PROGNOSIS OF HYPERTENSION

Risks of untreated hypertension
Strong association between blood pressure and the incidence of major coronary artery disease manifestations, congestive heart failure, stroke, and total mortality have now been established. Risk of any of these is also modified by other risk factors. Tobacco smoke effects the risk for all the previously mentioned end points. Lipid abnormalities have a role in the predictability of coronary artery disease and total mortality. Proper management of other risk factors is very essential in the prevention of cardiovascular diseases. (8)
Among 3,56,222 men screened for the MRFIT trial more than 2000 coronary deaths occurred during six years follow up. Detailed cross tabulation showed a very strong graded relationship between blood pressure and coronary artery disease death in this group. Systolic blood pressure was more strongly associated with the coronary artery disease death than was diastolic blood pressure, and isolated systolic blood pressure was an important risk in middle aged men. Smoking and high cholesterol increase these risks. (9)
30 years’ follow up data of the original Framingham Cohort of 5070 men and women between 30 and 62 years of age showed blood pressure to be a very strong and consistend predictor of coronary artery disease, stroke, T.I.A. and congestive heart failure. Other factors like obesity, ECG evidence of LV hypertrophy, and X-ray evidence of heart enlargement were additional predictors noticed in this study.(10)

Risks of treated hypertension
The design and results of 17 large scale, controlled clinical trials of the effect of drug treatment for hypertension were reviewed by Kitlar and his colleagues. 7 trials conducted in city populations with more severe hypertension (diastolic 100 to 120 or higher), including the more severe stratum of the VA trial, showed large reductions in strokes and other hypertensive events, and in one trial, the total mortality. Of 11 trials with less severe hypertension (diastolic below 105) only 9 studies were adequately done. Of the 43,000 patients in these 9 studies, a reduction in the mean diastolic pressure of 5.8 mm Hg showed a significant 11% fall in total mortality. This was largely due to the 38% reduction in fatal strokes and similar reduction in non-fatal strokes. Coronary artery disease was 8 percent less in drug treated group but this difference was not significant. (11)
Even though it is claimed that all declines in stroke mortality were due to the treatment of high blood pressure, a critical look at these studies suggests that anti-hypertensive treatment probably resulted in about 16 to 25 percent decline in stroke mortality. Three-quarters of the decline in stroke mortality in the USA during the period 1970 to 1980 is definitely due to factors other than anti-hypertensive treatment. (12) Treatment of hypertension is not without any danger.(13)

NON-PHARMACOLOGIC TREATMENT OF HYPERTENSION
Drug treatment of severe hypertension has been proved to be effective in lowering the disabling and fatal complications of hypertension, although the proof of the same has not been satisfactorily documented. (13) Now, drug treatment has been extended increasingly to patients with milder forms of hypertension. (14) The latter involves millions of people and the long term effects of mildly evelated HBP have not been adequately recorded. There is also growing concern of the long term safety of drug therapy in this group. (15) Diuretics, which are the most widely used drugs in the treatment of mild HBP, have come up into greater scrutiny in this regard. (15) Some of the risks attributed to diuretics seem to be imaginary. (16)
There is a significant number of patients who, even with a careful diagnosis of mild hypertension, become normotensive over a period of time and on placebo only. (17) Western world does not realise the economic burden of treating unnecessarily millions of mild hypertensions with costly drugs which might ruin our health services. (16)
With this backdrop non-pharmacologic treatment of mild hypertension becomes mandatory. It will help reduce the cost of drugs and/or their dosage with concomitant reduction in the unpleasant side-effects of these drugs. If they are tried in addition to drugs, even in the severe hypertensive patients, the side effects will be less . (17)
It is now common knowledge that the level of BP in isolation has very little prognostic value. (18) It is the accompanying bad risk factors, like smoking, and serum cholesterol, etc., which ultimately decide the outcome. This is another reason why we should be vigorous in non-drug therapy of hypertension.
The measures to be discussed in some detail are:
(I) smoking, (ii) weight control, (iii) alcohol, (iv) physical exercise, (v) stress management and relaxation exercises, (vi) diet and (vii) acculturation.

