January 2005, Volume 27, No. 1
Update Articles

Management of systemic hypertension: an update for primary care physicians

N N Chan 陳諾, P C Y Tong 唐俊業, J C N Chan 陳重娥

HK Pract 2005;27:4-14

Summary

Hypertension is an important cause of cardiovascular morbidity and mortality worldwide. Despite advances in pharmacotherapy and establishment of treatment guidelines, its management has remained suboptimal with substantial underdiagnosis, undertreatment and poor control rates. With increasing amount of large-scale clinical trial data being available, there is continuous update on guidelines as well as treatment goals. Results from recent landmark hypertension trials such as the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) and VALUE (Valsartan Antihypertensive Long-Term Use Evaluation) are likely to change future hypertension management. This article aims to evaluate outcomes of recent hypertension trials and provide an update on hypertension management for family physicians.

摘要

全世界高血壓都是常見的心血管疾病及其死亡的重要原因。雖然，已經制定了治療指引，藥物治療也不斷進步，但是由於診斷不足、治療不足、控制欠佳，高血壓的整體治療情況並不理想。隨著大型臨床實驗數據不斷增加，治療指引和目標也不斷更新。近期重要的相關研究，如ALLHAT（The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial)和VALUE (Valsartan Antihypertensive Long-Term Use Evaluation），可能進一步改變高血壓治療指引。本文評估這些近期研究的成果，並向基層醫生提供最新的高血壓治療方法做為參考。

Introduction

Elevated arterial pressure is one of the most important modifiable risk factors for cardiovascular disease and renal disease globally1,2 and especially in Asian populations.3,4 Although the potential consequences of hypertension are widely recognized, its detection, treatment and control has been poor worldwide. With increasing knowledge from large-scale clinical trials, the target for blood pressure control has decreased over the years and new guidelines have been established to improve management. Together with the availability of new drugs, management of this condition is expected to improve.

Scale of the problem

Results from several national surveys in China showed that the prevalence of hypertension has increased dramatically over the years. In 1960, the estimated number of hypertension cases among Chinese adults was 30 million, which has increased to 59 million in 1980 and 94 million in 1990.5 More recently, the International Collaborative Study of Cardiovascular Disease in ASIA (InterASIA) conducted a national survey in China (2000-2001) which showed a prevalence of 27.2%, or 130 million adults age 35 to 74 years. Alarmingly, 44.7% were aware of their diagnosis and only 28.2% were taking antihypertensive medication. Of those who were prescribed antihypertensive drug(s), less than a third had a blood pressure <140/90mmHg.6 In Hong Kong, more than one tenth of the population has hypertension and the control rate was no more than 50%.7 Many factors are responsible for poor blood pressure control including drug compliance, education level and socioeconomic conditions.8 Identification of these factors would help to improve blood pressure control.

Guidelines for hypertension

Many guidelines have been established over the years. These guidelines include the JNC-7 (USA Joint National Committee on prevention, Detection, Evaluation, and Treatment of High Blood Pressure),9 ESH-ESC (European Society of Hypertension-European Society of Cardiology),10 WHO/ISH (World Health Organisation-International Society of Hypertension),11 BHS (British Hypertension Society)12 and ANBP2 (The Second Australian National Blood Pressure Study).13 They differ considerably in the first choice of antihypertensive drugs. For instance, the JNC-7 guideline suggests that thiazide diuretics should be the initial drug of choice for uncomplicated hypertension9 whereas the ANBP2 suggests that angiotensin-converting enzyme inhibitors are better initial drug treatment.14 On the other hand, the BHS guideline suggests initial treatment with any one of the 4 drug classes (the AB/CD algorithm).12 None of the guidelines have taken into account special patient groups such as obese hypertensive patients or post-menopausal hypertension. The existence of multiple guidelines for a single condition reflects the complexity in its management. In daily clinical practice, family physician should fully assess the patient and take into account the overall cardiovascular risk profile as well as other co-morbidities before deciding on the best drug (or drug combination) therapy.

