Objective: Funnel plots (plots of effect estimates against sample size) may be useful to detect bias in meta-analyses that were later contradicted by large trials. We examined whether a simple test of asymmetry of funnel plots predicts discordance of results when meta-analyses are compared to large trials, and we assessed the prevalence of bias in published meta-analyses. Design: Medline search to identify pairs consisting of a meta-analysis and a single large trial (concordance of results was assumed if effects were in the same direction and the meta-analytic estimate was within 30% of the trial); analysis of funnel plots from 37 meta-analyses identified from a hand search of four leading general medicine journals 1993-6 and 38 meta-analyses from the second 1996 issue of the Cochrane Database of Systematic Reviews . Main outcome measure: Degree of funnel plot asymmetry as measured by the intercept from regression of standard normal deviates against precision. Results: In the eight pairs of meta-analysis and large trial that were identified (five from cardiovascular medicine, one from diabetic medicine, one from geriatric medicine, one from perinatal medicine) there were four concordant and four discordant pairs. In all cases discordance was due to meta-analyses showing larger effects. Funnel plot asymmetry was present in three out of four discordant pairs but in none of concordant pairs. In 14 (38%) journal meta-analyses and 5 (13%) Cochrane reviews, funnel plot asymmetry indicated that there was bias. Conclusions: A simple analysis of funnel plots provides a useful test for the likely presence of bias in meta-analyses, but as the capacity to detect bias will be limited when meta-analyses are based on a limited number of small trials the results from such analyses should be treated with considerable caution. Key messages Systematic reviews of randomised trials are the best strategy for appraising evidence; however, the findings of some meta-analyses were later contradicted by large trials Funnel plots, plots of the trials9 effect estimates against sample size, are skewed and asymmetrical in the presence of publication bias and other biases Funnel plot asymmetry, measured by regression analysis, predicts discordance of results when meta-analyses are compared with single large trials Funnel plot asymmetry was found in 38% of meta-analyses published in leading general medicine journals and in 13% of reviews from the Cochrane Database of Systematic Reviews Critical examination of systematic reviews for publication and related biases should be considered a routine procedure

/pdf/bias-in-meta-analysis-detected-by-a-simple-graphical-test-5erh428s5c.pdf

Bias in meta-analysis detected by a simple, graphical test

"The Seventh Report of the Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure" provides a new guideline
for hypertension prevention and management. The following are the key messages(1) In persons older than 50 years, systolic blood pressure (BP) of
more than 140 mm Hg is a much more important cardiovascular disease
(CVD) risk factor than diastolic BP; (2) The risk of CVD, beginning at 115/75
mm Hg, doubles with each increment of 20/10 mm Hg; individuals who are normotensive
at 55 years of age have a 90% lifetime risk for developing hypertension; (3)
Individuals with a systolic BP of 120 to 139 mm Hg or a diastolic BP of 80
to 89 mm Hg should be considered as prehypertensive and require health-promoting
lifestyle modifications to prevent CVD; (4) Thiazide-type diuretics should
be used in drug treatment for most patients with uncomplicated hypertension,
either alone or combined with drugs from other classes. Certain high-risk
conditions are compelling indications for the initial use of other antihypertensive
drug classes (angiotensin-converting enzyme inhibitors, angiotensin-receptor
blockers, β-blockers, calcium channel blockers); (5) Most patients with
hypertension will require 2 or more antihypertensive medications to achieve
goal BP (<140/90 mm Hg, or <130/80 mm Hg for patients with diabetes
or chronic kidney disease); (6) If BP is more than 20/10 mm Hg above goal
BP, consideration should be given to initiating therapy with 2 agents, 1 of
which usually should be a thiazide-type diuretic; and (7) The most effective
therapy prescribed by the most careful clinician will control hypertension
only if patients are motivated. Motivation improves when patients have positive
experiences with and trust in the clinician. Empathy builds trust and is a
potent motivator. Finally, in presenting these guidelines, the committee recognizes
that the responsible physician's judgment remains paramount.

https://jamanetwork.com/journals/jama/articlepdf/196589/JSC30096.pdf

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report.

