretics and calcium channel blockers do not. Since carriers of the FGB-455 minor “A” allele have higher levels of fibrinogen while ACE inhibitors lower it, we hypothesize that “A” allele carriers benefit more from antihypertensive treatment with ACE inhibitors than calcium channel blockers or diuretics, relative to “GG” genotype individuals.
Methods
The GenHAT study (ancillary to ALLHAT) genotyped hypertensive participants for several hypertension-related candidate genes, making this a post-hoc analysis of a randomized trial. In total, 90.1% of the ALLHAT population was successfully genotyped for FGB-455. We included participants (n=30,076) randomized to one of three antihypertensive medications (lisinopril, amlodipine, chlorthalidone), with two treatment comparisons: lisinopril versus chlorthalidone and lisinopril versus amlodipine. The primary outcome of ALLHAT/GenHAT was coronary heart disease, defined as fatal CHD or non-fatal MI, and secondary outcomes included stroke, heart failure, all-cause mortality and end-stage renal disease (ESRD) with mean follow-up time of 4.9 years. Genotype-by-treatment interactions (pharmacogenetic effects) were tested with Cox regression.
Results
Stroke: Common “GG” homozygotes had higher risk on lisinopril versus amlodipine (HR=1.38, p<0.001), while minor “A” allele carriers had slightly lower risk (HR=0.96, p=0.76; p-value for interaction=0.03). Mortality: “GG” homozygotes had higher risk on lisinopril versus amlodipine (HR=1.12, p=0.02) or chlorthalidone (1.05, p=0.23), while “A” allele carriers had slightly lower risk (HR=0.92, p=0.33 for lisinopril versus amlodipine, HR=0.88, p=0.08 for lisinopril versus chlorthalidone; p-value for interactions 0.04 and 0.03, respectively). ESRD: “GG” homozygotes had higher risk on lisinopril versus chlorthalidone (HR=1.27, p=0.08), while “A” allele carriers had lower risk (HR=0.64, p=0.12; p-value for interaction=0.03).
Conclusions
There was evidence of pharmacogenetic effects of FBG-455 on stroke, ESRD and mortality, suggesting that relative to those homozygous for the common allele, variant allele carriers of the FGB gene at position -455 have a better outcome if randomized to lisinopril than chlorthalidone (for mortality and ESRD) or amlodipine (for mortality and stroke). For the models in which a pharmacogenetic effect was observed, the outcome rates among “GG” homozygotes were higher in those randomized to lisinopril versus amlodipine or chlorthalidone, whereas minor “A” allele carriers had lower event rates when randomized to lisinopril versus the other medications.
doi:10.1097/FPC.0b013e32832a8e81
PMCID: PMC2764310  PMID: 19352213
FGB -455; fibrinogen gene; pharmacogenetics; hypertension; antihypertensive medication; cardiovascular disease
3.  The Effects of Mandatory Prescribing of Thiazides for Newly Treated, Uncomplicated Hypertension: Interrupted Time-Series Analysis 
PLoS Medicine  2007;4(7):e232.
Background
The purpose of our study was to evaluate the effects of a new reimbursement rule for antihypertensive medication that made thiazides mandatory first-line drugs for newly treated, uncomplicated hypertension. The objective of the new regulation was to reduce drug expenditures.
Methods and Findings
We conducted an interrupted time-series analysis on prescribing data before and after the new reimbursement rule for antihypertensive medication was put into effect. All patients started on antihypertensive medication in 61 general practices in Norway were included in the analysis. The new rule was put forward by the Ministry of Health and was approved by parliament. Adherence to the rule was monitored only minimally, and there were no penalties for non-adherence. Our primary outcome was the proportion of thiazide prescriptions among all prescriptions made for persons started on antihypertensive medication. Secondary outcomes included the proportion of patients who, within 4 mo, reached recommended blood-pressure goals and the proportion of patients who, within 4 mo, were not started on a second antihypertensive drug. We also compared drug costs before and after the intervention. During the baseline period, 10% of patients started on antihypertensive medication were given a thiazide prescription. This proportion rose steadily during the transition period, after which it remained stable at 25%. For other outcomes, no statistically significant differences were demonstrated. Achievement of treatment goals was slightly higher (56.6% versus 58.4%) after the new rule was introduced, and the prescribing of a second drug was slightly lower (24.0% versus 21.8%). Drug costs were reduced by an estimated Norwegian kroner 4.8 million (€0.58 million, US$0.72 million) in the first year, which is equivalent to Norwegian kroner 1.06 per inhabitant (€0.13, US$0.16).
Conclusions
Prescribing of thiazides in Norway for uncomplicated hypertension more than doubled after a reimbursement rule requiring the use of thiazides as the first-choice therapy was put into effect. However, the resulting savings on drug expenditures were modest. There were no significant changes in the achievement of treatment goals or in the prescribing of a second antihypertensive drug.
