Antihypertensive therapy: time to review the goal?

Hypertension heads into the 90's The use of conventional therapy to control BP has failed to prevent both the development and

progression of coronary heart disease . Furthermore, several recent studies Including a community based study from Dalby in Sweden and the Medical Research Council trial , have demonstrated that antihypertensive therapy does not restore the mortality of treated hypertensives to that of the non hypertensive population . HypertenSion and ItS relationship with atherosclerOSIS and other cardlovas cular risk factors IS still unclear , but a number of other factors may account for the failure to Improve coronary heart disease outcome. It IS pOSSible that the BP reduction achieved by drug treatment IS too small . However, studies have revealed that hypertensive treatment IS effective In only a small fraction of patients anyway . It IS estimated that only one-half of hypertensive patients have been identified, half of them are treated and only half of these have BP that IS optimally controlled Another possible factor is that the means by which a drug lowers BPis important for the prevention of coronary heart disease. 'vVt"lile cefiain drug families have propedles Wt"UCII (nay be lavoulabie 101 the I_Heveflilull of atherosclerosIS , until the exact mechanisms Involved in both hypertension and atherosclerosIs are known , this must be regarded as purely speculative . A final pOSSibility IS that while treating hyper tension, other important risk factors are being Ignored or even aggravated For example the Medical Research CounCil trial revealed that patients who smoked and received {j-blockers were more likely to suffer a stroke. Other pOSSible deleterious effects of hypertensive treatment Include metaboliC effects such as changes in blood lipids, electrolytes and glucose levels. All such possibilities should be considered while there IS no defined link between hypertension and coronary heart disease

In recent times , stepped care therapy comprising a cardioselective p-blocker. then a diuretiC as the second choice, followed by a vasodilator as the step 3 drug has been developed . Such regimens have become popular both with patients , because of reduced adverse effects , and With doctors , because of their simplicity and efficacy. However, It appears that as many as 30-40% of patients on such a regimen show contraindications to I:l-blockers or diuretics , or have drug-induced adverse symp toms leading to withdrawal from therapy.

With the advent of new drug classes, alternative therapeutic options and combinations are now available, and in view of the disappointing mortality rates of treated hypertensives a different ap­proach to the treatment of hypertension may be Justified. In the conventional stepped care schedule, it is possible for a patient to take ~ 2 drugs which exert no antihypertensive effects but merely cause adverse reactions . A preferable approach would be to select the most appropriate monotherapy for each individual, and by monitoring the patient's response over a period of months, to select the most efficacious and best tolerated drug . Only then , If it is necessary , should a second drug With an established synergism or additive action, be considered . Examples of SUitable drug combinations in the treatment of hypertension include /3-blockers plus diuretiCS, calcium antagonists (nifedipine or dihydropyridine type) or a-blockers : ACE inhibitors plus diuretics , or calCium antagonists : a-blockers plus calcium antagonists .

Such a stepped-care protocol will dominate the treatment of hypertension in the forseeable future Until the inter-relationship between hypertension and atherosclerosis IS understood the hypertensive patient, even when treated successfully, Will be at risk of coronary heart disease. Reid Jl. Journal 01 Hypertension 6: 3-8, Jan 1988 ,,,2

Considering the metabolic side effects of antihypertensive therapy Recently, it has been recognised that metabolic changes caused by some antihypertensive drugs

are important cardiovascular risk factors, and thus BP reduction should not be the only aim of hyper­tension management.

Diuretics are effective antihypertensive agents In salt-sensitive patients . However, patients receiv ­ing diuretics in the Multiple Risk Factor Intervention Trial (MRFIT) had a relatively high mortality rate . and other studies have shown that diuretic-induced hypokalaemia can cause ventricular arrhythmias, even in patients without evidence of underlYing cardiac disease. Concomitant use of a potassium sparing diuretiC can reduce the risk of arrhythmia development, although magnesium, as well as potassium depletion, may be Important. Additionally, potaSSium depletion can reduce the patients ability to survive a myocardial Infarction which IS important in the light of recent eVidence Indicating that cardiac dysfunction IS common In patients with hypertension

Thiazide and loop diuretics increase serum cholesterol and triglyceride levels and may adversely affect the LDL/HDL ratiO, thus increaSing the risk of atherosclerOSIS development Hyperlipidaemla has been reported with doses of hydrochlorothiazide as low as 12.5 mg/day. p-Blockers Without In ­trinsic sympathomimetic activity increase triglyceride and lower HDL cholesterol levels . However, the atherogeniC potential of /3-blockers has not been fully established in man or in animal models CalCium antagonists and ACE inhibitors do not significantly affect serum lipids, and ai-blockers , central (I

agonists and ll//3-blockers may have a favourable effect. Welghl reduction IS probabl y more Important than drug therapy in influencing the lipid profile, particularly in obese patients A baseline lipid prof tie should be performed on all patients with hypertension .