The National High Blood Pressure Education Program presents the complete Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Like its predecessors, the purpose is to provide an evidence-based approach to the prevention and management of hypertension. The key messages of this report are these: in those older than age 50, systolic blood pressure (BP) of greater than 140 mm Hg is a more important cardiovascular disease (CVD) risk factor than diastolic BP; beginning at 115/75 mm Hg, CVD risk doubles for each increment of 20/10 mm Hg; those who are normotensive at 55 years of age will have a 90% lifetime risk of developing hypertension; prehypertensive individuals (systolic BP 120-139 mm Hg or diastolic BP 80-89 mm Hg) require health-promoting lifestyle modifications to prevent the progressive rise in blood pressure and CVD; for uncomplicated hypertension, thiazide diuretic should be used in drug treatment for most, either alone or combined with drugs from other classes; this report delineates specific high-risk conditions that are compelling indications for the use of other antihypertensive drug classes (angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, beta-blockers, calcium channel blockers); two or more antihypertensive medications will be required to achieve goal BP (<140/90 mm Hg, or <130/80 mm Hg) for patients with diabetes and chronic kidney disease; for patients whose BP is more than 20 mm Hg above the systolic BP goal or more than 10 mm Hg above the diastolic BP goal, initiation of therapy using two agents, one of which usually will be a thiazide diuretic, should be considered; regardless of therapy or care, hypertension will be controlled only if patients are motivated to stay on their treatment plan. Positive experiences, trust in the clinician, and empathy improve patient motivation and satisfaction. This report serves as a guide, and the committee continues to recognize that the responsible physician's judgment remains paramount.

Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure

ABCD
: Appropriate Blood pressure Control in Diabetes
ABI
: ankle–brachial index
ABPM
: ambulatory blood pressure monitoring
ACCESS
: Acute Candesartan Cilexetil Therapy in Stroke Survival
ACCOMPLISH
: Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hypertension
ACCORD
: Action to Control Cardiovascular Risk in Diabetes
ACE
: angiotensin-converting enzyme
ACTIVE I
: Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events
ADVANCE
: Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation
AHEAD
: Action for HEAlth in Diabetes
ALLHAT
: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart ATtack
ALTITUDE
: ALiskiren Trial In Type 2 Diabetes Using Cardio-renal Endpoints
ANTIPAF
: ANgioTensin II Antagonist In Paroxysmal Atrial Fibrillation
APOLLO
: A Randomized Controlled Trial of Aliskiren in the Prevention of Major Cardiovascular Events in Elderly People
ARB
: angiotensin receptor blocker
ARIC
: Atherosclerosis Risk In Communities
ARR
: aldosterone renin ratio
ASCOT
: Anglo-Scandinavian Cardiac Outcomes Trial
ASCOT-LLA
: Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm
ASTRAL
: Angioplasty and STenting for Renal Artery Lesions
A-V
: atrioventricular
BB
: beta-blocker
BMI
: body mass index
BP
: blood pressure
BSA
: body surface area
CA
: calcium antagonist
CABG
: coronary artery bypass graft
CAPPP
: CAPtopril Prevention Project
CAPRAF
: CAndesartan in the Prevention of Relapsing Atrial Fibrillation
CHD
: coronary heart disease
CHHIPS
: Controlling Hypertension and Hypertension Immediately Post-Stroke
CKD
: chronic kidney disease
CKD-EPI
: Chronic Kidney Disease—EPIdemiology collaboration
CONVINCE
: Controlled ONset Verapamil INvestigation of CV Endpoints
CT
: computed tomography
CV
: cardiovascular
CVD
: cardiovascular disease
D
: diuretic
DASH
: Dietary Approaches to Stop Hypertension
DBP
: diastolic blood pressure
DCCT
: Diabetes Control and Complications Study
DIRECT
: DIabetic REtinopathy Candesartan Trials
DM
: diabetes mellitus
DPP-4
: dipeptidyl peptidase 4
EAS
: European Atherosclerosis Society
EASD
: European Association for the Study of Diabetes
ECG
: electrocardiogram
EF
: ejection fraction
eGFR
: estimated glomerular filtration rate
ELSA
: European Lacidipine Study on Atherosclerosis
ESC
: European Society of Cardiology
ESH
: European Society of Hypertension
ESRD
: end-stage renal disease
EXPLOR
: Amlodipine–Valsartan Combination Decreases Central Systolic Blood Pressure more Effectively than the Amlodipine–Atenolol Combination
FDA
: U.S. Food and Drug Administration
FEVER
: Felodipine EVent Reduction study
GISSI-AF
: Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico-Atrial Fibrillation
HbA1c
: glycated haemoglobin
HBPM
: home blood pressure monitoring
HOPE
: Heart Outcomes Prevention Evaluation
HOT
: Hypertension Optimal Treatment
HRT
: hormone replacement therapy
HT
: hypertension
HYVET
: HYpertension in the Very Elderly Trial
IMT
: intima-media thickness
I-PRESERVE
: Irbesartan in Heart Failure with Preserved Systolic Function
INTERHEART
: Effect of Potentially Modifiable Risk Factors associated with Myocardial Infarction in 52 Countries
INVEST
: INternational VErapamil SR/T Trandolapril
ISH
: Isolated systolic hypertension
JNC
: Joint National Committee
JUPITER
: Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin
LAVi
: left atrial volume index
LIFE
: Losartan Intervention For Endpoint Reduction in Hypertensives
LV
: left ventricle/left ventricular
LVH
: left ventricular hypertrophy
LVM
: left ventricular mass
MDRD
: Modification of Diet in Renal Disease
MRFIT
: Multiple Risk Factor Intervention Trial
MRI
: magnetic resonance imaging
NORDIL
: The Nordic Diltiazem Intervention study
OC
: oral contraceptive
OD
: organ damage
ONTARGET
: ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial
PAD
: peripheral artery disease
PATHS
: Prevention And Treatment of Hypertension Study
PCI
: percutaneous coronary intervention
PPAR
: peroxisome proliferator-activated receptor
PREVEND
: Prevention of REnal and Vascular ENdstage Disease
PROFESS
: Prevention Regimen for Effectively Avoiding Secondary Strokes
PROGRESS
: Perindopril Protection Against Recurrent Stroke Study
PWV
: pulse wave velocity
QALY
: Quality adjusted life years
RAA
: renin-angiotensin-aldosterone
RAS
: renin-angiotensin system
RCT
: randomized controlled trials
RF
: risk factor
ROADMAP
: Randomized Olmesartan And Diabetes MicroAlbuminuria Prevention
SBP
: systolic blood pressure
SCAST
: Angiotensin-Receptor Blocker Candesartan for Treatment of Acute STroke
SCOPE
: Study on COgnition and Prognosis in the Elderly
SCORE
: Systematic COronary Risk Evaluation
SHEP
: Systolic Hypertension in the Elderly Program
STOP
: Swedish Trials in Old Patients with Hypertension
STOP-2
: The second Swedish Trial in Old Patients with Hypertension
SYSTCHINA
: SYSTolic Hypertension in the Elderly: Chinese trial
SYSTEUR
: SYSTolic Hypertension in Europe
TIA
: transient ischaemic attack
TOHP
: Trials Of Hypertension Prevention
TRANSCEND
: Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease
UKPDS
: United Kingdom Prospective Diabetes Study
VADT
: Veterans' Affairs Diabetes Trial
VALUE
: Valsartan Antihypertensive Long-term Use Evaluation
WHO
: World Health Organization

### 1.1 Principles

The 2013 guidelines on hypertension of the European Society of Hypertension (ESH) and the European Society of Cardiology …

/pdf/2013-esh-esc-guidelines-for-the-management-of-arterial-4ydvs5ifsx.pdf

2013 ESH/ESC Guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).

2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.