Atle Fretheim and colleagues found that the prescribing of thiazides in Norway for uncomplicated hypertension more than doubled after a rule requiring their use as first-choice therapy was put into effect.
Editors' Summary
Background.
High blood pressure (hypertension) is a common medical condition, especially among elderly people. It has no obvious symptoms but can lead to heart attacks, heart failure, strokes, or kidney failure. It is diagnosed by measuring blood pressure—the force that blood moving around the body exerts on the inside of arteries (large blood vessels). Many factors affect blood pressure (which depends on the amount of blood being pumped round the body and on the size and condition of the arteries), but overweight people and individuals who eat fatty or salty food are at high risk of developing hypertension. Mild hypertension can often be corrected by making lifestyle changes, but many patients also take one or more antihypertensive agents. These include thiazide diuretics and several types of non-thiazide drugs, many of which reduce heart rate or contractility and/or dilate blood vessels.
Why Was This Study Done?
Antihypertensive agents are a major part of national drug expenditure in developed countries, where as many as one person in ten is treated for hypertension. The different classes of drugs are all effective, but their cost varies widely. Thiazides, for example, are a tenth of the price of many non-thiazide drugs. In Norway, the low use of thiazides recently led the government to impose a new reimbursement rule aimed at reducing public expenditure on antihypertensive drugs. Since March 2004, family doctors have been reimbursed for drug costs only if they prescribe thiazides as first-line therapy for uncomplicated hypertension, unless there are medical reasons for selecting other drugs. Adherence to the rule has not been monitored, and there is no penalty for non-adherence, so has this intervention changed prescribing practices? To find out, the researchers in this study analyzed Norwegian prescribing data before and after the new rule came into effect.
What Did the Researchers Do and Find?
The researchers analyzed the monthly antihypertensive drug–prescribing records of 61 practices around Oslo, Norway, between January 2003 and November 2003 (pre-intervention period), between December 2003 and February 2004 (transition period), and between March 2004 and January 2005 (post-intervention period). This type of study is called an “interrupted time series”. During the pre-intervention period, one in ten patients starting antihypertensive medication was prescribed a thiazide drug. This proportion gradually increased during the transition period before stabilizing at one in four patients throughout the post-intervention period. A slightly higher proportion of patients reached their recommended blood-pressure goal after the rule was introduced than before, and a slightly lower proportion needed to switch to a second drug class, but both these small differences may have been due to chance. Finally, the researchers estimated that the observed change in prescribing practices reduced drug costs per Norwegian by US$0.16 (€0.13) in the first year.
What Do These Findings Mean?
Past attempts to change antihypertensive-prescribing practices by trying to influence family doctors (for example, through education) have largely failed. By contrast, these findings suggest that imposing a change on them (in this case, by introducing a new reimbursement rule) can be effective (at least over the short term and in the practices included in the study), even when compliance with the change is not monitored nor noncompliance penalized. However, despite a large shift towards prescribing thiazides, three-quarters of patients were still prescribed non-thiazide drugs (possibly because of doubts about the efficacy of thiazides as first-line drugs), which emphasizes how hard it is to change doctors' prescribing habits. Further studies are needed to investigate whether the approach examined in this study can effectively contain the costs of antihypertensive drugs (and of drugs used for other common medical conditions) in the long term and in other settings. Also, because the estimated reduction in drug costs produced by the intervention was relatively modest (although likely to increase over time as more patients start on thiazides), other ways to change prescribing practices and produce savings in national drug expenditures should be investigated.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040232.
MedlinePlus encyclopedia page on hypertension (in English and Spanish)
UK National Institute for Health and Clinical Excellence information on hypertension for patients, carers, and professionals
American Heart Association information for patients on high blood pressure
An open-access research article describing the potential savings of using thiazides as the first-choice antihypertensive drug
A previous study in Norway, published in PLoS Medicine, examined what happened when doctors were actively encouraged to make more use of thiazides. There was also an economic evaluation of what this achieved
doi:10.1371/journal.pmed.0040232
PMCID: PMC1904466  PMID: 17622192
4.  HEART FAILURE IN ALLHAT: DID BLOOD PRESSURE MEDICATION AT STUDY ENTRY INFLUENCE OUTCOME? 
Lower heart failure (HF) rates in individuals on chlorthalidone versus amlodipine, lisinopril, or doxazosin were unanticipated in ALLHAT. HF differences appeared early, leading to questions about the possible influence of pre-enrollment antihypertensive drugs. A post-hoc study evaluated hospitalized HF events. During year one, 479 individuals had HF, with pre-entry antihypertensive medication data obtained on 301 (63%). Case-only analysis examined interactive effects (interaction odds ratio [ratio of odds ratios]) of previous medication and ALLHAT treatment on HF outcomes, e.g., did treatment effect differ by pre-entry antihypertensive class? Among cases, 39%, 37%, 17%, and 47% were on pre-entry diuretics, ACE-inhibitors, beta-blockers, and calcium-channel-blockers, respectively. Interaction odds ratio for year one HF for amlodipine versus chlorthalidone for those on versus not on diuretics pre-entry was 1.08(95%CI,0.53-2.21,p=0.83); for lisinopril versus chlorthalidone, 1.33(95%CI,0.65-2.74,p=0.44); and for doxazosin versus chlorthalidone, 1.13(95%CI,0.57-2.25,p=0.73). Controlling for other pre-entry antihypertensives yielded similar results. There was no significant evidence that pre-entry drug type explained observed hospitalized HF differences by ALLHAT treatment.
