James M. Wright, MD, PhD, CRCP(C), Professor, Departments of Anesthesiology, Pharmacology & Therapeutics and Medicine, University of BC, Coordinating Editor, Cochrane Hypertension Review Group, Vancouver, BC.

Abstract
Choosing the optimal first-line drug for patients with hypertension must address a hierarchy of treatment goals: reduction in mortality and morbidity, efficacy in lowering blood pressure, ensuring tolerability, and minimizing cost. This article examines the evidence for the different classes of first-line antihypertensive drugs in light of these four goals. The evidence indicates that first-line low-dose thiazides are better than or equivalent to other antihypertensive drug classes for each of the goals of therapy in both people with hypertension in general and in older adults ≥ 60 years of age.
Keywords: hypertension, thiazide, first-line, older adults, evidence-based.

Norm Campbell, MD, FRCPC, Departments of Medicine, Community Health Sciences, and Pharmacology and Therapeutics, University of Calgary, Calgary; Libin
Cardiovascular Institute, Calgary, AB.

Sailesh Mohan, MD, MPH, Departments of Medicine, Community Health Sciences, and Pharmacology and Therapeutics, University of Calgary, Calgary; Libin Cardiovascular Institute,
Calgary, AB.

Abstract:

As over 9 in 10 older adults will develop hypertension, it is important for clinicians to routinely assess blood pressure. It is as important to treat hypertension in older adults as it is in
younger people. In general, select a low-dose diuretic. Beta-blockers are not as effective at preventing stroke as other major antihypertensive drug classes. Specifi c indications for drug classes
are provided. Target the blood pressure levels to <140/90 mmHg in general, <130/80 mmHg in people with diabetes or chronic kidney disease, and focus on systolic blood pressure control. If blood
pressure control is not achieved using a moderate dose of your initial selection, add a second antihypertensive drug.

Key Words: hypertension, antihypertensive drugs, pharmacotherapy, cardiovascular disease, stroke.

Introduction

It is estimated that over 90% of normotensive people age 55-65 will eventually develop hypertension if they live an average lifespan.¹ Hypertension is not to be ignored as it is the
leading risk for death and disability in older people, and is both preventable and treatable.^2,3 Two-thirds of stroke and half of ischemic heart disease and heart failure are attributable
to elevated blood pressure, and the absolute risk from hypertension increases with age.⁴ Most older adults are or will become candidates for antihypertensive therapy.



Lifestyle changes can both prevent and treat hypertension. When used in combination with antihypertensive drugs, such changes can considerably reduce the number and doses of medication
required.⁵ Recent data indicate that few Canadians make lifestyle changes after a diagnosis of hypertension. In Canadians over age 60, there is only a 3.2% reduction in smoking after a
diagnosis of hypertension, and there is no change in body mass index, physical inactivity, or excess alcohol consumption.⁶ Lifestyle changes are thus markedly underutilized and this leads
to overreliance on pharmacotherapy.



As pharmacotherapy does offer important benefits, especially in light of the difficulty in promoting lifestyle changes that could result in lowered blood pressure, it is important to review the
principles of instituting antihypertensive therapy. This article aims to assist clinicians in selecting appropriate initial antihypertensive therapy.



Prior to prescribing antihypertensive drugs it is important to assess the person for white coat hypertension, secondary hypertension, and factors such as pain or stress that may temporarily increase
blood pressure. White coat hypertension and secondary hypertension are more common among older people. White coat hypertension can be easily detected and followed by home measurement of blood
pressure. Importantly the threshold for hypertension using home measurement of blood pressure is 135/85 mmHg or higher. Ambulatory blood pressure is recommended to be considered to confirm the
diagnosis of white coat hypertension.