Angiotensin-converting enzyme (ACE) inhibitors have been shown to improve exercise performance, patient well-being and survival in patients with heart failure. l-4 Both captopril and enalapril have been approved for use in heart failure and it is likely that several other ACE inhibitors will be approved within the near future. Although they differ in duration of action and side-effect profile, it has generally been thought that one ACE inhibitor is equal to another in effcctiveness.5 This concept has now been challenged by Pouleur et a1,6 who found in a retrospective analysis of baseline therapy in the Xamoterol Mortality Trial that patients receiving baseline therapy with captopril had a significantly higher mortality than those receiving enalapril. Pouleur et al postulate that the higher mortality of patients receiving captopril in their study was due to the fact that captopril’s duration of action is shorter than that of enalapril. Because captopril is recommended to be used 3 times daily, compared with 2 times daily for enalapril in patients with heart failure, compliance may have been worse with captopril, thereby leaving patients exposed to the adverse effects of rerun-angiotensin system activation. Furthermore, many investigators in their study administered captopril at a lower than recommended dose or on a twice-daily rather than a threetimes daily schedule in order to reduce the cost of chronic therapy. However, one should be skeptical of any retrospective analysis such as that performed by Pouleur et al. Their trial was not designed, nor statistically empowered, to explore the relative difference in effectiveness between captopril and enalapril. Nevertheless, one cannot ignore the possibility that significant differences in the effectiveness of various ACE inhibitors might exist. If differences in the effectiveness of ACE inhibitors do exist, how might they be explained? One explanation is that proposed by Pouleur et a1.6 Should the

/pdf/angiotensin-converting-inhibitors-in-patients-with-1tdi0cjz0s.pdf

Angiotensin-converting inhibitors in patients with congestive heart failure: A class effect?

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) investigators found that patients with essential hypertension and one additional risk factor for coronary artery disease events when randomized to the thiazide diuretic chlorthalidone had a significant reduction in the incidence of hospitalization for heart failure (HHF) compared with those randomized to the angiotensin-converting enzyme inhibitor (ACEI) lisinopril, the dihydropyridine calcium channel blocker (CCB) amlodipine, or the a-adrenergic receptor– blocking agent doxazosin, independent of its effect on lowering blood pressure (BP). In this issue of the Journal, the authors present evidence refuting the criticism that differences in therapy prior to randomization may have influenced the results. The finding that chlorthalidone was more effective than the other randomized strategies in preventing HHF has important implications since HHF is associated with an increased risk of subsequent mortality and has important health cost implications since HHF is the most frequent and expensive cause of hospitalization in patients older than 65 years. The finding that chlorthalidone was more effective than the other strategies in preventing HHF is plausible since high-risk patients with hypertension often develop myocardial fibrosis and hypertrophy resulting in diastolic dysfunction and a decrease in ventricular compliance such that a relatively small increase in dietary sodium intake and ⁄or a decrease in renal function with a resultant increase in sodium retention and an increase in plasma volume could lead to a marked increase in left ventricular end-diastolic pressure with resultant pulmonary congestion and peripheral edema. An increase in sodium excretion and decrease in plasma volume associated with diuretic use might prevent this sequence of events better than with the other recommended strategies. It is important to ask, however, how these results should influence the treatment of patients with high-risk hypertension. While chlorthalidone has been shown to be effective in reducing HHF in ALLHAT, a large percentage of high-risk patients with hypertension will require >1 antihypertensive agent (40.7% of patients in ALLHAT randomized to chlorthalidone were taking >1 antihypertensive agent at 5 years). If one considers that at least 2 drugs are necessary to control BP in many high-risk patients with hypertension, should 1 be a diuretic such as chlorthalidone? The recent Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial showed that the combination of an ACEI + amlodipine was more effective in reducing cardiovascular (CV) events including CV death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for angina pectoris, and need for coronary revascularization but not HHF in high-risk patients with hypertension compared with an ACE-I+ the thiazide diuretic hydrochlorothiazide (HCTZ) at equal BP reduction (confirmed in a subset by ambulatory BP monitoring [ABPM]). It can From the University of Michigan School of Medicine – Cardiology, Ann Arbor, MI Address for correspondence: Bertram Pitt, MD, University of Michigan School of Medicine – Cardiology, 1500 East Medical Center Drive, Ann Arbor, MI 48104 E-mail: bpitt@umich.edu

/pdf/the-role-of-chlorthalidone-in-patients-with-high-risk-4issn7n0ym.pdf

The role of chlorthalidone in patients with high-risk hypertension.

