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1.  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
2.  Comparative effectiveness of antihypertensive medication for primary prevention of cardiovascular disease: systematic review and multiple treatments meta-analysis 
BMC Medicine  2012;10:33.
Background
We conducted a systematic review of evidence from randomized controlled trials to answer the following research question: What are the relative effects of different classes of antihypertensive drugs in reducing the incidence of cardiovascular disease outcomes for healthy people at risk of cardiovascular disease?
Methods
We searched MEDLINE, EMBASE, AMED (up to February 2011) and CENTRAL (up to May 2009), and reference lists in recent systematic reviews. Titles and abstracts were assessed for relevance and those potentially fulfilling our inclusion criteria were then assessed in full text. Two reviewers made independent assessments at each step. We selected the following main outcomes: total mortality, myocardial infarction and stroke. We also report on angina, heart failure and incidence of diabetes. We conducted a multiple treatments meta-analysis using random-effects models. We assessed the quality of the evidence using the GRADE-instrument.
Results
We included 25 trials. Overall, the results were mixed, with few significant dif-ferences, and with no drug-class standing out as superior across multiple outcomes. The only significant finding for total mortality based on moderate to high quality evidence was that beta-blockers (atenolol) were inferior to angiotensin receptor blockers (ARB) (relative risk (RR) 1.14; 95% credibility interval (CrI) 1.02 to 1.28). Angiotensin converting enzyme (ACE)-inhibitors came out inferior to calcium-channel blockers (CCB) regarding stroke-risk (RR 1.19; 1.03 to 1.38), but superior regarding risk of heart failure (RR 0.82; 0.69 to 0.94), both based on moderate quality evidence. Diuretics reduced the risk of myocardial infarction compared to beta-blockers (RR 0.82; 0.68 to 0.98), and lowered the risk of heart failure compared to CCB (RR 0.73; 0.62 to 0.84), beta-blockers (RR 0.73; 0.54 to 0.96), and alpha-blockers (RR 0.51; 0.40 to 0.64). The risk of diabetes increased with diuretics compared to ACE-inhibitors (RR 1.43; 1.12 to 1.83) and CCB (RR 1.27; 1.05 to 1.57).
Conclusion
Based on the available evidence, there seems to be little or no difference between commonly used blood pressure lowering medications for primary prevention of cardiovascular disease. Beta-blockers (atenolol) and alpha-blockers may not be first-choice drugs as they were the only drug-classes that were not significantly superior to any other, for any outcomes.
Review registration: CRD database ("PROSPERO") CRD42011001066
doi:10.1186/1741-7015-10-33
PMCID: PMC3354999  PMID: 22480336
3.  The 2010 Canadian Hypertension Education Program recommendations for the management of hypertension: Part 2 – therapy 
OBJECTIVE:
To update the evidence-based recommendations for the prevention and treatment of hypertension in adults for 2010.
OPTIONS AND OUTCOMES:
For lifestyle and pharmacological interventions, randomized trials and systematic reviews of trials were preferentially reviewed. Changes in cardiovascular morbidity and mortality were the primary outcomes of interest. However, for lifestyle interventions, blood pressure lowering was accepted as a primary outcome given the general lack of long-term morbidity and mortality data in this field. Progressive renal impairment was also accepted as a clinically relevant primary outcome among patients with chronic kidney disease.
EVIDENCE:
A Cochrane Collaboration librarian conducted an independent MEDLINE search from 2008 to August 2009 to update the 2009 recommendations. To identify additional studies, reference lists were reviewed and experts were contacted. All relevant articles were reviewed and appraised independently by both content and methodological experts using prespecified levels of evidence.
RECOMMENDATIONS:
For lifestyle modifications to prevent and treat hypertension, restrict dietary sodium to 1500 mg (65 mmol) per day in adults 50 years of age or younger, to 1300 mg (57 mmol) per day in adults 51 to 70 years of age, and to 1200 mg (52 mmol) per day in adults older than 70 years of age; perform 30 min to 60 min of moderate aerobic exercise four to seven days per week; maintain a healthy body weight (body mass index 18.5 kg/m2 to 24.9 kg/m2) and waist circumference (less than 102 cm for men and less than 88 cm for women); limit alcohol consumption to no more than 14 standard drinks per week for men or nine standard drinks per week for women; follow a diet that emphasizes fruits, vegetables and low-fat dairy products, dietary and soluble fibre, whole grains and protein from plant sources, and that is low in saturated fat and cholesterol; and consider stress management in selected individuals with hypertension.
For the pharmacological management of hypertension, treatment thresholds and targets should be predicated on the patient’s global atherosclerotic risk, target organ damage and comorbid conditions. Blood pressure should be decreased to less than 140/90 mmHg in all patients, and to less than 130/80 mmHg in patients with diabetes mellitus or chronic kidney disease. Most patients will require more than one agent to achieve these target blood pressures. Antihypertensive therapy should be considered in all adult patients regardless of age (caution should be exercised in elderly patients who are frail). For adults without compelling indications for other agents, considerations for initial therapy should include thiazide diuretics, angiotensin-converting enzyme (ACE) inhibitors (in patients who are not black), long-acting calcium channel blockers (CCBs), angiotensin receptor blockers (ARBs) or beta-blockers (in those younger than 60 years of age). A combination of two first-line agents may also be considered as initial treatment of hypertension if systolic blood pressure is 20 mmHg above target or if diastolic blood pressure is 10 mmHg above target. The combination of ACE inhibitors and ARBs should not be used, unless compelling indications are present to suggest consideration of dual therapy.
Agents appropriate for first-line therapy for isolated systolic hypertension include thiazide diuretics, long-acting dihydropyridine CCBs or ARBs. In patients with coronary artery disease, ACE inhibitors, ARBs or beta-blockers are recommended as first-line therapy; in patients with cerebrovascular disease, an ACE inhibitor/diuretic combination is preferred; in patients with proteinuric nondiabetic chronic kidney disease, ACE inhibitors or ARBs (if intolerant to ACE inhibitors) are recommended; and in patients with diabetes mellitus, ACE inhibitors or ARBs (or, in patients without albuminuria, thiazides or dihydropyridine CCBs) are appropriate first-line therapies. In selected high-risk patients in whom combination therapy is being considered, an ACE inhibitor plus a long-acting dihydropyridine CCB is preferable to an ACE inhibitor plus a thiazide diuretic. All hypertensive patients with dyslipidemia should be treated using the thresholds, targets and agents outlined in the Canadian lipid treatment guidelines. Selected patients with hypertension who do not achieve thresholds for statin therapy, but who are otherwise at high risk for cardiovascular events, should nonetheless receive statin therapy. Once blood pressure is controlled, low-dose acetylsalicylic acid therapy should be considered.
VALIDATION:
All recommendations were graded according to the strength of the evidence and voted on by the 63 members of the Canadian Hypertension Education Program Evidence-Based Recommendations Task Force. All recommendations reported here achieved at least 80% consensus. These guidelines will continue to be updated annually.
SPONSORS:
The Canadian Hypertension Education Program process is sponsored by the Canadian Hypertension Society, Blood Pressure Canada, the Public Health Agency of Canada, the College of Family Physicians of Canada, the Canadian Pharmacists Association, the Canadian Council of Cardiovascular Nurses, and the Heart and Stroke Foundation of Canada.
PMCID: PMC2886555  PMID: 20485689
Antihypertensive drugs; Blood pressure; Guidelines; High blood pressure; Hypertension; Lifestyle interventions
4.  Hypertension as a Risk Factor: Is It Different in Ischemic Stroke and Acute Myocardial Infarction Comparative Cross-Sectional Study? 