doi:10.1111/j.1751-7176.2009.00149.x
PMCID: PMC2788785  PMID: 19751458
heart failure; hypertension; clinical trials; diuretics
5.  Baseline depressive symptoms are not associated with clinically important levels of incident hypertension during two years of follow-up: the Multi-Ethnic Study of Atherosclerosis 
Hypertension  2010;55(2):408.
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.
doi:10.1161/HYPERTENSIONAHA.109.139824
PMCID: PMC2821214  PMID: 20065156
Multi-Ethnic Study of Atherosclerosis; depression; hypertension; blood pressure; imputation; censored normal regression
6.  Does the aldosterone: renin ratio predict the efficacy of spironolactone over bendroflumethiazide in hypertension? A clinical trial protocol for RENALDO (RENin-ALDOsterone) study 
Background
High blood pressure is an important determinant of cardiovascular disease risk. Treated hypertensives do not attain a risk level equivalent to normotensives. This may be a consequence of suboptimal blood pressure control to which indiscriminate use of antihypertensive drugs may contribute. Indeed the recent ALLHAT[1]study suggests that thiazides should be given first to virtually all hypertensives. Whether this is correct or whether different antihypertensive therapies should be targeted towards different patients is a major unresolved issue, which we address in this study.
The measurement of the ratio of aldosterone: renin is used to identify hypertensive subjects who may respond well to treatment with the aldosterone antagonist spironolactone. It is not known if subjects with a high ratio have aldosteronism or aldosterone-sensitive hypertension is debated but it is important to know whether spironolactone is superior to other diuretics such as bendroflumethiazide in this setting.
Methods/design
The study is a double-blind, randomised, crossover, controlled trial that will randomise 120 hypertensive subjects to 12 weeks treatment with spironolactone 50 mg once daily and 12 weeks treatment with bendroflumethiazide 2.5 mg once daily. The 2 treatment periods are separated by a 2-week washout period. Randomisation is stratified by aldosterone: renin ratio to include equal numbers of subjects with high and low aldosterone: renin ratios.
Primary Objective – To test the hypothesis that the aldosterone: renin ratio predicts the antihypertensive response to spironolactone, specifically that the effect of spironolactone 50 mg is greater than that of bendroflumethiazide 2.5 mg in hypertensive subjects with high aldosterone: renin ratios.
Secondary Objectives – To determine whether bendroflumethiazide induces adverse metabolic abnormalities, especially in subjects with high aldosterone: renin ratios and if baseline renin measurement predicts the antihypertensive response to spironolactone and/or bendrofluazide
Discussion
The numerous deleterious effects of hypertension dictate the need for a systematic approach for its treatment. In spite of various therapies, resistant hypertension is widely prevalent. Among various factors, primary aldosteronism is an important cause of resistant hypertension and is now more commonly recognised. More significantly, hypertensives with primary aldosteronism are also exposed to various other deleterious effects of excess aldosterone. Hence treating hypertension with specific aldosterone antagonists may be a better approach in this group of patients. It may lead on to better blood pressures with fewer medications.
doi:10.1186/1471-2261-7-14
PMCID: PMC1877813  PMID: 17490489
7.  Patterns of Antihypertensive Therapy Among Patients with Diabetes 
Background
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.
Objective
To evaluate utilization patterns of antihypertensive agents and blood pressure (BP) control among diabetic patients with hypertension.
Design
Retrospective cohort study.
Patients/Participants
In all, 9,975 patients with diabetes and hypertension as of March 2001 from an outpatient medical center of the Department of Veterans Affairs.
Measures
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.
Results
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.
Conclusions
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.
doi:10.1111/j.1525-1497.2005.0170.x
PMCID: PMC1490215  PMID: 16117753
hypertension control; diabetes; multidrug regimens; prescribing patterns; evidence base
8.  Validation of Heart Failure Events in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Participants Assigned to Doxazosin and Chlorthalidone 
Background
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).
Conclusion
Results of the validation process supported findings of increased heart failure in the ALLHAT doxazosin treatment arm compared to the chlorthalidone treatment arm.
doi:10.1186/1468-6708-3-10
PMCID: PMC149403  PMID: 12459039
heart failure; alpha-blocker; diuretic; clinical trial
9.  ALLHAT FINDINGS REVISITED IN THE CONTEXT OF SUBSEQUENT ANALYSES, OTHER TRIALS AND META-ANALYSES 
Archives of internal medicine  2009;169(9):832-842.