Need to reach blood pressure goal

The controversy surrounding the relative merits of blood pressure reduction versus choice of antihypertensive drug for cardiovascular protection has been largely clarified following the publication of the VALUE (Valsartan Antihypertensive Long-Term Use Evaluation) study.15 This is a double-blind randomized controlled study comparing valsartan-based and amlodipine-based regimen which involved 15,245 hypertensive patients at high risk of cardiovascular events. The primary endpoint was a composite of fatal and non-fatal cardiac events. The trial was event driven with a mean follow-up period of 4.2 years. Significantly, blood pressure control was not similar between groups. Amlodipine-based treatment group had better blood pressure control than valsartan-based treatment group. The primary outcome was not significantly different between the two arms. However, of the secondary endpoints, myocardial infarction was significantly more frequent in the valsartan-based treatment group. In addition, higher odds ratios in favour of amlodipine were noted for all endpoints during the first 6 months when blood pressure differences between treatment groups were greatest. It should be stressed that the anti-ischaemic effect of amlodipine may also have contributed to the lower rates of myocardial infarction, compared to valsartan group. These data from the VALUE study showed that even small differences in blood pressure control (4.0/2.1mmHg after 1month; 1.5/1.3 mmHg after 1 year) can result in large differences in event outcomes.15 Hence this study sends a powerful message confirming the paramount importance of meticulous blood pressure control in a relatively short period of time (weeks rather than months) for high-risk individuals.

Drug class comparisons: insight from ALLHAT

While treatment to blood pressure goal is crucial, the specific drug class used to achieve blood pressure target may also be relevant and this has been an issue of concern. The ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) study is, to date, the largest clinical trial to assess the efficacy of various antihypertensive drugs on cardiovascular endpoints.16 It included 33,357 hypertensive patients randomized to treatments, including chlorthalidone, amlodipine, lisinopril and doxazosin. Doses were titrated to achieve a blood pressure goal of 140/90mmHg. Step 2 add-on drugs included atenolol, reserpine or clonidine, with hydralazine being used as a Step 3 add-on drug. The subjects were followed up for 5 years. The doxazosin arm was discontinued early due to a high incidence of heart failure. The major clinical findings16 are summarized as follows:

  1. No difference in the primary outcome of combined fatal coronary heart disease (CHD) or non-fatal or fatal myocardial infarction, and the secondary outcomes of all cause mortality, end-stage renal disease, peripheral vascular disease, or cancer, between the 3 treatment groups.
  2. Lisinopril had a 10% higher incidence of combined cardiovascular disease, a 15% higher incidence of stroke and a 19% higher incidence of heart failure than chlorthalidone.
  3. Amlodipine had a 38% higher incidence of heart failure compared to chlorthalidone.

The results of the ALLHAT study should be interpreted with caution. Notably, in the lisinopril group, the systolic blood pressure was 2 mmHg higher compared to chlorthalidone group for the 5-year period.16 This is most likely to be a result of the unusual treatment protocol. The addition of atenolol as a Step 2 add-on drug to lisinopril does not make it an appropriate combination since both drugs act on the renin-angiotensin system. In contrast, adding atenolol to either chlorthalidone or amlodipine has synergistic effects on blood pressure reduction. Furthermore, the high incidence of heart failure in amlodipine-treatment group may be an overestimation since the definition of heart failure in this study was very loose. It is plausible that many cases of amlodipine-induced ankle oedema were classified as heart failure. Indeed, the ALLHAT study has been intensively criticized mainly because of its unusual study design.17,18 Nevertheless, based on the results of the ALLHAT study, thiazide diuretics have been advocated by JNC-7 as the preferred drugs for the initial treatment of uncomplicated hypertension.9 This recommendation from the U.S., however, has not been shared by guidelines from other countries.14

Evaluation of hypertensive patients

Family physicians should obtain a thorough medical history and perform appropriate examinations. Several essential investigations are required (Box 1). The evaluation aims to assess possible causes of hypertension, associated cardiovascular risk factors, evidence of target-organ damage and comorbid disease, all of which may influence treatment decisions. More complex hypertension cases may require specialist referral (Box 2).

Blood pressure targets

It is now clear that in the management of hypertension, the crucial issue is treat-to-target rather than debating which is the best initial antihypertensive drug. The following blood pressure targets should be achieved:9,19,20

  • 140/90 mmHg   Hypertensive patients without diabetes or kidney disease
  • 130/80 mmHg   Hypertensive patients with diabetes or kidney disease
  • 125/75 mmHg   Hypertensive patients with proteinuria >1g/d

    • Evidence-based choice of antihypertensive therapies

    Non-pharmacological interventions

    While drug therapy is the mainstay in the management of hypertension, life-style modification should not be neglected. A number of clinical trials such as TOHP-1 (the first Trial of Hypertension Prevention),21 TOHP-2 (the follow-up Trial Hypertension Prevention),22 TOMHS (the Treatment of Mild Hypertension Study),23 and the DASH (Dietary Approaches to Stop Hypertension) study24 showed that weight reduction and restriction of sodium intake to 100mmol/d are effective measures in blood pressure reduction. In addition to blood pressure, weight reduction through diet and exercise confers benefits to other cardiovascular risk factors such as lipids.