Objective. To assess differences in age of onset, hypertension duration, type of drug, treatment compliance, and salt-free diet compliance between patients with stroke and myocardial infarction. Patients and Methods. The study was conducted in 3 hospitals in Baghdad between June 2010 and June 2011. First group includes 81 stroke patients (36 females and 45 males), age ranges between (33–82 years). Second group includes 110 myocardial infarction patients (46 females and 64 males), ages ranges from (23–76 years). Results. Salt-free diet noncompliance was seen in 69% and 62% of Myocardial infarction and stroke groups, respectively. Silent hypertension was seen in 6.3% and 19.7% of myocardial infarction and stroke groups, respectively. Noncompliant on antihypertensive therapy was seen in 61%, 71%, and 48% of the total, myocardial infarction, and stroke groups, respectively. The drug type was 24% angiotensin converting enzyme inhibitor, 18.8% combined drugs, 16.2% Beta Blocker, 11% angiotensin 11 receptor blocker, 10.4% calcium channel blocker and 7.3% diuretic. In stroke group, the commonest drug was 23% angiotensin converting inhibitor and the least (5%) was angiotensin receptor blocker. In myocardial infarction group, the commonest drug was 25% Angiotensin Converting Inhibitor and the least (8%) was diuretic. Discussion and Conclusion. Silent hypertension was high in Iraq. Salt-free diet noncompliance was high in both groups; drug noncompliance was significantly higher in patients with myocardial infarction. Angiotensin 11 receptor blocker use was associated significantly with myocardial infarction more than in stroke.
doi:10.4061/2011/701029
PMCID: PMC3199046  PMID: 22028953
5.  Antihypertensive treatment with ACE inhibitors or beta-blockers and risk of incident atrial fibrillation in a general hypertensive population 
American journal of hypertension  2009;22(5):538-544.
Background
Secondary analyses of clinical trial data suggest that, compared with other agents, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) are associated with lower risk of incident atrial fibrillation (AF) in patients with heart failure, but data from the hypertension trials have been inconsistent. Information is scant about the association of beta-blocker use with AF risk in hypertensive patients without heart failure.
Methods
We conducted a population-based case-control study to determine whether antihypertensive treatment with ACE inhibitors/ARBs or beta-blockers, compared with diuretics, was associated with the risk of incident AF in a community practice setting. All patients (810 AF cases, 1,512 control subjects) were members of Group Health, an integrated health-care delivery system, were pharmacologically treated for hypertension, and did not have heart failure. Medical records were reviewed to confirm the diagnosis of incident AF and to collect information on medical conditions and health behaviors. Information on antihypertensive medications was obtained from a pharmacy database.
Results
Single-drug users of an ACE inhibitor/ARB had a lower risk of incident AF compared with single-drug users of a diuretic (adjusted odds ratio [OR] 0.63, 95% confidence interval [CI] 0.44–0.91). Single-drug use of beta-blockers was not significantly associated with lower AF risk (OR 1.05, 95% CI 0.73–1.52), and none of the most commonly-used two-drug regimens was significantly associated with AF risk, compared with single-drug use of diuretic.
Conclusion
In a general hypertensive population without heart failure, single-drug use of ACE inhibitors/ARBs was associated with lower AF risk.
doi:10.1038/ajh.2009.33
PMCID: PMC2672972  PMID: 19265792
6.  The 2009 Canadian Hypertension Education Program recommendations for the management of hypertension: Part 2 – therapy 
OBJECTIVE:
To update the evidence-based recommendations for the prevention and management of hypertension in adults for 2009.
OPTIONS AND OUTCOMES:
For lifestyle and pharmacological interventions, evidence from randomized controlled trials and systematic reviews of trials was preferentially reviewed. Changes in cardiovascular morbidity and mortality were the primary outcomes of interest. However, for lifestyle interventions, blood pressure lowering was accepted as a primary outcome given the lack of long-term morbidity and mortality data in this field. Progression of kidney dysfunction was also accepted as a clinically relevant primary outcome among patients with chronic kidney disease.
EVIDENCE:
A Cochrane collaboration librarian conducted an independent MEDLINE search from 2007 to August 2008 to update the 2008 recommendations. To identify additional published studies, reference lists were reviewed and experts were contacted. All relevant articles were reviewed and appraised independently by both content and methodological experts using prespecified levels of evidence.
RECOMMENDATIONS:
For lifestyle modifications to prevent and treat hypertension, restrict dietary sodium to less than 2300 mg (100 mmol)/day (and 1500 mg to 2300 mg [65 mmol to 100 mmol]/day in hypertensive patients); perform 30 min to 60 min of aerobic exercise four to seven days per week; maintain a healthy body weight (body mass index 18.5 kg/m2 to 24.9 kg/m2) and waist circumference (smaller than 102 cm for men and smaller than 88 cm for women); limit alcohol consumption to no more than 14 units per week in men or nine units per week in women; follow a diet that is reduced in saturated fat and cholesterol, and that emphasizes fruits, vegetables and low-fat dairy products, dietary and soluble fibre, whole grains and protein from plant sources; and consider stress management in selected individuals with hypertension. For the pharmacological management of hypertension, treatment thresholds and targets should be predicated on by the patient’s global atherosclerotic risk, target organ damage and comorbid conditions. Blood pressure should be decreased to lower than 140/90 mmHg in all patients, and to lower than 130/80 mmHg in those with diabetes mellitus or chronic kidney disease. Most patients will require more than one agent to achieve these target blood pressures. Antihypertensive therapy should be considered in all adult patients regardless of age (caution should be exercised in elderly patients who are frail). For adults without compelling indications for other agents, initial therapy should include thiazide diuretics. Other agents appropriate for first-line therapy for diastolic and/or systolic hypertension include angiotensin-converting enzyme (ACE) inhibitors (in patients who are not black), long-acting calcium channel blockers (CCBs), angiotensin receptor antagonists (ARBs) or beta-blockers (in those younger than 60 years of age). A combination of two first-line agents may also be considered as the initial treatment of hypertension if the systolic blood pressure is 20 mmHg above the target or if the diastolic blood pressure is 10 mmHg above the target. The combination of ACE inhibitors and ARBs should not be used. Other agents appropriate for first-line therapy for isolated systolic hypertension include long-acting dihydropyridine CCBs or ARBs. In patients with angina, recent myocardial infarction or heart failure, beta-blockers and ACE inhibitors are recommended as first-line therapy; in patients with cerebrovascular disease, an ACE inhibitor/diuretic combination is preferred; in patients with proteinuric nondiabetic chronic kidney disease, ACE inhibitors or ARBs (if intolerant to ACE inhibitors) are recommended; and in patients with diabetes mellitus, ACE inhibitors or ARBs (or, in patients without albuminuria, thiazides or dihydropyridine CCBs) are appropriate first-line therapies. All hypertensive patients with dyslipidemia should be treated using the thresholds, targets and agents outlined in the Canadian Cardiovascular Society position statement (recommendations for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease). Selected high-risk patients with hypertension who do not achieve thresholds for statin therapy according to the position paper should nonetheless receive statin therapy. Once blood pressure is controlled, acetylsalicylic acid therapy should be considered.
VALIDATION:
All recommendations were graded according to strength of the evidence and voted on by the 57 members of the Canadian Hypertension Education Program Evidence-Based Recommendations Task Force. All recommendations reported here achieved at least 95% consensus. These guidelines will continue to be updated annually.