Background:
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.
Methods:
Subgroup and explanatory analyses from a long-term 4-arm double-blind randomized antihypertensive treatment trial in diverse North American settings.
Results:
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).
Conclusions:
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.
doi:10.1001/archinternmed.2009.60
PMCID: PMC2803011  PMID: 19433694
10.  Comparative effects of non-steroidal anti-inflammatory drugs (NSAIDs) on blood pressure in patients with hypertension 
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1186/1471-2261-12-93
PMCID: PMC3502533  PMID: 23092442
NSAIDs; Hypertension; Blood pressure; Propensity score
11.  First-Line First? Trends in Thiazide Prescribing for Hypertensive Seniors 
PLoS Medicine  2005;2(4):e80.
Background
Evidence of reduced cardiovascular morbidity and mortality as well as cost support thiazide diuretics as the first-line choice for treatment of hypertension. The purpose of this study was to determine the proportion of senior hypertensives that received thiazide diuretics as first-line treatment, and to determine if cardiovascular and other potentially relevant comorbidities predict the choice of first-line therapy.
Methods and Findings
British Columbia PharmaCare data were used to determine the cohort of seniors (residents aged 65 or older) who received their first reimbursed hypertension drug during the period 1993 to 2000. These individual records were linked to medical and hospital claims data using the British Columbia Linked Health Database to find the subset that had diagnoses indicating the presence of hypertension as well as cardiovascular and other relevant comorbidities. Rates of first-line thiazide prescribing as proportion of all first-line treatment were analysed, accounting for patient age, sex, overall clinical complexity, and potentially relevant comorbidities. For the period 1993 to 2000, 82,824 seniors who had diagnoses of hypertension were identified as new users of hypertension drugs. The overall rate at which thiazides were used as first-line treatment varied from 38% among senior hypertensives without any potentially relevant comorbidity to 9% among hypertensives with previous acute myocardial infarction. The rate of first-line thiazide diuretic prescribing for patients with and without potentially relevant comorbidities increased over the study period. Women were more likely than men, and older patients were more likely than younger, to receive first-line thiazide therapy.
Conclusions
Findings indicate that first-line prescribing practices for hypertension are not consistent with the evidence from randomized control trials measuring morbidity and mortality. The health and financial cost of not selecting the most effective and least costly therapeutic options are significant.
Prescription practices for hypertension were not consistent with existing evidence--newer and more expensive drugs were prescribed preferentially despite evidence that thiazides are equally or more effective
doi:10.1371/journal.pmed.0020080
PMCID: PMC1087212  PMID: 15839739
12.  Using imputed pre-treatment cholesterol in a propensity score model to reduce confounding by indication: results from the multi-ethnic study of atherosclerosis 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1471-2288-13-81
PMCID: PMC3694006  PMID: 23800038
Multiple imputation; Confounding by indication; Propensity score; Inverse probability of treatment weights; Statins
13.  Clinical Outcomes by Race in Hypertensive Patients with and without the Metabolic Syndrome in ALLHAT 
Archives of internal medicine  2008;168(2):207-217.
Background
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).
Methods
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).
Results
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.
Conclusions
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.
doi:10.1001/archinternmed.2007.66
PMCID: PMC2805022  PMID: 18227370
14.  Heart Failure with Preserved and Reduced Left Ventricular Ejection Fraction in ALLHAT 
Circulation  2008;118(22):2259-2267.
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 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).
Conclusions
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.
doi:10.1161/CIRCULATIONAHA.107.762229
PMCID: PMC2775475  PMID: 19001024
antihypertensive therapy; hypertension, detection and control; diuretics; angiotensin-converting enzyme inhibitors; calcium channel blockers; heart failure; ejection fraction
15.  New-onset diabetes and antihypertensive treatment 
Introduction
Chronic diseases substantially contribute to the continuous increase in health care expenditures, including type-2 diabetes mellitus as one of the most expensive chronic diseases.
Arterial hypertension presents a risk factor for the development of type-2 diabetes mellitus.
Numerous analyses have demonstrated that antihypertensive therapies promote the development of type-2-diabetes mellitus. Studies indicate, that the application of angiotensin converting enzyme (ACE) inhibitors and angiotensin-receptor-blockers (ARB) lead to less new-onset diabetes compared to beta-blockers, diuretics and placebo. Given that beta-blockers and diuretics impair the glucose metabolism, the metabolic effects of different antihypertensive drugs should be regarded; otherwise not only the disease itself, but also antihypertensive therapies may promote the development of new-onset diabetes. Even though, the cost of ACE inhibitors and ARB are higher, the use in patients with metabolic disorders could be cost-effective in the long-term if new-onset diabetes is avoided.
Objectives
To evaluate which class of antihypertensive agents promote the development or the manifestation of type-2 diabetes mellitus. How high is the incidence of new-onset diabetes during antihypertensive therapy and how is treatment-induced type-2 diabetes mellitus evaluated clinically? Which agents are therefore cost-effective in the long term? Which ethical, social or legal aspects should be regarded?