    Thiazide diuretics

    The JNC-7 guideline recommends the use of thiazide diuretics as the preferred drug in patients with uncomplicated hypertension and without compelling indication for other drugs (Table 1).9 This recommendation is based on results of the ALLHAT study16 and most of other outcome studies25 in which treatment with thiazide diuretics has been shown to reduce cardiovascular events, especially in elderly patients.26 Diuretics also enhance efficacy of multiple drug regimens and are of low cost. The metabolic side effects of hypokalaemia, hyperglycaemia, hyperlipidaemia and hyperuricaemia occur with low dose therapy or when combined with other drugs.27 Serum potassium levels should be monitored regularly in patients on thiazide diuretics.

    Angiotensin-converting enzyme (ACE) inhibitors

    There is accumulating evidence that ACE inhibitors are effective in reducing cardiovascular complications in hypertensive subjects. In the HOPE (The Heart Outcomes Prevention Evaluation) study, ramipril significantly reduced the rates of death, myocardial infarction and stroke in a broad range of high-risk patients without heart failure.28 They are particularly effective when combined with thiazide diurectics. In the PROGRESS (The Perindopril Protection against Recurrent Stroke Study) trial, combination therapy with perindopril and indapamide produced a much greater reduction in blood pressure than either drug alone (12/5mmHg vs 5/3mmHg). This translated into a significant risk reduction in stroke (by 43% compared with placebo).29 Angiotensin-converting enzyme inhibitors are also the drug of choice in diabetic nephropathy though the evidence is stronger for type 130 than type 2 diabetic patients.31 In Hong Kong Chinese hypertensive type 2 diabetic patients, it has been shown that treatment with enalapril was associated with greater reduction of albuminuria than nifedipine over a 5-year period.32 The recently published DETAIL (Diabetics Exposed to Telmisartan and Enalapril) study comparing the efficacy of ramipiril and telmisartan in halting the deterioration of glomerular filtration rate in type 2 diabetic patients with nephropathy showed similar efficacy over a 5-year period.33 There is some evidence that combination with calcium channel blocker may provide additional renal protective effect in normoalbuminuric type 2 diabetic hypertensive patients. In the BENEDICT (Bergamo Nephrologic Diabetes Complications Trial) study, the use of trandolapril plus verapamil and trandolapril monotherapy decreased incidence of microalbuminuria compared to verapamil or placebo over 3.6 years.34 Benefits have also been shown in the diabetic population without nephropathy in terms of cardiovascular outcomes,35 and discontinuation of therapy is associated with a significant increase in mortality in Hong Kong Chinese.36 ACE inhibitors are also drug of choice in patients with heart failure.37 There is, however, no additional benefit in using ACE inhibitor therapy in stable CHD with normal cardiac function.38