PMCID: PMC2707169  PMID: 19417859
Antihypertensive drugs; Blood pressure; Guidelines; High blood pressure; Hypertension; Lifestyle interventions
7.  The 2007 Canadian Hypertension Education Program recommendations for the management of hypertension: Part 2 – therapy 
OBJECTIVE:
To provide updated, evidence-based recommendations for the prevention and management of hypertension in adults.
OPTIONS AND OUTCOMES:
For lifestyle and pharmacological interventions, evidence was reviewed from randomized controlled trials and systematic reviews of trials. Changes in cardiovascular morbidity and mortality were the primary outcomes of interest. However, for lifestyle interventions, blood pressure lowering was accepted as a primary outcome given the lack of long-term morbidity and mortality data in this field. For treatment of patients with kidney disease, the progression of kidney dysfunction was also accepted as a clinically relevant primary outcome.
EVIDENCE:
A Cochrane collaboration librarian conducted an independent MEDLINE search from 2005 to August 2006 to update the 2006 Canadian Hypertension Education Program recommendations. In addition, reference lists were scanned and experts were contacted to identify additional published studies. All relevant articles were reviewed and appraised independently by both content and methodological experts using prespecified levels of evidence.
RECOMMENDATIONS:
Dietary lifestyle modifications for prevention of hypertension, in addition to a well-balanced diet, include a dietary sodium intake of less than 100 mmol/day. In hypertensive patients, the dietary sodium intake should be limited to 65 mmol/day to 100 mmol/day. Other lifestyle modifications for both normotensive and hypertensive patients include: performing 30 min to 60 min of aerobic exercise four to seven days per week; maintaining a healthy body weight (body mass index of 18.5 kg/m2 to 24.9 kg/m2) and waist circumference (less than 102 cm in men and less than 88 cm in women); limiting alcohol consumption to no more than 14 units per week in men or nine units per week in women; following a diet reduced in saturated fat and cholesterol, and one that emphasizes fruits, vegetables and low-fat dairy products, dietary and soluble fibre, whole grains and protein from plant sources; and considering stress management in selected individuals with hypertension.
For the pharmacological management of hypertension, treatment thresholds and targets should take into account each individual’s global atherosclerotic risk, target organ damage and any comorbid conditions: blood pressure should be lowered to lower than 140/90 mmHg in all patients and lower than 130/80 mmHg in those with diabetes mellitus or chronic kidney disease. Most patients require more than one agent to achieve these blood pressure targets. In adults without compelling indications for other agents, initial therapy should include thiazide diuretics; other agents appropriate for first-line therapy for diastolic and/or systolic hypertension include angiotensin-converting enzyme (ACE) inhibitors (except in black patients), long-acting calcium channel blockers (CCBs), angiotensin receptor blockers (ARBs) or beta-blockers (in those younger than 60 years of age). First-line therapy for isolated systolic hypertension includes long-acting dihydropyridine CCBs or ARBs. Certain comorbid conditions provide compelling indications for first-line use of other agents: in patients with angina, recent myocardial infarction, or heart failure, beta-blockers and ACE inhibitors are recommended as first-line therapy; in patients with cerebrovascular disease, an ACE inhibitor plus diuretic combination is preferred; in patients with nondiabetic chronic kidney disease, ACE inhibitors are recommended; and in patients with diabetes mellitus, ACE inhibitors or ARBs (or, in patients without albuminuria, thiazides or dihydropyridine CCBs) are appropriate first-line therapies. All hypertensive patients with dyslipidemia should be treated using the thresholds, targets and agents outlined in the Canadian Cardiovascular Society position statement (recommendations for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease). Selected high-risk patients with hypertension who do not achieve thresholds for statin therapy according to the position paper should nonetheless receive statin therapy. Once blood pressure is controlled, acetylsalicylic acid therapy should be considered.
VALIDATION:
All recommendations were graded according to strength of the evidence and voted on by the 57 members of the Canadian Hypertension Education Program Evidence-Based Recommendations Task Force. All recommendations reported here achieved at least 95% consensus. These guidelines will continue to be updated annually.
PMCID: PMC2650757  PMID: 17534460
Antihypertensive drugs; Blood pressure; Guidelines; High blood pressure; Hypertension; Lifestyle interventions
8.  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
9.  Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies 
Objectives To determine the quantitative efficacy of different classes of blood pressure lowering drugs in preventing coronary heart disease (CHD) and stroke, and who should receive treatment.
Design Meta-analysis.
Data source Medline (1966-2007).
Study selection Randomised trials of blood pressure lowering drugs recording CHD events and strokes. 108 trials studied differences in blood pressure between study drug and placebo (or control group not receiving the study drug) (“blood pressure difference trials”), and 46 trials compared drugs (“drug comparison trials”). Seven trials with three randomised groups fell into both categories. The results were interpreted in the context of those expected from the largest published meta-analysis of cohort studies, totalling 958 000 people.
Participants 464 000 people defined into three mutually exclusive categories: participants with no history of vascular disease, a history of CHD, or a history of stroke.
Results In the blood pressure difference trials β blockers had a special effect over and above that due to blood pressure reduction in preventing recurrent CHD events in people with a history of CHD: risk reduction 29% (95% confidence interval 22% to 34%) compared with 15% (11% to 19%) in trials of other drugs. The extra effect was limited to a few years after myocardial infarction, with a risk reduction of 31% compared with 13% in people with CHD with no recent infarct (P=0.04). In the other blood pressure difference trials (excluding CHD events in trials of β blockers in people with CHD), there was a 22% reduction in CHD events (17% to 27%) and a 41% (33% to 48%) reduction in stroke for a blood pressure reduction of 10 mm Hg systolic or 5 mm Hg diastolic, similar to the reductions of 25% (CHD) and 36% (stroke) expected for the same difference in blood pressure from the cohort study meta-analysis, indicating that the benefit is explained by blood pressure reduction itself. The five main classes of blood pressure lowering drugs (thiazides, β blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers) were similarly effective (within a few percentage points) in preventing CHD events and strokes, with the exception that calcium channel blockers had a greater preventive effect on stroke (relative risk 0.92, 95% confidence interval 0.85 to 0.98). The percentage reductions in CHD events and stroke were similar in people with and without cardiovascular disease and regardless of blood pressure before treatment (down to 110 mm Hg systolic and 70 mm Hg diastolic). Combining our results with those from two other studies (the meta-analyses of blood pressure cohort studies and of trials determining the blood pressure lowering effects of drugs according to dose) showed that in people aged 60-69 with a diastolic blood pressure before treatment of 90 mm Hg, three drugs at half standard dose in combination reduced the risk of CHD by an estimated 46% and of stroke by 62%; one drug at standard dose had about half this effect. The present meta-analysis also showed that drugs other than calcium channel blockers (with the exception of non-cardioselective β blockers) reduced the incidence of heart failure by 24% (19% to 28%) and calcium channel blockers by 19% (6% to 31%).