Methods
A systematic literature review was conducted including clinical trials with at least ten participants which reported new-onset diabetes in the course of antihypertensive treatment. The trials had to be published after 1966 (after 2003 for economic publications) in English or German.
Results
A total of 34 clinical publications meet the inclusion criteria. Of these, eight publications focus on the development of diabetes mellitus under treatment with diuretic and/or beta-blockers, six publications focused on ACE inhibitors alone or in combination with calcium-channel-blockers, ten publications on ARB and/or ACE inhibitors with respect to their effects on new-onset diabetes or their preventive aspects. Furthermore, five publications investigate the role of calcium-channel-antagonists in the development of diabetes, and five publications indicate the development of new-onset diabetes with different antihypertensive agents amongst each other or in comparison to no antihypertensive treatment. The clinical trials show a significant difference in the development of new-onset diabetes. Therapies with diuretics and/or beta-blockers result in a higher incidence of new-onset diabetes. ARB as well as ACE inhibitors have a preventive effect and calcium-channel-blockers show a neutral position regarding the development of new-onset diabetes.
Two publications report on economic results. The first one evaluates the cost-effectiveness of ARB alone or in combination with calcium-channel-blockers in comparison to diuretics alone or in combination with beta-blockers. The second publication compares economic outcomes of calcium-channel-blockers and beta-blockers considering the development of new-onset diabetes. Treatment with the ARB candesartan lead to savings in total costs of 549 US-Dollar per patient and in incremental costs of 30,000 US-Dollar per diabetes mellitus avoided. In the second publication, costs to the amount of 18,965 Euro in Great Britain and 13,210 Euro in Sweden are quoted for an avoided event. The treatment with calcium-channel-blockers compared to beta-blockers is proven to be more cost-effective.
No publications were identified regarding ethical, social and legal aspects.
Discussion
The available meta-analyses allow for a high clinical evidence level. A few studies vary in terms of diabetes definition and study duration. In most of the trials, the incidence of new-onset diabetes is not an endpoint. The evaluation of treatment-induced diabetes mellitus cannot be conducted, due to the lack of sufficient results in the identified literature. The two economic studies do not address all the objectives sufficiently. Ethical, social and legal aspects are discussed but not analysed systematically.
Conclusion
Based on these studies, sufficient evidence to confirm the presumption that diuretics and/or beta-blockers promote the development of new-onset diabetes compared to other antihypertensive agents, especially in patients who are predisposed, is presented with this report. Trials reflecting the clinical relevance of treatment-induced diabetes mellitus compared to existing diabetes mellitus regarding cardiovascular outcomes are required. Also health economic evaluations considering the development of new-onset diabetes should be conducted for the different classes of antihypertensive agents.
doi:10.3205/hta000081
PMCID: PMC3010880  PMID: 21289876
diabetes mellitus, type 2; hypertension; Angiotensin-converting enzyme inhibitors; Angiotensin II type receptor blockers; calcium channel blockers; diuretics
16.  Adverse effect profile of trichlormethiazide: a retrospective observational study 
Background
Trichlormethiazide, a thiazide diuretic, was introduced in 1960 and remains one of the most frequently used diuretics for treating hypertension in Japan. While numerous clinical trials have indicated important side effects of thiazides, e.g., adverse effects on electrolytes and uric acid, very few data exist on serum electrolyte levels in patients with trichlormethiazide treatment. We performed a retrospective cohort study to assess the adverse effects of trichlormethiazide, focusing on serum electrolyte and uric acid levels.
Methods
We used data from the Clinical Data Warehouse of Nihon University School of Medicine obtained between Nov 1, 2004 and July 31, 2010, to identify cohorts of new trichlormethiazide users (n = 99 for 1 mg, n = 61 for 2 mg daily dosage) and an equal number of non-users (control). We used propensity-score matching to adjust for differences between users and control for each dosage, and compared serum chemical data including serum sodium, potassium, uric acid, creatinine and urea nitrogen. The mean exposure of trichlormethiazide of 1 mg and 2 mg users was 58 days and 64 days, respectively.
Results
The mean age was 66 years, and 55% of trichlormethiazide users of the 1 mg dose were female. In trichlormethiazide users of the 2 mg dose, the mean age was 68 years, and 43% of users were female. There were no statistically significant differences in all covariates (age, sex, comorbid diseases, past drugs, and current antihypertensive drugs) between trichlormethiazide users and controls for both doses. In trichlormethiazide users of the 2 mg dose, the reduction of serum potassium level and the elevation of serum uric acid level were significant compared with control, whereas changes of mean serum sodium, creatinine and urea nitrogen levels were not significant. In trichlormethiazide users of the 1 mg dose, all tests showed no statistically significant change from baseline to during the exposure period in comparison with control.