    Angiotensin II receptor antagonists

    Angiotensin II receptor antagonists are also known as angiotensin receptor blockers (ARBs). This class of drugs has largely been reserved for patients who are unable to tolerate ACE inhibitors (mainly due to cough). The under-usage of ARBs may also be related to cost issues. It has been shown that cardiovascular mortality is greatly reduced with ARB therapy in hypertensive patients with LVH when compared with a b-blocker.39 Evidence is also strong for renal protection in type 2 diabetic patients with nephropathy as shown by the RENAAL (Reduction In Endpoints in NIDDM with Angiotensin II Antagonist Losartan)40 and IDNT (Irbesartan Diabetic Nephropathy Trial) studies.41 The renal protective effects of ARB (only evidence in losartan) appeared to be even greater in Asians,42 a population in which prevalence of diabetic renal complications is particularly high. In a prospective study of Hong Kong Chinese, it has been shown that losartan (but not felodipine) has anti-albuminuric effects in both diabetic and non-diabetic patients with hypertension.43 In addition, benefit in total mortality reduction is also seen with ARB therapy in patients with heart failure,44,45 an effect similar to ACE inhibitor but better tolerated with lower incidence of cough.45 In the VALUE study, despite lower efficacy in blood pressure reduction in the valsartan-based regimen compared with amlodipine-based regimen, the valsartan treatment group had significantly lower incidence of heart failure.15 A new ARB, olmesartan, will soon become available which is thought to have better tissue binding affinity. As with ACE inhibitor therapy, ARBs are contraindicated in patients with renal artery stenosis, and caution is required in patients with renal impairment due to risk of hyperkalaemia. Bedside auscultation for femoral bruit is often useful in identifying subjects for renal doppler assessment given the close relationship between peripheral vascular disease and renovascular disease. The incidence of cough, which is high in some Asian countries,47 is no higher in ARBs when compared to placebos. Similarly, angioedema is also less common with ARBs. A potential benefit in renin-angiotensin system blockade is decreased incidence of new-onset diabetes,46 especially in overweight hypertensive subjects with the metabolic syndrome. This subject has been reviewed recently.48

    Calcium channel blockers

    A 45-year old woman presented with weight gain, coarsening facial features and hypertension.

    Calcium channel blockers (CCBs) are generally effective and safe antihypertensive drugs with neutral effects on metabolic profiles. The dihydropyridine group of CCBs (such as nifedipine) is as effective as diuretics in blood pressure reduction.49 Good efficacy can also be achieved when combined with a b-blocker. As monotherapy, they should be avoided in patients with CHD as reflex tachycardia could potentially exacerbate angina although in the recent ACTION (A Coronary disease Trial Investigating Outcome with Nifedipine gastrointestinal therapeutic system) trial, addition of nifedipine GITS had no effect on the rate of myocardial infarction.50 Unlike nifedipine, the third generation dihydropyridinem, amlodipine, does not induce reflex tachycardia and has been widely used as first or second line drug for uncomplicated hypertension. In the VALUE study, treatment with amlodipine-based regimen have greater blood pressure reduction than valsartan-based regimen, especially during the first 3-6 months of trial which accounted for greater risk reduction in stroke and myocardial infarction observed during that period.15 Ankle oedema is not uncommon and tends to occur at high dose. Like amlodipine, the non-dihydropyridine type of CCBs (such as diltiazem) has anti-ischaemic properties and is useful as anti-anginal therapy. Combination of non-dihydropyridine type of CCBs (such as diltiazem or verapamil) with b-blocker should be used with caution due to the risk of precipitating heart failure and heart block. Interestingly, there is some evidence that CCBs are more effective in patients who are unable to restrict their sodium intake.51

    -Blockers

    -Blockers have long been regarded as first line hypertensive drugs10 and widely used as comparative therapy in randomized controlled clinical trials of hypertension.39,52-54 They are generally effective with blood pressure lowering efficacy not inferior to drugs in other classes.55 They are suitable in patients with a hyperdynamic circulation, in those with angina or post-myocardial infarction. One of the most widely prescribed b-blockers for hypertension in Hong Kong is atenolol. Its efficacy in reducing cardiovascular morbidity and mortality is clearly inferior to losartan for the same degree of blood pressure control in hypertensive patients with LVH as shown in the LIFE (Losartan Intervention For Endpoint reduction in hypertension) study.39 Furthermore, there is a tendency for higher incidence of new-onset diabetes.39 In a recent meta-analysis, Carlberg and colleagues analysed all randomized controlled trials that assessed the effect of atenolol on cardiovascular morbidity and mortality in patients with primary hypertension.56 They found that when comparing atenolol and placebo in four major studies, despite major difference in blood pressure lowering in favour of atenolol, there were no outcome differences between atenolol and placebo. More alarmingly, when compared with other active treatment there was a significantly higher mortality with atenolol in five studies (comprising over 17,000 patients) of substantial follow-up period (mean 4.6 years).56 Although these findings may not apply to other b-blockers, they clearly challenge the widespread use of atenolol as first line antihypertensive drugs. The adverse outcome data may be related to the unfavourable metabolic profile which makes b-blockers unsuitable for the overweight hypertensive subjects with the metabolic syndrome,57,58 especially when combined with thiazide diuretics. Furthermore, the incidence of glucose intolerance and erectile dysfunction is more common with this combination.