Conclusions With the exception of the extra protective effect of β blockers given shortly after a myocardial infarction and the minor additional effect of calcium channel blockers in preventing stroke, all the classes of blood pressure lowering drugs have a similar effect in reducing CHD events and stroke for a given reduction in blood pressure so excluding material pleiotropic effects. The proportional reduction in cardiovascular disease events was the same or similar regardless of pretreatment blood pressure and the presence or absence of existing cardiovascular disease. Guidelines on the use of blood pressure lowering drugs can be simplified so that drugs are offered to people with all levels of blood pressure. Our results indicate the importance of lowering blood pressure in everyone over a certain age, rather than measuring it in everyone and treating it in some.
doi:10.1136/bmj.b1665
PMCID: PMC2684577  PMID: 19454737
10.  The value of lowering blood pressure 
According to the Canadian Heart Health Survey, only 14% of Canadian hypertensive patients are aware of their disease and are treated appropriately. One of the reasons for this could be that physicians are confused by an excess of confusing and contradictory information regarding the choice of drugs. Two recent publications may contribute to a much-needed simplification of the problem. The Blood Pressure Lowering Treatment Trialists’ Collaboration published a meta-analysis based on 29 randomized trials that comprised a total of more that 162,000 participants. The treatment regimens were based on angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, diuretics, beta-blockers and calcium channel blockers. The main finding of the meta-analysis was that treatment with any of the blood pressure-lowering regimens reduced the risk of major cardiovascular events, and the extent of these risk reductions was directly related to the degree of blood pressure lowering.
The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) compared valsartan with amlodipine. At the end of the study, the reductions in blood pressure from baseline were 17.3/9.9 mmHg in the amlodipine group and 15.2/8.2 mmHg in the valsartan group (P<0.0001). There was a significantly lower incidence of myocardial infarction in the amlodipine group (4.1%) than in the valsartan group (4.8%). From these two studies, it would be reasonable to conclude that the treatment of elevated blood pressure has two main goals: to achieve a normal blood pressure and to produce a happy patient. The agent or agents used to obtain these goals are relatively unimportant.
PMCID: PMC2538980  PMID: 16450020
Coronary artery disease; Hypertension; Stroke
11.  Mortality and morbidity during and after ALLHAT: Results by gender 
Hypertension  2013;61(5):977-986.
To determine whether an angiotensin-converting enzyme inhibitor (lisinopril) or calcium channel blocker (amlodipine) is superior to a diuretic (chlorthalidone) in reducing cardiovascular disease incidence in gender subgroups, we carried out a prespecified subgroup analysis of 15,638 female and 17,719 male participants in the Antihypertensive and Lipid-Lowering to Prevent Heart Attack Trial (ALLHAT). Total follow-up (active treatment + passive surveillance using national administrative databases to ascertain deaths and hospitalizations) was 8 to 13 years. The primary outcome was fatal coronary heart disease or nonfatal myocardial infarction. Secondary outcomes included all-cause mortality, stroke, combined cardiovascular disease (coronary heart disease death, nonfatal myocardial infarction, stroke, angina, coronary revascularization, heart failure, or peripheral vascular disease), and end-stage renal disease. In-trial rates of heart failure, stroke, and combined cardiovascular disease were significantly higher for lisinopril compared to chlorthalidone, and rates of heart failure were significantly higher for amlodipine compared to chlorthalidone in both men and women. There were no significant treatment gender interactions. These findings did not persist through the extension period with the exception of the heart failure result for amlodipine versus chlorthalidone, which did not differ significantly by gender. For both women and men, rates were not lower in the amlodipine or lisinopril groups than in the chlorthalidone group for either the primary coronary heart disease outcome or any other cardiovascular disease outcome, and chlorthalidone-based treatment resulted in the lowest risk of heart failure. Neither lisinopril nor amlodipine is superior to chlorthalidone for initial treatment of hypertension in either women or men.
doi:10.1161/HYPERTENSIONAHA.111.00213
PMCID: PMC4114223  PMID: 23529173
hypertension; gender; diuretic; calcium channel blocker; ACE inhibitor
12.  Combinations of olmesartan and a calcium channel blocker or a diuretic in elderly hypertensive patients: a randomized, controlled trial1 
Journal of Hypertension  2014;32(10):2054-2063.
Objective:
The aim of the present study was to compare the cardiovascular effects of olmesartan, an angiotensin II receptor blocker, combined with a calcium channel blocker (CCB) or a diuretic, in a prospective, randomized, open-label, blinded endpoint trial.
Methods:
Japanese hypertensive patients aged at least 65 to less than 85 years with SBP at least 140 mmHg and/or DBP at least 90 mmHg with antihypertensive treatment, or SBP at least 160 mmHg and/or DBP at least 100 mmHg without antihypertensive treatment were randomized to receive olmesartan with either a dihydropyridine CCB or a low-dose diuretic. If SBP and/or DBP remained at least 140 and/or at least 90 mmHg, the other antihypertensive drug was added. The primary endpoint was a composite of fatal and nonfatal cardiovascular events. The median follow-up time was 3.3 years.
Results:
Blood pressure decreased similarly in both groups. The primary endpoint occurred in 116/2568 patients (4.5%) in the olmesartan plus CCB group and in 135/2573 patients (5.3%) in the olmesartan plus diuretic group [hazard ratio 0.83, 95% confidence interval (CI) 0.65–1.07, P = 0.16]. Rates of all-cause death and cardiovascular deaths were similar. Among patients aged at least 75 years, the incidence of stroke tended to be lower in the olmesartan plus CCB group than in the olmesartan plus diuretic group (hazard ratio 0.63, 95% CI 0.38–1.02, P = 0.059, interaction P = 0.019). Fewer patients in the olmesartan plus CCB group (8.2%, 211/2568) than in the olmesartan plus diuretic group (9.8%, 253/2573; P = 0.046) experienced serious adverse events.
Conclusion:
Despite no significant difference in cardiovascular events, the different safety profiles suggest that the combination of olmesartan and CCB may be preferable to that of olmesartan and diuretic.
doi:10.1097/HJH.0000000000000281
PMCID: PMC4166009  PMID: 24999799
blood pressure; calcium channel blockers; diuretics; hypertension; olmesartan; randomized controlled trial
13.  Failure of Evidence-based Medicine in the Treatment of Hypertension in Older Patients 
OBJECTIVE
Throughout the 1990s, the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure recommended initial antihypertensive therapy with a thiazide diuretic or a β-blocker based on evidence from randomized, controlled trials, unless an indication existed for another drug class. The committee also recommended β-blockers in hypertensive patients with a history of myocardial infarction (MI), and angiotensin-converting enzyme (ACE) inhibitors in patients with congestive heart failure (CHF). Our objective was to determine whether prescribing practices for older hypertensive patients are consistent with evidence-based guidelines.
METHODS
We examined prescription patterns from January 1, 1991 through December 31, 1995 for 23,748 patients 65 years or older with a new diagnosis of hypertension from the New Jersey Medicaid program and that state's Pharmacy Assistance for the Aged and Disabled program (PAAD). We linked drug use data with information on demographic variables and comorbid medical conditions.
RESULTS
During the study period, calcium channel blockers were the most commonly prescribed initial therapy for hypertension (41%), followed by ACE inhibitors (24%), thiazide diuretics (17%), and β-blockers (10%). Eliminating patients with diabetes mellitus, CHF, angina, or history of MI did not substantially affect these results. Overall, initial use of a thiazide declined from 22% in 1991 to 10% in 1995, while initial use of a calcium channel blocker increased from 28% to 43%, despite publication during these years of studies demonstrating a benefit of thiazides in older patients. Only 15% of older hypertensive patients with a history of MI received β-blockers.