Conclusions
Our study showed adverse effects of decreased serum potassium and increased serum uric acid with trichlormethiazide treatment, and suggested that a lower dose of trichlormethiazide may minimize these adverse effects. These findings support the current trend in hypertension therapeutics to shift towards lower doses of thiazides.
doi:10.1186/1475-2840-10-45
PMCID: PMC3118327  PMID: 21605415
17.  Diuretic Use, Increased Serum Urate and the Risk of Incident Gout in a Population-based Study of Hypertensive Adults: the Atherosclerosis Risk in the Communities Cohort 
Arthritis and Rheumatism  2012;64(1):121-129.
Objective
To quantify the role of diuretic use on gout development in an adult population with hypertension.
Methods
ARIC, a prospective population-based cohort from 4 US communities, consists of 4 visits over a 9-year period. Participants were included in this analysis if they answered the gout query, were free of gout at baseline, and had hypertension (medication to treat hypertension or a blood pressure ≥ 140/90 mmHg). Trained interviewers recorded antihypertensive use. Incident gout was defined as self-reported onset after baseline. Using a time-dependent Cox Proportional Hazards model, we estimated the hazard rate ratio (HR) of incident gout by time-varying diuretic use, adjusted for confounders, and tested for mediation by serum urate level.
Results
There were 5,789 hypertensive participants; 37% were treated with a diuretic. Use of any diuretic (HR=1.48, 95% CI: 1.11, 1.98), thiazide diuretic (HR=1.44, 95% CI: 1.00, 2.10), and loop diuretic (HR=2.31, 95% CI: 1.36, 3.91) was associated with incident gout compared with not using any diuretic, thiazide diuretic or loop diuretics, respectively. After adjusting for serum urate, the association between diuretic use and gout was null. Use of antihypertensive medication other than diuretic agents was associated with decreased gout risk (adjusted HR=0.64 95% CI: 0.49, 0.86) compared to untreated hypertension. The longitudinal change in serum urate was 0.72 mg/dL (95% CI: 0.57, 0.87) higher in those who initiated a diuretic compared with those who did not (p-value<0.001).
Conclusions
Thiazide and loop diuretics were associated with increased gout risk, an association mediated by a change in serum urate.
doi:10.1002/art.33315
PMCID: PMC3253199  PMID: 22031222
gout; hypertension; diuretics; uric acid
18.  A Retrospective Longitudinal Cohort Study of Antihypertensive Drug Use and New-Onset Diabetes in Taiwanese Patients 
BioMed Research International  2012;2013:287696.
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.
doi:10.1155/2013/287696
PMCID: PMC3591187  PMID: 23509704
19.  Drug management for hypertension in type 2 diabetes in family practice 
Canadian Family Physician  2009;55(7):728-734.
ABSTRACT
OBJECTIVE
To describe the number and classes of antihypertensive medications prescribed to patients with type 2 diabetes in community family practices, and to estimate the aggressiveness or “dosage intensity” of prescribing for hypertension in these situations.
DESIGN
Practice-based, cross-sectional observational study.
SETTING
Seventeen rural and urban family practices in the Maritime Family Practice Research Network in Nova Scotia, New Brunswick, and Prince Edward Island.
PARTICIPANTS
A total of 670 patients with type 2 diabetes, ranging from 25 to 92 years of age.
MAIN OUTCOME MEASURES
Number, classes, and combinations of classes of antihypertensive medications prescribed, as well as an index of each medication’s dosage intensity.
RESULTS
Almost 80% of patients studied had hypertension. Participants with hypertension were taking an average of 2.5 medications, and 47.6% were taking 3 or more antihypertensive medications, but only 27.1% reached target blood pressure values of less than 130/80 mm Hg. Older patients took more antihypertensive medications, but there were no differences by sex. More than 90% were taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, 66% were taking diuretics, 41% were taking β-blockers, and 38% were taking calcium channel blockers. We cannot describe the sequence in which antihypertensive medication classes were added, but analysis of patients taking multiple drug classes suggests that most patients were started on angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, followed by diuretics, β-blockers, or calcium channel blockers. The most commonly used medications were prescribed at higher than two-thirds the maximum dose effective for hypertension.
CONCLUSION
Hypertension is very common among family practice patients with type 2 diabetes; of those patients, few reach target blood pressures. Practice-based strategies to increase dosing and number of medications prescribed might be required.
PMCID: PMC2718608  PMID: 19602663
20.  Primary prevention of CVD: treating hypertension 
Clinical Evidence  2010;2010:0214.
Introduction
Hypertension (persistent diastolic blood pressure of 90 mm Hg or greater and systolic blood pressure 140 mm Hg or greater) affects 20% of the world's adult population, and increases the risk of cardiovascular disease, end-stage renal disease, and retinopathy.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of different antihypertensive drugs for people with hypertension? What are the effects of dietary modification for people with hypertension? We searched: Medline, Embase, The Cochrane Library, and other important databases up to December 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 21 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: a low-salt diet, antihypertensive drugs, calcium supplements, fish oil supplements, magnesium supplements, and potassium supplements.