10 INPHARMA"' 6 Aug 1988 0156-2703/88/ 0806-0010/ 0$0100/ 0 © ADIS Press

Glucose intolerance can occur with diuretic therapy, mainly because of hypokalaemia blunting the response of insulin to glucose. However, diuretics also increase renin and catecholamine release, and angiotensin and norepinephrine stimulate glucose production. Consequently, lower drug doses are used and have since been shown not to affect glucose tolerance. However, if intolerance develops, bumetanide can be used, or a drug from another class. Calcium antagonists are relatively free of adverse effects on glucose metabolism, although mild hyperglycaemia has been reported. ACE in­hibitors may improve glucose tolerance, perhaps because of increased insulin sensitivity secondary to kinin breakdown. Centrally-acting (l'-agonists and a1-blockers generally do not adversely influence glucose homeostasis. Part of the problem with glucose intolerance may be because of the recent observation that patients with essential hypertension frequently have insulin resistance.

In conclusion, antihypertensive agents can cause adverse metabolic effects namely electrolyte abnormalities, hyperlipidaemia or glucose intolerance, which may increase the risk of cardiovascular disease and thus should be considered during treatment. Hoiland OB. Pool PE American Journal of Cardiology 61 ' 53H·59H. Jun 1988 , .. ' Does thiazide-induced hypokalaemia cause arrhythmias?

There has been little evidence of any reduction in coronary heart disease-related mortality in trials involving antihypertensive drugs. As many antihypertensive regimens are thiazide based, it has been postulated that diuretic-induced hypokalaemia and possible secondary hypokalaemia-related arrhyth­mias may be involved. However, a recent study [see Clinical Pharmacology section, this issue, p 17] has shown no evidence of increased ectopia in hypertensive patients treated with hydrochlorothiazide. However, in this study there was evidence that patients with a greater degree of ectopia at baseline developed more hypokalaemia. Thus, the validity of the results from a trial that studies the relationship between ectopia and thiazide-induced hypokalaemia must be at question. Even if the evidence for thiazide-induced arrhythmias is somewhat doubtful, it is worth noting that in the Medical Research Council trial there was no difference in mortality and cardiac events in thiazide- and It-blocker-treated groups. Thus, it seems that diuretic-induced hypokalaemia does not cause cardiac death.

However, there is considerable evidence to suggest that thiazide-induced potassium depletion is associated with disturbances in glucose and insulin metabolism. Thus, low dose thiazides, restriction of sodium intake, addition of potassium sparing drugs or potassium supplementation are recom­mended to reduce thiazide-induced hypokalaemia. Langford HG. Archives of In lerna I Medicine 148 1255·1256, Jun 1988 ,,..

Recommendations for a national policy on hypertenSion in New Zealand Recent published data on the low cost effectiveness of the management of mild hypertension

(diastolic BP 8O-94mm Hg) has led to a need for reappraisal of current therapeutic strategies and the formulation of a new national policy in New Zealand,

Of people aged 35-64 years, approximately 20% have been diagnosed as hypertensive (BP ~ 160/ 95mm Hg). In New Zealand, approximately 10% of hypertension can be attributed to excessive alcohol consumption and 50% of the population are overweight. Smoking represents another modifiable risk factor for the development of elevated BP, The degree of hypertension correlates with risk of death, By population analysis, only 2,6% have a diastolic BP of ~ 105mm Hg which correlates with a risk of a fatal event of 70 / 1000 population / 6 years and accounts for 15% of the excess deaths associated with hypertension, Although mild hypertension carries a lower fatality risk ( 17/1000 population / 6 years), it accounts for 57% of excess deaths because of the higher proportion of the population with mildly elevated BP, However, the cost effectiveness of pharmacological treatment of mild hypertension is low. Cost effectiveness of therapy depends on the treatment employed and the patient population treated. Individualised non-pharmacological interventions may be more costly than drug therapy, but a population-based non-pharmacological intervention policy would have negligible individual costs with substantial effects on mortality. The effect on mortality of a national policy which could be realistically expected to decrease average weight by 10% would be the same as a policy which treated high risk hypertensives (diastolic BP ~ 100mm Hg). A combination of these strategies could decrease the number of deaths by 15%.

Thus, the authors recommended a population strategy for the primary prevention of hypertension by non-pharmacological means in addition to an individualised treatment of high risk patients with diastolic BP ~ 105mm Hg and end organ damage. Pharmacological management of patients with a diastolic BP < 105mm Hg without additional cardiovascular risk factors should be retained for those patients resistant to continued lifestyle modification. The first choice of drug therapy for hypertensive patients should continue to be thiazide diuretics or (J-blockers . Newer agents such as lr-blockers, calcium antagonists and ACE inhibitors have not demonstrated an improved preventive effect on cardiovascular disease than these traditional agents and, while they may provide a better quality of life, they are considerably more expensive ($NZ20/patient/annum for thiazide therapy vs $NZ400/ patient/annum for calcium antagonist therapy), Goal diastolic BP should be 90mm Hg Registers of general practice patients may facilitate the management of hypertension in the community. Beagtehofe R. Bonola R Jackson R Stewarl A New Zealand Medical Journal 101 480·483. 27 Jut 1988 .. , 0156·2703/ 88/ 08OfHXJ11 / 0S01.00/ 0 © ADIS Press INPHA,."A· 6 Aug 1988 11