The hemodynamic effects of the inotropic agents prenalterol and dobutamine were compared in a canine model of acute ischemic heart failure following two-vessel coronary artery constriction. Intravenous infusions of both inotropic agents resulted in improvement of cardiac output, left ventricular maximum dP/dt, and contractile force in the nonischemic zone and in a decrease in systemic vascular resistance. No significant changes occurred in ischemic zone contractile force or left ventricular end-diastolic pressure following either inotropic agent compared to saline controls. Significant differences between the two inotropic agents consisted of prenalterol's markedly longer duration of action (hemodynamic half life of 3 hr after discontinuation compared to a value of 1.7 min after dobutamine discontinuation) and greater augmentation of cardiac output at high-dose dobutamine due to greater increases in heart rate. However, similar hemodynamic effects were noted with prenalterol and dobutamine at doses which increased nonischemic contractile force 50%. Both inotropic agents were associated with ventricular arrhythmias in the acute ischemic state. Implications regarding the use of prenalterol and dobutamine in clinical acute ischemic low-output states are discussed.

Comparative effects of prenalterol and dobutamine in a canine model of acute ischemic heart failure.

To determine the feasibility and predictive value of early exercise testing 72 hours after acute myocardial infarction, 109 consecutive patients who received reperfusion therapy were prospectively evaluated. In the group studied, in 87 (80%) the course was uncomplicated 3 days after admission, as defined by a lack of congestive heart failure, arrhythmias and angina, and 53 patients (49%) performed heart rate-limited (140 beats/min) treadmill exercise. These patients exercised for 7.9 +/- 3.4 minutes, achieving a heart rate of 129 +/- 11 beats/min and a systolic blood pressure of 151 +/- 27 mm Hg. The exercise test was not accompanied by any protracted ischemia, infarction or significant arrhythmias. Accompanying tomographic thallium-201 scintigraphy demonstrated a reversible perfusion defect in 14 patients (26%), no evidence for ischemia in 36 patients (69%) and an equivocal result in 3 patients (6%). Of the 14 patients with a positive exercise-thallium test result, 4 had an adverse clinical outcome of either reinfarction, postinfarction angina or ventricular tachycardia during hospital days 4 to 10; an adverse in-hospital outcome was not seen in the 40 patients with a negative exercise-thallium test result (p = 0.009). Thus, early exercise testing after acute myocardial infarction is safe in selected patients with an uncomplicated course and the test is predictive of in-hospital clinical outcomes.

/pdf/exercise-testing-three-days-after-onset-of-acute-myocardial-3pargwtrnv.pdf

Exercise Testing Three Days After Onset of Acute Myocardial Infarction

The mechanisms associated with aldosterone production both systemically and locally as well as the effects of aldosterone blockade on the pathophysiology of heart failure (HF) have been extensively reviewed in this series and elsewhere. This article will review the clinical evidence supporting the use of aldosterone blocking agents (AB)in patients with HF and speculate on some potential future uses.

/pdf/the-role-of-aldosterone-blockade-in-patients-with-heart-2zhn93lexm.pdf

Bertram Pitt

Papers

Angiotensin-converting inhibitors in patients with congestive heart failure: A class effect?

The role of chlorthalidone in patients with high-risk hypertension.

Comparative effects of prenalterol and dobutamine in a canine model of acute ischemic heart failure.

Exercise Testing Three Days After Onset of Acute Myocardial Infarction

The role of aldosterone blockade in patients with heart failure.