Key Points
Hypertension (persistent diastolic blood pressure of 90 mm Hg or greater and systolic blood pressure 140 mm Hg or greater) affects 20% of the world's adult population, and increases the risk of cardiovascular disease, end-stage renal disease, and retinopathy. Risk factors for hypertension include age, sex, race/ethnicity, genetic predisposition, diet, physical inactivity, obesity, and psychological and social characteristics.
No antihypertensive drug has been found to be more effective than the others at reducing all-cause mortality, cardiovascular mortality, or MI. Apparent differences in outcomes with different antihypertensive drugs may be due to different levels of blood pressure reduction.Diuretics may be more effective than ACE inhibitors, calcium channel blockers, and alpha-blockers at reducing heart failure.Beta-blockers may be as effective as diuretics at reducing stroke, but calcium channel blockers may be even more effective than beta-blockers or diuretics.ACE inhibitors may be more effective than calcium channel blockers for prevention of coronary heart disease.Choice of second-line antihypertensive agent should be based on other co-morbidities and likely adverse effects as we don't know which is the most likely to reduce cardiovascular events.
We found no RCT evidence assessing whether dietary modification reduces morbidity or mortality from hypertension compared with a normal diet. Advice to reduce dietary intake of salt to below 50 mmoles daily and fish oil supplementation may reduce systolic blood pressure by approximately 1 to 5 mm Hg and reduce diastolic blood pressure by 1 to 3 mm Hg in people with hypertension.We do not know whether supplementation with potassium, magnesium, or calcium is effective in reducing blood pressure.Potassium supplementation should not be used in people with kidney failure, or in people taking drugs that can increase potassium levels.Combinations of potassium plus calcium, potassium plus magnesium, and calcium plus magnesium may be no more effective than no supplementation in reducing blood pressure.
PMCID: PMC2907625  PMID: 21733198
21.  A Review of the Adverse Effects of Peripheral Alpha-1 Antagonists in Hypertension Therapy 
Background
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.
Methods
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).
Results
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.
Conclusion
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.
doi:10.1186/1468-6708-3-7
PMCID: PMC134479  PMID: 12097149
22.  Antihypertensive Medication Classes Used among Medicare Beneficiaries Initiating Treatment in 2007–2010 
PLoS ONE  2014;9(8):e105888.
Background
After the 2003 publication of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines, there was a 5–10% increase in patients initiating antihypertensive medication with a thiazide-type diuretic, but most patients still did not initiate treatment with this class. There are few contemporary published data on antihypertensive medication classes filled by patients initiating treatment.
Methods and Findings
We used the 5% random Medicare sample to study the initiation of antihypertensive medication between 2007 and 2010. Initiation was defined by the first antihypertensive medication fill preceded by 365 days with no antihypertensive medication fills. We restricted our analysis to beneficiaries ≥65 years who had two or more outpatient visits with a hypertension diagnosis and full Medicare fee-for-service coverage for the 365 days prior to initiation of antihypertensive medication. Between 2007 and 2010, 32,142 beneficiaries in the 5% Medicare sample initiated antihypertensive medication. Initiation with a thiazide-type diuretic decreased from 19.2% in 2007 to 17.9% in 2010. No other changes in medication classes initiated occurred over this period. Among those initiating antihypertensive medication in 2010, 31.3% filled angiotensin-converting enzyme inhibitors (ACE-Is), 26.9% filled beta blockers, 17.2% filled calcium channel blockers, and 14.4% filled angiotensin receptor blockers (ARBs). Initiation with >1 antihypertensive medication class decreased from 25.6% in 2007 to 24.1% in 2010. Patients initiated >1 antihypertensive medication class most commonly with a thiazide-type diuretic and either an ACE-I or ARB.
Conclusion
These results suggest that JNC 7 had a limited long-term impact on the choice of antihypertensive medication class and provide baseline data prior to the publication of the 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults from the Panel Members Appointed to the Eighth Joint National Committee (JNC 8).
doi:10.1371/journal.pone.0105888
PMCID: PMC4143342  PMID: 25153199
23.  Demographic, medical, and behavioral characteristics associated with over the counter non-steroidal anti-inflammatory drug use in a population based cohort: results from the Multi-Ethnic Study of Atherosclerosis 
Background
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.
Objective
To evaluate characteristics of OTC versus prescription NSAID users
Methods
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.
Results
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).
Conclusions
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.
doi:10.1002/pds.2065
PMCID: PMC3014611  PMID: 21182156
Aspirin; over the counter drug use; ethnicity; Multi-Ethnic Study of Atherosclerosis
24.  Myocardial infarction and stroke associated with diuretic based two drug antihypertensive regimens: population based case-control study 
Objective To examine the association of myocardial infarction and stroke incidence with several commonly used two drug antihypertensive treatment regimens.