Initiation of Therapy

There are a large number of specific antihypertensive drugs that both lower blood pressure and reduce death and disability for older people.⁷ The initial drug to be used is an important
choice. The blood pressure lowering to be expected by the use of one drug alone is about 9/5 mmHg; hence most people will require combinations of drugs to bring blood pressure down to recommended
levels for optimal cardiovascular protection (Table 1).⁸ Initial therapy using two antihypertensive drugs is a consideration if the pretreatment blood pressure is 160/100 mmHg or more (or
150/90 mmHg or more in people with diabetes).⁷

For older people, drug therapy generally should be initiated if the blood pressure averages above 140 mmHg systolic or 90 mmHg diastolic and in most people should be lowered to less than 140 mmHg
systolic and less than 90 mmHg diastolic.⁷ For people with diabetes or chronic kidney disease, treatment should be initiated if the blood pressure averages greater than 130 mmHg systolic
or 80 mmHg diastolic and should be lowered to less than these values.⁷ Systolic blood pressure is a more important cardiovascular risk than diastolic blood pressure in older adults, is
often less well controlled, and requires greater clinician attention.



In 2009, CHEP is emphasizing maintaining blood pressure below 130/80 mmHg in people with diabetes. Up to 80% of deaths in people with diabetes are due to cardiovascular disease and up to 75% of
specific cardiovascular complications in people with diabetes are attributable to high blood pressure.⁹ Controlling blood pressure in people with hypertension and diabetes results in very
large reductions in death and cardiovascular event rates, and reduces the progression of renal disease and retinopathy.^10,11 However, despite the strong clinical benefits of blood pressure
lowering, a recent Ontario survey found that two-thirds of individuals with diabetes and hypertension were not achieving blood pressure targets.¹² Both diabetes and hypertension commonly
coexist in older people, and hence clinicians need to be vigilant for the deadly duo and pay particular attention to blood pressure control.



There have been concerns that treatment may prevent stroke in the oldest old but increase other adverse events, including total mortality.¹³ However, in 2008, a large randomized controlled
trial demonstrated large reductions in cardiovascular events and total mortality by lowering blood pressure with a diuretic with or without a angiotensin-converting enzyme (ACE) inhibitor in people
over age 80.¹⁴ Most studies, including this latter trial, included predominantly healthy people. Caution should be exercised in lowering blood pressure in older adults who are frail or
have significant postural hypotension or have substantial comorbidity, in whom reduction in blood pressure would not be expected to improve quality or quantity of life.⁷

Uncomplicated Hypertension

Initial therapy should be selected from antihypertensive drugs that optimally reduce cardiovascular events. These include low-dose thiazide-type diuretics, ACE inhibitors, long-acting calcium channel
blockers and angiotensin receptor blockers.⁷ Beta-blockers are not as effective at preventing stroke as low-dose thiazide-type diuretics, long-acting calcium channel blockers, and
angiotensin receptor blockers in older adults and therefore should not be selected as initial therapy in those over age 60 unless there is a compelling indication (Table 2).^15-20
Currently, there are no clinical trials to assess whether direct renin inhibitors improve cardiovascular outcomes of hypertensive patients, hence prescription of the newly released class should only
be considered in patients where proven therapies are unable to control blood pressure.

Choosing between Possible First-Line Choices

Table 2 outlines the specific pharmacotherapeutic recommendations of CHEP (2009) in different clinical settings.⁷ There are often several different potential first-line therapies to choose
among. Some principals can be used to help guide the initial selection. In the absence of a specific indication for a drug class, in general, older people have a better hypotensive response to
monotherapy with a low-dose diuretic or long-acting calcium channel blocker.²¹ Thiazide-like diuretics are very inexpensive, are well tolerated, and have the same cardiovascular benefits
as other classes, and therefore, in the authors’ opinion, should be the default choice if there is no contraindication to diuretics or specific indication for a different drug class (Figure 1).
Persistence with diuretic therapy is slightly lower than other drug classes and erectile dysfunction related to diuretics occurs in about 2% of people. Active gout can be precipitated by diuretic
therapy and hence diuretics should be avoided as initial therapy in people who have gout unless they are already prescribed therapy to prevent gout (e.g., allopurinol). Diuretics can also cause a
slight increase in blood glucose and lipid levels. The outcomes of people with diabetes, impaired glucose tolerance, or normal glucose levels are improved to the same extent with diuretics as with an
ACE inhibitor or calcium channel blocker. Hence, these clinical situations are not a valid reason to avoid prescribing a diuretic.²² Initial starting drugs and doses include
hydrochlorothiazide 12.5-25 mg/day, indapamide 1.25-2.5 mg/day, and chlorthalidone 12.5-25 mg/day (1/4-1/2 tablet). If single-drug antihypertensive therapy is anticipated, using a combination
diuretic tablet (hydrochlorothizide 12.5-25 mg with spironolactone or amiloride) will reduce the risk of developing hypokalemia and dysglycemia.