CONCLUSIONS
Prescribing practices for older hypertensive patients are not consistent with evidence-based guidelines. Interventions are needed to encourage evidence-driven prescribing practices for the treatment of hypertension.
doi:10.1046/j.1525-1497.2000.91020.x
PMCID: PMC1495604  PMID: 11089713
hypertension; evidence-based medicine; older patients
14.  Increase in blood glucose concentration during antihypertensive treatment as a predictor of myocardial infarction: population based cohort study 
BMJ : British Medical Journal  2003;326(7391):681.
Objective
To investigate the impact of an increase in blood glucose on the risk of developing myocardial infarction, with particular emphasis on people taking antihypertensive drugs.
Design
Prospective population based cohort study.
Setting
Uppsala, Sweden.
Participants
1860 men who had participated in 1970-3 at age 50 in a health survey aimed at identifying risk factors for cardiovascular disease and were re-examined at age 60 and then followed for 17.4 years.
Main outcome measure
Myocardial infarction after age 60.
Results
The incidence of myocardial infarction was significantly higher in men treated for hypertension than in those without such treatment (23% v 13.5%, P<0.0001). Participants who developed myocardial infarction after the age of 60 (n=253) showed a significantly larger increase in blood glucose between age 50 and 60 than did those without myocardial infarction. In multivariate Cox proportional hazard models increase in blood glucose was an independent risk factor for myocardial infarction (P=0.0001) in men receiving antihypertensive treatment at age 60 (n=291, mainly β blockers and thiazide diuretics) but not in those without such treatment. The impact of increase in blood glucose declined after inclusion of serum proinsulin concentrations at baseline but was still significant. A significant interaction existed between proinsulin concentration (a marker of insulin resistance) at baseline and antihypertensive treatment on increase in blood glucose.
Conclusions
Increase in blood glucose between the ages of 50 and 60 and baseline proinsulin concentration were important risk factors for myocardial infarction in men receiving antihypertensive treatment, indicating that both an insulin resistant state and the metabolic impact of β blockers and diuretics increase the risk of myocardial infarction.
What is already known on this topicPatients with hypertension are resistant to insulin stimulated glucose uptake and are hyperinsulinaemic compared with normotensive controlsTreatment with β blockers and thiazide diuretics further increases insulin resistance, thereby increasing the risk of developing type 2 diabetes mellitus or impaired glucose toleranceThe influence of metabolic changes induced by antihypertensive treatment on the risk of myocardial infarction has been questionedWhat this study addsMen who received antihypertensive treatment showed a larger increase in blood glucose during a 10 year period than those without such treatmentIncrease in blood glucose during antihypertensive treatment was a significant, independent risk factor for myocardial infarction in men with an insulin resistant state at baseline
PMCID: PMC152364  PMID: 12663403
15.  Diabetes: treating hypertension 
BMJ Clinical Evidence  2009;2009:0608.
Introduction
Among people with diabetes, around 40% of those aged 45 years, and more than 60% of those aged 75 years and over, will have a blood pressure greater than 140/90 mmHg. Major cardiac events occur in approximately 5% of people with diabetes and untreated hypertension each year, and the risk is higher in those with other risk factors, such as diabetic nephropathy.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of antihypertensives in people with diabetes and hypertension? What are the effects of different blood pressure targets in people with diabetes and hypertension? We searched: Medline, Embase, The Cochrane Library, and other important databases up to February 2009 (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 22 systematic reviews, RCTs, or observational studies that met our inclusion criteria.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: alpha-blockers; angiotensin II receptor antagonists; angiotensin-converting enzyme (ACE) inhibitors; beta-blockers; blood pressure targets (lower or higher); calcium-channel blockers; and diuretics.
Key Points
Among people with diabetes, around 40% of those aged 45 years, and more than 60% of those aged 75 years and over, will have a blood pressure greater than 140/90 mmHg. Major cardiac events occur in approximately 5% of people with diabetes and untreated hypertension each year, and the risk is higher in those with other risk factors, such as diabetic nephropathy.
We cannot be sure how different treatments compare in people with diabetes and hypertension. However, evidence suggests that either angiotensin-converting enzyme (ACE) inhibitors or diuretics are effective first-line treatments. ACE inhibitors reduce the risks of renal disease compared with placebo, and they seem to reduce cardiovascular events compared with calcium-channel blockers. However, they can cause cough and angio-oedema. Diuretics, such as chlorthalidone, reduce cardiovascular events compared with placebo, but they may increase glucose, cholesterol, and uric acid levels.Diuretics seem as effective as ACE inhibitors at preventing cardiovascular events, and they may be more effective than calcium-channel blockers at reducing the risk of heart failure. Beta-blockers may be as effective as ACE inhibitors at reducing onset of renal disease and other diabetes-related cardiovascular and microvascular events, or diabetes-related death. However, they may cause weight gain and increase the need for glucose-lowering treatment. Calcium-channel blockers seem as effective as diuretics, more effective than beta-blockers, and less effective than ACE inhibitors at reducing cardiovascular events overall, and amlodipine may be less effective at preventing heart failure compared with chlorthalidone. Angiotensin II receptor antagonists may reduce cardiovascular mortality, and seem to be associated with a lower rate of hypokalaemia compared with beta-blockers in people with diabetes, hypertension, and LVH. We don't know whether alpha-blockers reduce cardiovascular events in people with diabetes and hypertension.
It seems likely that more intensive treatment to achieve a greater reduction in blood pressure leads to a greater reduction in cardiovascular events and overall mortality. However, it is difficult to specify a target blood pressure in people with diabetes and hypertension.
PMCID: PMC2907833  PMID: 21726474
16.  Diabetes: treating hypertension 
Clinical Evidence  2012;2012:0608.
Introduction
Among people with diabetes, about 40% of those aged 45 years, and more than 60% of those aged 75 years or over, will have a blood pressure over 140/90 mmHg. Major cardiac events occur in approximately 5% of people with diabetes and untreated hypertension each year, and the risk is higher in those with other risk factors, such as diabetic nephropathy.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of antihypertensives in people with diabetes and hypertension? What are the effects of different blood pressure targets in people with diabetes and hypertension? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2011 (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 24 systematic reviews, RCTs, or observational studies that met our inclusion criteria.
Conclusions
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: alpha-blockers, angiotensin II receptor antagonists, angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, blood pressure targets (lower or higher), calcium-channel blockers, and diuretics.
Key Points
Among people with diabetes, about 40% of those aged 45 years, and >60% of those aged 75 years or over, will have a blood pressure >140/90 mmHg. Major cardiac events occur in approximately 5% of people with diabetes and untreated hypertension each year, and the risk is higher in those with other risk factors, such as diabetic nephropathy.
We cannot be sure how different treatments compare in people with diabetes and hypertension. However, evidence suggests that either angiotensin-converting enzyme (ACE) inhibitors or diuretics are effective first-line treatments.
ACE inhibitors reduce the risks of renal disease compared with placebo, and they seem to reduce cardiovascular events compared with calcium-channel blockers. However, they can cause cough and angio-oedema.
Diuretics, such as chlortalidone, reduce cardiovascular events compared with placebo, but they may increase glucose, cholesterol, and uric acid levels. Diuretics seem as effective as ACE inhibitors at preventing cardiovascular events, and they may be more effective than calcium-channel blockers at reducing the risk of heart failure.
Beta-blockers may be as effective as ACE inhibitors at reducing onset of renal disease and other diabetes-related cardiovascular and microvascular events, or diabetes-related death. However, they may cause weight gain and increase the need for glucose-lowering treatment.
Calcium-channel blockers seem as effective as diuretics, more effective than beta-blockers, and less effective than ACE inhibitors at reducing cardiovascular events overall, and amlodipine may be less effective at preventing heart failure compared with chlortalidone.