    -Blockers

    -Blockers such as doxazosin, prazosin and terazosin are useful add-on drugs in the management of hypertension and have previously been widely used in patients with end-stage renal disease. In the ALLHAT study, the doxazosin arm was discontinued early due to high incidence of heart failure.16 Despite this finding, a-blockers are generally safe in patients with normal cardiac function, do not have adverse metabolic effects and are suitable in hypertensive patients with benign prostatic hypertrophy.59 Caution is required in the elderly due to postural hypotension.

    Centrally-acting drugs

    These drugs, including methyldopa and clonidine, act through the a2-adrenoreceptor in the central nervous system to reduce sympathetic vasomotor tone. Their use is generally limited by side-effects such as drowsiness, depression and dry mouth. Methyldopa still has a role in the management of hypertension in pregnancy. Clonidine, however, is rarely used due to the risk of hypertensive crisis on sudden withdrawal. With the availability of other antihypertensive drugs having better efficacy and tolerability, these drugs are rarely used nowadays.

    Achieving blood pressure goal: need for multiple drug therapy

    Multiple complex pathophysiological processes are involved in the pathogenesis of primary hypertension. Hence single drug therapy targeting a specific mechanism is often inadequate to achieve target blood pressure levels. In fact, it has been shown that monotherapy for hypertension is only successful in achieving blood pressure target in 50-60% of cases.60 In major hypertension clinical trials, more than three antihypertensive drugs are often required to achieve blood pressure goals (Figure 1).20,61-65 In Hong Kong, a survey from a local hospital showed that 60% of patients were taking more than one antihypertensive drug.66 Despite multiple drug therapy, only 63% of subjects in the ALLHAT trial achieve blood pressure <140/90mmHg.16 The generally recommended approach in drug combination is to start with a low-dose drug and add in another low-dose drug rather than titrating up the dose of a single drug to minimize side-effects. Certain drug class combinations produce synergistic effects. For instance, adding an ACE inhibitor or ARB to a thiazide diuretic will compensate for the hypokalaemic effect of diuretics. Combination of ACE inhibitors and CCBs also produces sustained blood pressure reduction than either drug alone.67 In the recent INVEST (The International Verapamil-Trandolapril Study) trial, verapamil-trandolapril-based regimen was clinically as effective as the atenolol-hydrochlorothiazide-based regimen in hypertensive patients with CHD.68 Given the well-recognized synergism of various classes of antihypertensive drugs, many fixed low-dose antihypertensive drugs are now available27 which not only improves efficacy but may also improve drug compliance. In addition to hypertension management, the overall cardiovascular risk management should be strongly emphasized. This includes the appropriate use of lipid-lowering drugs and anti-platelet drugs for further reduction in cardiovascular complications.

    Conclusion

    Controlling hypertension remains a challenge for family physicians. Recent clinical trials have demonstrated the importance of tight blood pressure control in reducing cardiovascular complications and emphasized the need for multiple drug therapy to achieve blood pressure goals. Adherence to guidelines is important but cannot replace clinical judgment and discussion with the patient. The clinician should bear in mind the compelling indications for specific classes of drugs. Low-dose multiple drug therapy is effective and minimizes potential side-effects. In any hypertensive patient, the overall cardiovascular risk profile needs to be taken into account in the management to minimize the risk of future cardiovascular events.

    Key messages

    1. Despite being a major risk factor for cardiovascular disease, hypertension is poorly controlled worldwide.
    2. Several hypertension guidelines exist which vary in terms of recommended initial drug therapy.
    3. Recent hypertension trials demonstrate the paramount importance of blood pressure control regardless of the class of antihypertensive drug used.
    4. Achieving blood pressure goal is often difficult and frequently requires multiple drug therapy.
    5. The use of ACE inhibitors or ARBs is indicated in patients with signs of target-organ damage (LVH or albuminuria).
    6. In addition to blood pressure, management of global cardiovascular risk factors is of paramount importance.

    N N Chan, MRCP, MD
    Clinical Director,
    Qualigenics Diabetes Centre.

    P C Y Tong, PhD, FRCP
    Associate Professor,

    J C N Chan, MD, FRCP
    Professor,
    Department of Medicine & Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong.

    Correspondence to : Dr N N Chan, Clinical Director, Qualigenics Diabetes Centre, Upper level, Pier 3, 11 Man Kwong Street, Central, Hong Kong.

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