In older people for whom initial use of a low-dose thiazide-like diuretic is not indicated, a long-acting calcium channel blocker will lower blood pressure to a similar extent or slightly greater
extent as a diuretic.²³ Edema is a more common problem with dihydropyridine (e.g., amlodipine, nifedipine) than nondihydropyridine calcium channel blockers (e.g., verapamil, diltiazam).
When using nondihydropyridine calcium channel blockers, be alert for potential drug interactions (nondihydropyridine calcium channel blockers are CYP 3A4 inhibitors), the contraindication in people
with systolic heart failure and the potential to cause heart block in people with atrio-ventricular (A-V) conduction defects or people who are using other drugs that reduce A-V conduction (e.g.,
beta-blocker). Typical initial choices of calcium channel blockers and their doses include amlodipine 2.5-5 mg/day, Adalat (nifedipine) XL 20-30 mg/day, diltiazam (in extended release form) 120-240
mg/day and verapamil (in extended release form) 240 mg/day. A recent randomized controlled trial has concluded that calcium channel blocker therapy paired with an ACE inhibitor is superior to a
diuretic paired to a ACE inhibitor.²⁴ However, methodological issues in the conduct of the trial may preclude the study affecting therapeutic recommendations.



Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers may be used as initial choices of antihypertensive drugs for older adults although, based on differing efficacy to lower
blood pressure, the National Institute of Clinical Evaluation suggests they be selected after considering a diuretic and calcium channel blocker first.^7,21 In general, the ACE inhibitors
and angiotensin receptor blockers are excellent to add to the initial choice if blood pressure targets are not achieved with single drug treatment.²¹ A large randomized controlled trial
using ACE inhibitors in isolated systolic hypertension has not been conducted, and hence CHEP does not recommend ACE inhibitors in that setting. Cough and angioedema are adverse effects of specific
concern with ACE inhibitors. Numerous ACE inhibitors and angiotensin receptor blockers with different starting doses are in common use.



Conclusion

Maximal blood pressure lowering effect from most antihypertensive drug classes requires about 4-6 weeks, and therefore titration of therapy in the absence of a medical urgency can occur at that
interval. About 80% of the blood pressure lowering of most drug classes is achieved at half of the maximum dose, while side effects are much more common in the higher half of the dose
range.⁸ Therefore, use a combination of two drugs if there is an inadequate response to the initial therapy at moderate dose. Notably, based on a new clinical trial in 2008, CHEP now
recommends the combination of an ACE inhibitor with a ARB only be considered in selected and closely monitored people with advanced heart failure or proteinuric nephropathy.



When prescribing the initial drug it is reasonable to advise the patient that good blood pressure control usually requires lifestyle changes plus two or more drugs. This helps avoid the potential
disappointment and concerns if the initial therapy does not control the blood pressure.

The unhealthy lifestyles that cause hypertension (especially nutrition) usually elevate other cardiovascular risks, and hence a comprehensive approach to identifying and managing cardiovascular risks
is required. In particular, carefully screening for dyslipidemia and diabetes is required as these diagnoses will have a major impact on cardiovascular outcomes and treatments. Age itself is the
greatest risk factor for cardiovascular disease,⁴ and therefore all older adults with hypertension should be considered for blood pressure-lowering pharmacotherapy. Nevertheless, care
needs to be taken that the person truly has hypertension by excluding white coat hypertension and acute hypertensive responses to physical or emotional stresses, performing an appropriate diagnostic
work-up, and assessing the person for increased risks of hypotensive complications.



Appropriate antihypertensive pharmacotherapy is an effective mechanism to reduce cardiovascular morbidity and mortality in older adults. Individualized, simplified, but rational regimes of relatively
inexpensive antihypertensive drugs can control the blood pressure of most people. More information on treatment of hypertension including patient handouts can be found at "http://www.hypertension.ca">www.hypertension.ca.