We found conflicting evidence on long-term outcomes with angiotensin II receptor antagonists (ARBs).
We don't know whether alpha-blockers reduce cardiovascular events in people with diabetes and hypertension.
It seems likely that more intensive treatment to achieve a greater reduction in blood pressure leads to a greater reduction in cardiovascular events and overall mortality. However, it is difficult to specify a target blood pressure in people with diabetes and hypertension.
PMCID: PMC3314422  PMID: 22456232
17.  The 2008 Canadian Hypertension Education Program recommendations for the management of hypertension: Part 2 – therapy 
OBJECTIVE:
To update the evidence-based recommendations for the prevention and management of hypertension in adults.
OPTIONS AND OUTCOMES:
For lifestyle and pharmacological interventions, evidence was preferentially reviewed from randomized controlled trials and systematic reviews of trials. Changes in cardiovascular morbidity and mortality were the primary outcomes of interest. However, for lifestyle interventions, blood pressure lowering was accepted as a primary outcome given the lack of long-term morbidity and mortality data in this field. Progression of kidney dysfunction was also accepted as a clinically relevant primary outcome among patients with chronic kidney disease.
EVIDENCE:
A Cochrane collaboration librarian conducted an independent MEDLINE search from 2006 to August 2007 to update the 2007 recommendations. To identify additional published studies, reference lists were reviewed and experts were contacted. All relevant articles were reviewed and appraised independently by content and methodological experts using prespecified levels of evidence.
RECOMMENDATIONS:
For lifestyle modifications to prevent and treat hypertension, restrict dietary sodium intake to less than 100 mmol/day (and 65 mmol/day to 100 mmol/day in hypertensive patients); perform 30 min to 60 min of aerobic exercise four to seven days per week; maintain a healthy body weight (body mass index 18.5 kg/m2 to 24.9 kg/m2) and waist circumference (smaller than 102 cm for men and smaller than 88 cm for women); limit alcohol consumption to no more than 14 units per week in men or nine units per week in women; follow a diet that is reduced in saturated fat and cholesterol, and one that emphasizes fruits, vegetables and low-fat dairy products, dietary and soluble fibre, whole grains and protein from plant sources; and consider stress management in selected individuals with hypertension. For the pharmacological management of hypertension, treatment thresholds and targets should be predicated on by the patient’s global atherosclerotic risk, target organ damage and comorbid conditions. Blood pressure should be decreased to lower than 140/90 mmHg in all patients, and to lower than 130/80 mmHg in those with diabetes mellitus or chronic kidney disease. Most patients will require more than one agent to achieve these target blood pressures. For adults without compelling indications for other agents, initial therapy should include thiazide diuretics. Other agents appropriate for first-line therapy for diastolic and/or systolic hypertension include angiotensin-converting enzyme (ACE) inhibitors (in nonblack patients), long-acting calcium channel blockers (CCBs), angiotensin receptor antagonists (ARBs) or beta-blockers (in those younger than 60 years of age). A combination of two first-line agents may also be considered for initial treatment of hypertension if systolic blood pressure is 20 mmHg above target or if diastolic blood pressure is 10 mmHg above target. Other agents appropriate for first-line therapy for isolated systolic hypertension include long-acting dihydropyridine CCBs or ARBs. In patients with angina, recent myocardial infarction or heart failure, beta-blockers and ACE inhibitors are recommended as first-line therapy; in patients with cerebrovascular disease, an ACE inhibitor/diuretic combination is preferred; in patients with protein-uric nondiabetic chronic kidney disease, ACE inhibitors are recommended; and in patients with diabetes mellitus, ACE inhibitors or ARBs (or, in patients without albuminuria, thiazides or dihydropyridine CCBs) are appropriate first-line therapies. All hypertensive patients with dyslipidemia should be treated using the thresholds, targets and agents outlined in the Canadian Cardiovascular Society position statement (recommendations for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease). Selected high-risk patients with hypertension but who do not achieve thresholds for statin therapy according to the position paper should nonetheless receive statin therapy. Once blood pressure is controlled, acetylsalicylic acid therapy should be considered.
VALIDATION:
All recommendations were graded according to strength of the evidence and voted on by the 57 members of the Canadian Hypertension Education Program Evidence-Based Recommendations Task Force. All recommendations reported here achieved at least 95% consensus. These guidelines will continue to be updated annually.
PMCID: PMC2643190  PMID: 18548143
Antihypertensive drugs; Blood pressure; Guidelines; High blood pressure; Hypertension; Lifestyle interventions
18.  Choices, persistence and adherence to antihypertensive agents: Evidence from RAMQ data 
BACKGROUND:
Most treatment recommendations for hypertension are based on criteria that consider efficacy, safety and cost. Given the need for long-term use of antihypertensive agents, treatment compliance should also be taken into consideration in the selection process.
OBJECTIVE:
The purpose of the present study was to estimate persistence and adherence to antihypertensive agents in a real-life setting.
METHODS:
Persistence and adherence to treatment were estimated using data from the Regie de l’assurance maladie du Quebec.
RESULTS:
Data from a random sample of 4561 subjects with a diagnosis of hypertension covered by the Regie de l’assurance maladie du Quebec drug plan and using one of the antihypertensive agents reimbursed by the drug plan for the first time between January 2000 and December 2001 were analyzed. The persistence rate observed after a two-year period with diuretics was significantly lower (52.8%) than with any other classes of antihyperten-sive agent (P<0.01). Persistence rates for beta-blockers, calcium channel blockers, angiotensin-II receptor blockers and angiotensin-I converting enzyme inhibitors were 69.3%, 64.3%, 60.9% and 58.9%, respectively. After two years, the proportion of patients who were 80% adherent to their treatment was 64.9% for angiotensin-I converting enzyme inhibitors, 65.0% for angiotensin-II receptor blockers, 64.2% for calcium channel blockers, 60.3% for beta-blockers and 50.9% for diuretics. The proportion of patients who were 80% adherent to their treatment was significantly lower for diuretics than with any other antihypertensive agents (P<0.01).
CONCLUSION:
Persistence and adherence to treatment are essential to treatment success. Results of the present study indicate that, in a real-life setting, patients are significantly less compliant to diuretics than to any other antihypertensive agents.
PMCID: PMC2644030  PMID: 18401466
Compliance; Hypertension; Population health
19.  Antihypertensive drug treatment changes in the general population: the colaus study 
Background
Changes in antihypertensive drug treatment are paramount in the adequate management of patients with hypertension, still, there is little information regarding changes in antihypertensive drug treatment in Switzerland. Our aim was to assess those changes and associated factors in a population-based, prospective study.
Methods
Data from the population-based, CoLaus study, conducted among subjects initially aged 35–75 years and living in Lausanne, Switzerland. 772 hypertensive subjects (371 women) were followed for a median of 5.4 years. Data Subjects were defined as continuers (no change), switchers (one antihypertensive class replaced by another), combiners (one antihypertensive class added) and discontinuers (stopped treatment). The distribution and the factors associated with changes in antihypertensive drug treatment were assessed.