Design Population based case-control study.
Setting Group Health Cooperative, Seattle, WA, USA.
Participants Cases (n=353) were aged 30-79 years, had pharmacologically treated hypertension, and were diagnosed with a first fatal or non-fatal myocardial infarction or stroke between 1989 and 2005. Controls (n=952) were a random sample of Group Health members who had pharmacologically treated hypertension. We excluded individuals with heart failure, evidence of coronary heart disease, diabetes, or chronic kidney disease.
Exposures One of three common two drug combinations: diuretics plus β blockers; diuretics plus calcium channel blockers; and diuretics plus angiotensin converting enzyme inhibitors or angiotensin receptor blockers.
Main outcome measures Myocardial infarction or stroke.
Results Compared with users of diuretics plus β blockers, users of diuretics plus calcium channel blockers had an increased risk of myocardial infarction (adjusted odds ratio (OR) 1.98, 95% confidence interval 1.37 to 2.87) but not of stroke (OR 1.02, 95% CI 0.63 to 1.64). The risks of myocardial infarction and stroke in users of diuretics plus angiotensin converting enzyme inhibitors or angiotensin receptor blockers were slightly but not significantly lower than in users of diuretics plus β blockers (myocardial infarction: OR 0.76, 95% CI 0.52 to 1.11; stroke: OR 0.71, 95% CI 0.46 to 1.10).
Conclusions In patients with hypertension, diuretics plus calcium channel blockers were associated with a higher risk of myocardial infarction than other common two drug treatment regimens. A large trial of second line antihypertensive treatments in patients already on low dose diuretics is required to provide a solid basis for treatment recommendations.
doi:10.1136/bmj.c103
PMCID: PMC2811239  PMID: 20100777
25.  Artist® Tablets (Carvedilol) for Hypertensive Patients in Japan 
Drugs in R&d  2012;11(2):171-190.
Background: In Japan, when pharmaceutical companies launch a new drug, they are obligated to conduct a post-marketing survey to evaluate the safety and efficacy of the drug in accordance with Good Post-Marketing Surveillance Practice under Article 14.4 (re-examination) of the Pharmaceutical Affairs Law at contracted medical institutions. We report the results of a drug use survey, which we conducted as a post-marketing survey.
Objective: This prospective post-marketing drug use survey was conducted to assess the safety and efficacy of the β-adrenergic receptor antagonist (β-blocker) Artist® Tablets (carvedilol) in patients with hypertension in Japan.
Patients: Patients were carvedilol-naive and had essential hypertension or renal parenchymal hypertension.
Methods: This was a prospective survey conducted over 3 years from October 1993 to September 1996. The standard observation period for the patients was defined as 12 weeks of treatment with carvedilol.
Results: We collected data on 4961 patients at 561 medical institutions who had not been previously treated with carvedilol; 4574 patients were included in the safety analysis and 4422 in the efficacy analysis. The incidence of adverse drug reactions (the proportion of patients with adverse drug reactions) was 4.31% (197 of 4574 patients), which is less than that shown in the pre-approval clinical trial of carvedilol (6.85%[68 of 993]). The most common adverse drug reactions were bradycardia, dizziness, hypotension, headache, and feeling light-headed.
After 12 weeks’ treatment with carvedilol, systolic/diastolic blood pressure (SBP/DBP) was reduced from 168.2 ± 18.6/95.7 ± 11.3mmHg at baseline to 144.3 ± 17.3/83.4 ± 10.8mmHg. Patients were classified according to which antihypertensive drug they had been using when carvedilol treatment was initiated. Coadministered agents were calcium channel blockers (CCBs), angiotensinconverting enzyme inhibitors (ACEIs), diuretics, and a-adrenergic receptor antagonists (α-blockers). At 12 weeks, the change in SBP/DBP in the monotherapy group was −22.7/−12.2mmHg and that of each combination therapy subgroup, CCB, ACEI, diuretic, and b-blocker, was −26.1/−12.7mmHg, −25.4/−11.9mmHg, −26.3/−13.0mmHg, and −24.4/−11.5mmHg, respectively. The achievement rates for target BP (<140/90mmHg) were 29.5% in the monotherapy group, 34.8% in the CCB group, 31.3% in the ACEI group, 31.8% in the diuretic group, and 32.4% in the β-blocker group. There was no significant difference in the achievement of target BP among the four combination therapy subgroups (p = 0.475). These results indicate that carvedilol exerts reasonable BP reduction regardless of whether it is used as monotherapy or in combination therapy, and that the effect is not influenced by the coadministered drug. Moreover, carvedilol was also effective in reducing BP levels in elderly patients (≥65 years) and in patients with diabetes mellitus or renal diseases.
Conclusions: The results of this study reflect the results of clinical trials up to the time of approval and it was confirmed that carvedilol is a highly useful drug in the treatment of hypertension.
doi:10.2165/11592450-000000000-00000
PMCID: PMC3586121  PMID: 21679007

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