Dr. Mohan has no stated conflicts of interest. Dr. Campbell has given talks sponsored by Bayer, Sanofi Aventis, Biovail, Bristol Myers Squibb, Pfizer, Novartis and Merck-Frosst, and also has
been on advisory boards for Novartis, Pfizer, Servier, Boehringer Ingelheim and Schering-Plough.

KEY POINTS / CLINICAL PEARLS

M. Faisal Jhandir, MD, RVT, Clinical Assistant Professor of Medicine, Co-Chair Vascular Risk Reduction Program, University of Calgary, Calgary, AB.
Robert J. Herman, MD, FRCPC, Professor of Medicine, Head, Division of General Internal Medicine, University of Calgary, Calgary, AB.
Norm R.C. Campbell, MD, FRCPC, Professor of Medicine, Physiology and Pharmacology and Community Health Sciences, University of Calgary and Libin Cardiovascular Institute, Calgary, AB.

The World Health Organization has named hypertension the leading risk for death globally in adults. Antihypertensive therapy reduces the risks of major cardiovascular complications. As blood pressure increases with increasing age, frequent screening for hypertension is advisable in older adults. The risk of developing hypertension is about 90% even in normotensive 65 year olds. Until recently, data supporting antihypertensive therapy in the very old had been inconclusive. However, the HYVET trial published in 2008 shows a clear reduction in cardiovascular events and mortality. Based on this study the Canadian Hypertension Education Program recommends treating hypertension regardless of age. Attention should also be given to reducing overall cardiovascular risk.
Key words: hypertension, high blood pressure, older adults, recommendations, HYVET study.

Wilbert S. Aronow, MD, FACC, FAHA, AGSF, Department of Medicine, Cardiology Division, New York Medical College, Valhalla, NY, USA.

Numerous double-blind, randomized, placebo-controlled studies have documented that antihypertensive drug therapy reduces cardiovascular events in older adults. In the Hypertension in the Very Elderly Trial, individuals 80 years of age and older treated with antihypertensive drug therapy had, at 1.8-year follow-up, a 30% reduction in fatal or nonfatal stroke, a 39% reduction in fatal stroke, a 21% reduction in all-cause mortality (p=0.02), a 23% reduction in death from cardiovascular causes, and a 64% reduction in heart failure. The goal of treatment of hypertension in older adults is to reduce the blood pressure to <140/90 mmHg and to <130/80 mmHg in older persons with diabetes or chronic renal insufficiency. Older adults with diastolic hypertension should have their diastolic blood pressure reduced to 80-85 mmHg. Diuretics should be used as initial therapy in persons with no associated medical conditions. The selection of antihypertensive drug therapy in persons with associated medical conditions depends on their medical conditions. If the blood pressure is >20/10 mmHg above the goal blood pressure, drug therapy should be initiated with two antihypertensive drugs, one of which should be a thiazide-type diuretic. Other coronary risk factors must be treated.
Key words: hypertension, older adults, antihypertensive drug therapy, angiotensin-converting enzyme inhibitors, beta-blockers.

Kati Juva, MD, PhD, Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland.
Sari Rastas, MD, PhD, Department of Neuroscience and Neurology, University of Kuopio, Kuopio, Finland; Kauniala Disabled War Veterans’ Hospital, Espoo, Finland.
Tuula Pirttilä, PhD, Professor, Department of Neuroscience and Neurology, University of Kuopio and Kuopio University Hospital, Kuopio, Finland.

The harmful effects of high blood pressure on cardiovascular morbidity and mortality are well established. However, hypertension in the very old is an extremely complex issue. Current epidemiological data suggest that high blood pressure may be a marker of survival in the very old, and lowering blood pressure may lead to an increase in total mortality. In this review we will summarize the evidence on the association between blood pressure and mortality and discuss the implications of the data.
Key words: older adults, hypertension, survival, very old, blood pressure.

Anita W. Asgar, MD, FRCPC, Interventional Cardiology Fellow, Montreal Heart Institute, Montreal, QC.
Renee L. Schiff, MD, FRCPC, Echocardiography Fellow, Montreal Heart Institute, Montreal, QC.
Reda Ibrahim, MD, CSPQ, FRCPC, Interventional Cardiologist, Montreal Heart Institute, Associate Professor of Medicine, Universite de Montreal, Montreal, QC.