Results
During the study period, the prescription of diuretics decreased and of ARBs increased: at baseline, diuretics were taken by 46.9% of patients; angiotensin receptor blockers (ARB) by 44.7%, angiotensin converting enzyme inhibitors (ACEI) by 28.8%, beta-blockers (BB) by 28.0%, calcium channel blockers (CCB) by 18.9% and other antihypertensive drugs by 0.3%. At follow-up (approximately 5 years later), their corresponding percentages were 42.8%, 51.7%, 25.5%, 33.0% 20.7% and 1.0%. Among all participants, 54.4% (95% confidence interval: 50.8-58.0) were continuers, 26.9% (23.8-30.2) combiners, 12.7% (10.4-15.3) switchers and 6.0% (4.4-7.9) discontinuers. Combiners had higher systolic blood pressure values at baseline than the other groups (p < 0.05). Almost one third (30.6%) of switchers and 29.3% of combiners improved their blood pressure status at follow-up, versus 18.8% of continuers and 8.7% of discontinuers (p < 0.001). Conversely, almost one third (28.3%) of discontinuers became hypertensive (systolic ≥140 mm Hg or diastolic ≥90 mm Hg), vs. 22.1% of continuers, 16.3% of switchers and 11.5% of combiners (p < 0.001). Multivariate analysis showed baseline uncontrolled hypertension, ARBs, drug regimen (monotherapy/polytherapy) and overweight/obesity to be associated with changes in antihypertensive therapy.
Conclusion
In Switzerland, ARBs have replaced diuretics as the most commonly prescribed antihypertensive drug. Uncontrolled hypertension, ARBs, drug regimen (monotherapy or polytherapy) and overweight/obesity are associated with changes in antihypertensive treatment.
doi:10.1186/2050-6511-15-20
PMCID: PMC4021828  PMID: 24685255
Antihypertensive drug therapy; Prospective study; Switzerland; Switching; Persistence; Blood pressure; Combination; Discontinuation
20.  Combination therapy of hypertension in the elderly: a subgroup analysis of the Combination of OLMesartan and a calcium channel blocker or diuretic in Japanese elderly hypertensive patients trial 
Hypertension Research  2014;38(1):89-96.
Combination of OLMesartan and a calcium channel blocker or a diuretic in Japanese elderly hypertensive patients (COLM) trial demonstrated that olmesartan combinations with a CCB or diuretic have similar effects on reducing cardiovascular risk in elderly hypertensive patients. However, the safety profiles suggest that olmesartan combined with CCB may be preferable to olmesartan combined with diuretic. In this subgroup analysis, we further evaluated the effects and safety of these combinations in elderly (65–74 years old (y.o.)) and very elderly (75–84 y.o.) hypertensive patients. In the COLM trial, 5141 patients (2918 elderly and 2223 very elderly) were randomly assigned to receive olmesartan-based therapy with either CCB or diuretic. The hazard ratios and 95% confidence intervals, respectively, in the elderly age group and in the very elderly group were: 1.04 (0.72–1.50; olmesartan plus CCB vs. olmesartan plus diuretic, P=0.85) and 0.71 (0.51–0.99, P=0.045) for the primary composite end point, and 1.07 (0.67–1.72, P=0.77) and 0.64 (0.42–0.98, P=0.036) for the composite of hard end points. The hazard ratios for stroke (fatal and non-fatal) were 1.48 (0.88–2.48; olmesartan plus CCB vs. olmesartan plus diuretic, P=0.13) and 0.63 (0.39–1.02, P=0.059) (interaction-P=0.019). Withdrawal rates from the trial, withdrawal due to serious adverse event and the incidence of any adverse event were higher in the olmesartan plus diuretic group than in the olmesartan plus CCB group in both age groups. In conclusion, angiotensin receptor blocker (ARB) and CCB combination may be preferable to an ARB and diuretic combination in the very elderly hypertensive patients for the reduction of cardiovascular risk, particularly for the reduction in stroke risk.
doi:10.1038/hr.2014.144
PMCID: PMC4287656  PMID: 25253583
calcium channel blocker; combination therapy; diuretic; elderly hypertension; olmesartan
21.  Treatment of systemic hypertension 
Systemic hypertension is a major risk factor for cardiovascular disease and is present in 69% of patients with a first myocardial infarction, in 77% of patients with a first stroke, in 74% of patients with chronic heart failure, and in 60% of patients with peripheral arterial disease. Double-blind, randomized, placebo-controlled trials have found that antihypertensive drug therapy reduces cardiovascular events in patients aged younger than 80 years and in patients aged 80 years and older in the Hypertension in the Very Elderly Trial. Although the optimal blood pressure treatment goal has not been determined, existing epidemiologic and clinical trial data suggest that a reasonable therapeutic blood pressure goal should be <140/90 mm Hg in patients younger than 80 years and a systolic blood pressure of 140-145 mm Hg if tolerated in patients aged 80 years and older. Non-pharmacologic lifestyle measures should be encouraged both to prevent development of hypertension and as adjunctive therapy in patients with hypertension. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta blockers, calcium channel blockers, and diuretics have all reduced cardiovascular events in randomized trials. The choice of specific drugs depends on efficacy, tolerability, presence of specific comorbidities, and cost.
PMCID: PMC3427981  PMID: 22937486
Hypertension; diuretics; beta blockers; angiotensin-converting enzyme inhibitors; angiotensin receptor blockers; calcium channel blockers
22.  The Effects of Calcium Channel Blockers in the Prevention of Stroke in Adults with Hypertension: A Meta-Analysis of Data from 273,543 Participants in 31 Randomized Controlled Trials 
PLoS ONE  2013;8(3):e57854.
Background
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).
Conclusion
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.
doi:10.1371/journal.pone.0057854
PMCID: PMC3590278  PMID: 23483932
23.  Diabetes: prevention of cardiovascular events  
BMJ Clinical Evidence  2006;2006:0601.
Introduction
Diabetes mellitus is a major risk factor for cardiovascular disease. In the USA, a survey of deaths in 1986 suggested that 60−75% of people with diabetes die from cardiovascular causes.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of promoting smoking cessation; controlling blood pressure; treating dyslipidaemia; blood glucose control; treating multiple risk factors; revascularisation procedures; and antiplatelet drugs in people with diabetes? We searched: Medline, Embase, The Cochrane Library and other important databases up to November 2004 (BMJ 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 63 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: antihypertensive drugs, antihypertensive treatment, aspirin, clopidogrel, coronary artery bypass graft, diet, fibrates, glycaemic control (intensive versus conventional control), heparin (with or without glycoprotein IIb/IIIa inhibitors, or clopidogrel), lower target blood pressures, metformin, multiple risk factor treatment (intensive), percutaneous transluminal coronary angioplasty (plus stent), smoking cessation, statins (aggressive or moderate lipid lowering, low or standard dose), stent (plus glycoprotein IIb/IIIa inhibitors), thrombolysis.
Key Points
People with diabetes mellitus have 2−4 times the risk of cardiovascular disease, and are up to 3 times more likely to die after a myocardial infarction, compared with normoglycaemic people.
Intensive treatment of multiple risk factors in people with type 2 diabetes and microalbuminuria reduces the risk of cardiovascular disease compared with conventional treatment. Promotion of smoking cessation is likely to reduce cardiovascular events in people with diabetes, although no studies have specifically studied this.
Tight control of blood pressure and reduction of cholesterol reduces the risk of cardiovascular events in people with hypertension and diabetes. Angiotensin converting enzyme inhibitors, angiotensin receptor antagonists, beta-blockers, calcium channel blockers and diuretics have all been shown to have similar antihypertensive effects.Reduction of cholesterol with statins reduces cardiovascular morbidity and mortality in people with diabetes regardless of initial cholesterol levels, and fibrates may also be beneficial. Aspirin and clopidogrel have not been consistently shown to reduce cardiovascular events or mortality in people with diabetes and cardiovascular disease compared with controls, and increase the risk of bleeding.Intensive blood glucose control reduces the risk of cardiovascular events in people with type 1 diabetes, but has not been consistently shown to reduce cardiovascular morbidity or mortality in people with type 2 diabetes.
Coronary artery bypass grafts reduce 4 year mortality compared with percutaneous transluminal coronary angioplasty (PTCA) in people with diabetes, although longer term benefits are unclear. PTCA may reduce short term mortality or myocardial infarction compared with thrombolysis in people with diabetes and acute myocardial infarction.Adding glycoprotein IIb/IIIa inhibitors reduces cardiovascular morbidity and mortality compared with placebo in people with acute coronary syndrome or undergoing PTCA plus stenting.
PMCID: PMC2907631
24.  Spectrum of antihypertensive therapy in South Asians at a tertiary care hospital in Pakistan 
BMC Research Notes  2011;4:318.
Background
Despite available guidelines on hypertension (HTN), use of antihypertensives is variable. This study was designed to ascertain frequency of patients on monotherapy and > 1 antihypertensive therapy and also to ascertain proportion of patients on diuretic therapy.
Methods
It was a crossectional study conducted on 1191 adults(age > 18 yrs)hypertensive patients selected by computerized International Classification of Diseases -9-coordination and maintenance (ICD-9-CM) presenting to a tertiary care hospital in Pakistan. Data on demographics, comorbids, type of antihypertensive drug, number of antihypertensive drug and mean duration of antihypertensive drug was recorded over 1.5 year period (2008-09). Blood pressure was recorded on admission. Primary outcome was use of combination therapy and secondary outcome was use of diuretic therapy.
Results
A total of 1191 participants were included. Mean age(SD) was 62.55(12.47) years, 45.3%(540) were males. Diabetes was the most common comorbid; 46.3%(551). Approximately 85% of patients had controlled hypertension. On categorization of anti hypertensive use into 3 categories;41.2%(491) were on monotherapy,32.2%(384) were on 2 drug therapy,26.5%(316) were on ≥3 drug therapy. Among those who were on monotherapy for HTN;34%(167) were on calcium channel blockers,30.10%(148) were on beta blockers, 22.80%(112) were on Angiotensin converting enzyme (ACE) inhibitors,12%(59) were on diuretics and 2.20%(11) were on Angiotensin receptor blockers(ARB). Use of combination antihypertensive therapy was significantly high in patients with ischemic heart disease(IHD)(p < 0.001). Use of diuretics was in 31% (369) patients. Use of diuretics was significantly less in patients with comorbids of diabetes (p 0.02), Chronic kidney disease(CKD)(p 0.003), IHD (p 0.001) respectively
Conclusion
Most patients presenting to our tertiary care center were on combination therapy. Calcium channel blocker is the most common anti hypertensive drug used as monotherapy and betablockers are used as the most common antihypertensive in combination. Only a third of patients were on diuretic as an antihypertensive therapy.
doi:10.1186/1756-0500-4-318
PMCID: PMC3171374  PMID: 21884613
25.  Heart failure 
Clinical Evidence  2011;2011:0204.
Introduction
Heart failure occurs in 3% to 4% of adults aged over 65 years, usually as a consequence of coronary artery disease or hypertension, and causes breathlessness, effort intolerance, fluid retention, and increased mortality. The 5-year mortality in people with systolic heart failure ranges from 25% to 75%, often owing to sudden death following ventricular arrhythmia. Risks of cardiovascular events are increased in people with left ventricular systolic dysfunction (LVSD) or heart failure.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of multidisciplinary interventions for heart failure? What are the effects of exercise in people with heart failure? What are the effects of drug treatments for heart failure? What are the effects of devices for treatment of heart failure? What are the effects of coronary revascularisation for treatment of heart failure? What are the effects of drug treatments in people at high risk of heart failure? What are the effects of treatments for diastolic heart failure? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2010 (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 80 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: aldosterone receptor antagonists, amiodarone, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, anticoagulation, antiplatelet agents, beta-blockers, calcium channel blockers, cardiac resynchronisation therapy, coronary revascularisation, digoxin (in people already receiving diuretics and angiotensin-converting enzyme inhibitors), exercise, hydralazine plus isosorbide dinitrate, implantable cardiac defibrillators, multidisciplinary interventions, non-amiodarone antiarrhythmic drugs, and positive inotropes (other than digoxin).
Key Points
Heart failure occurs in 3% to 4% of adults aged over 65 years, usually as a consequence of coronary artery disease or hypertension, and causes breathlessness, effort intolerance, fluid retention, and increased mortality. The 5-year mortality in people with systolic heart failure ranges from 25% to 75%, often owing to sudden death following ventricular arrhythmia. Risks of cardiovascular events are increased in people with left ventricular systolic dysfunction (LVSD) or heart failure.
Multidisciplinary interventions may reduce admissions to hospital and mortality in people with heart failure compared with usual care. Exercise may reduce admissions to hospital due to heart failure compared with usual care. However, long-term benefits of these interventions remain unclear.
ACE inhibitors, angiotensin II receptor blockers, and beta-blockers reduce mortality and hospital admissions from heart failure compared with placebo, with greater absolute benefits seen in people with more severe heart failure. Combined treatment with angiotensin II receptor blockers and ACE inhibitors may lead to a greater reduction in hospital admission for heart failure compared with ACE inhibitor treatment alone.
Aldosterone receptor antagonists (spironolactone, eplerenone, and canrenoate) may reduce all-cause mortality in people with heart failure, but increase the risk of hyperkalaemia.
Digoxin slows the progression of heart failure compared with placebo, but may not reduce mortality.
Hydralazine plus isosorbide dinitrate may improve survival and quality-of-life scores compared with placebo in people with chronic congestive heart failure.
We don't know whether amiodarone, anticoagulants, or antiplatelets are effective at reducing mortality or hospital re-admission rates.
CAUTION: Positive inotropic agents (other than digoxin), calcium channel blockers, and antiarrhythmic drugs (other than amiodarone and beta-blockers) may all increase mortality and should be used with caution, if at all, in people with systolic heart failure.
Implantable cardiac defibrillators and cardiac resynchronisation therapy can reduce mortality in people with heart failure who are at high risk of ventricular arrhythmias. However, studies evaluating cardiac resynchronisation therapy were performed in centres with considerable experience, which may have overestimated the benefits.
We don't know how coronary revascularisation and drug treatment compare for reducing mortality in people with heart failure and left ventricular dysfunction because all the trials assessing this comparison were conducted before ACE inhibitors, aspirin, beta-blockers, and statins were in routine use, thus limiting their applicability to current clinical practice.
ACE inhibitors delay the onset of symptomatic heart failure, reduce cardiovascular events, and improve long-term survival in people with asymptomatic LVSD compared with placebo. Angiotensin II receptor blockers and ACE inhibitors seem equally effective at reducing all-cause mortality and cardiovascular mortality in people at high risk of heart failure.The combination of angiotensin II receptor blockers and ACE inhibitors seems no more effective than ACE inhibitors alone and causes more adverse effects.
ACE inhibitors or angiotensin II receptor blockers seem no more effective at reducing mortality or rate of hospital admissions for cardiovascular events in people with diastolic heart failure compared with placebo. We don't know whether treatments other than angiotensin II receptor blockers are beneficial in reducing mortality in people with diastolic heart failure as we found only one trial.
PMCID: PMC3275321  PMID: 21878135

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