Hypertension is a common health concern among older adults and constitutes an important risk factor for cardiovascular disease. Despite its prevalence, it is a constant management challenge. We review four aspects of hypertension management that have been of interest over the past year.
Key words: hypertension, diabetes, drug therapy, gender differences, resistant hypertension.

Silja Majahalme, MD, PhD, FESC, Cardiologist and Clinical Hypertension Specialist, Appleton Heart Institute/Appleton Cardiology Associates, Appleton, WI, USA.

Heart failure (HF) is an increasing problem in the older adult population, specifically among women. The majority of health care expenses are generated in the last few years of life, and hospitalization for HF is one of the major medical conditions influencing the expenditure. The nature of women’s HF differs from men: coronary artery disease is the most common etiologic factor for HF in men while women more often suffer from hypertensive heart disease, which results in stiffness of the left ventricle with relaxation problems, and diastolic HF. Most commonly there is a long history of poorly controlled hypertension. In acute situations these patients often present with florid edema and congestion along with significantly elevated blood pressure levels, which are both challenging to treat. This short review covers issues related to gender differences in etiology and epidemiology of HF, and evaluates current evidence for drug therapies.
Key words: epidemiology, heart failure, gender, myocardial infarction, hypertension.

Rachel L. McIntosh, B.Orth, Grad Dip Journ, Research Orthoptist, Retinal Vascular Imaging Centre, Eye Research Australia, University of Melbourne, Melbourne, Australia.
Tien Y. Wong, FRANZCO, FRCSE, PhD, Associate Professor of Ophthalmology, Retinal Vascular Imaging Centre, Eye Research Australia, University of Melbourne, Melbourne, Australia.

Hypertensive retinopathy has long been regarded as a risk indicator of mortality in persons with severe hypertension, but its value in contemporary clinical practice is uncertain. New population-based studies now show that hypertensive retinopathy signs are common in the general population of adults age 40 and older, including persons without a clinical diagnosis of hypertension. Some hypertensive retinopathy signs are associated not only with concurrent blood pressure levels, but with past blood pressure levels as well, suggesting that they reflect chronic hypertensive damage. Mild hypertensive retinopathy, such as generalized and focal retinal arteriolar narrowing and arteriovenous nicking, are only weakly associated with cardiovascular diseases. In contrast, moderate hypertensive retinopathy, such as retinal hemorrhages, cotton wool spots, and microaneurysms, are strongly associated with both subclinical and clinical cardiovascular diseases, including stroke and congestive heart failure. Thus, a clinical assessment of hypertensive retinopathy signs in older persons may provide useful information for cardiovascular risk stratification.
Key words: hypertensive retinopathy, retinal microvascular disease, hypertension, cardiovascular disease.

Norm R.C. Campbell, MD, FRCPC, Division of General Internal Medicine, University of Calgary, Calgary, AB.
J. George Fodor, MD, FRCPS, PhD, Ottawa Heart Institute, Ottawa, ON.
Robert Herman, MD, FRCPC, Division of General Internal Medicine, University of Calgary, Calgary, AB.
Pavel Hamet, MD, FRCPC, PhD, Research Center, CHUM, Montréal, QC (for the Canadian Hypertension Education Program).

Hypertension is a leading risk for morbidity and mortality in Canada. The older population is at greater risk from hypertension and has a greater reduction in cardiovascular risk with treatment than young patients. Frequent screening for hypertension is prudent as the estimated risk of developing hypertension is about 90%, even in normotensive 65-year-olds. Systolic blood pressure is a more relevant risk factor than diastolic blood pressure in older patients and is more difficult to treat to target. Most hypertensive patients will have multiple cardiovascular risks that require screening and management to reduce cardiovascular risk optimally. Lifestyle therapy is efficacious. Effective first-line drug therapies that reduce hypertension complications include thiazide-type diuretics, ACE inhibitors, long-acting calcium-channel blockers, and angiotensin-receptor blockers. Most patients require two or more drugs to achieve current blood pressure targets.
Key words: high blood pressure, hypertension, guidelines, recommendations, evidence-based medicine.