Whom to treat ?
The WHO has given clear guidelines for the treatment of mild - moderate hypertension, defined as diastolic pressure between 90 and 104 mm Hg without any target organ damage. These guidelines are probably not valid today as the MRFIT screening data has very clearly shown that it is the systolic pressure that is a greater risk indicator and diastolic pressure is probably not a risk indicator. The question of target organ damage is also difficult to decide on the bedside. There have been recent reports about very early invovlement of the kidneys even in mild hypertensives detected by such sensitive tests like microalbuminuria (radio-immunoassy method) suggesting early glomerular damage and beta NAG test to detect early tubular damage. (18) Majority of mild hypertensives have these tests positive, but by the conventional methods; the kidneys look normal in most patients with mild hypertension.
Hence the indication for treatment of mild hypertension could be assessed after making sure that the individual’s blood pressure is elevated above the normal on at least 3 different occasions and after 3 separate estimations each time. Though the Australian study has shown that about 30% of people with mildly elevated hypertension eventually become normotensive on placebo alone, other studies like the Hypertension Detection and Follow-up Programme (HDFP) (19) study have shown that a significant percentage of untreated mild hypertensives go on to severe hypertension in the succeeding 2 years. This makes it very difficult to find out who amongst the mild hypertensives eventually develops significant and established hypertension. There is a claim put forward by Pickering and his colleagues that the work place blood pressure correlates better with mortality and morbidity. It should be agreed that ambulatory blood pressure monitoring is still in the experimental stage and conclusions drawn so far may not be applicable to clinical practice today. It must be remembered that the cost involved is prohibitive for a country like ours.
We have put forward a hypothesis about a simple bedside test to the future course of mildly elevated blood pressures. (20)
The recommendations of the recent British Hypertension Society Working Party are as follows. (21)

1. Treat patients under 80 years with DBP over 100 mm Hg for 3-4 months.
2. Observe patients with pressures of 95-99 mm Hg every 3-4 months.
3. Use either diuretics or B-blockers as first line treatment.
4. Use other agents if these are contraindicated, ineffective or poorly tolerated.
5. Warn all patients against smoking and heavy alcohol.
6. Advice weight reduction in obese patients.

When in doubt it is better to treat than to wait. One can always review the situation. If the blood pressure quickly returns to normal and remains normal even after withdrawing the drugs, the treatment then may be stopped. One should keep a watch on the blood pressure at frequent intervals. Unlike what was thought in the olden days, a hypertensive on drugs need not be on drugs for ever. (21)
Recent studies have shown that in a small percentage of patients even with severe grades of elevated blood pressure, one may be able to stop drug therapy either permanently or for long periods of time after the pressure normalises for some time.
It must be stressed here that drug therapy is to be considered in mild hypertensives only after the other non-pharmacological avenues, discussed earlier, have all been exhausted.

Drugs in the Management of Hypertnesion
Most of the studies on mild hypertension starting from the United States Public Health Study, the HDFP study, the Oslo study, Australian study and MRC study, the EWPHE study and the IPPPSH study have all used the time hinoured conventional diuretics (with Potassium sparing diuretics in some) and beta-blockers. The newer vasodilator antihypertensive drugs have not been used in these studies. It is unlikely that large scale prospective studies will ever be done again using the newer drugs. We have to depend on smaller individual studies of these newer drugs. There is a growing view that large-sized multicentric clinical trials may not be very useful.

Diuretics
Majority of hypertensives including those in old age respond well to diuretics. They are the cheapest antihypertensive drugs. People also calim that diuretic treated hypertensives have less number of strokes. Thiazide diuretics have been the mainstay of antihypertensive treatment. Potassium sparing diuretics have been used in but two of the above mentioned studies. Loop diuretics and aldosterone antagonists have not been extensively studied.
Thiazide diuretics came under a cloud after the results of a subset analysis of Multiple Risk Factor Interventional Trial (MRFIT) study which showed that in that subset of patients with high blood pressure who entered the protocol with basal changes in the resting ECG, there have been twice as many deaths in the special care group as compared to the usual care group.
This was very quickly followed by studies from various centres which showed that Thiazides change the fat profile in treated hypertensives in such a way that the altered fat profile poses a greater risk for developing coronary atherosclerosis. There have been reports about diuretics increasing the uric acid levels and also producing significant hypokalaemia and hyperglycaemia. All these have been said to be the causes of increased morbidity in diuretic treated individuals.
The MRC study showed that the diuretic induced hypokalaemia is insignificant in the normal course but might become very marked and dangerous under stress of daily living. The potassium sparing diuretic combination used in EWPHE study did not produce this side effect. Interestingly, long term studies of diuretic treated individuals showed that the intitial alterations in the serum biochemistry of patients returns to the pre-treatment levels with time.
Our own data has shown that after 4 to 5 years, on diuretics the serum chemistry is much better with respect to the risk factor as compared to the serum chemistry of age and sex matched individuals who have not had diuretic therapy.( 22 )
It is quite premature now to condemn diuretics outright. It is suggested that when thiazide diuretics are used, the dosage should be kept to the minimum and a postassium supplement or potassium sparing agent like triamterene or amilioride should be used. Diuretics could be used even in old age with the same precautions. The only difference in old people is that treatment should be started with very small dose and gradually increased. Blood pressure should always be measured with the patients lying and standing as in many elderly people, the standing blood pressure is near normal even when lying blood pressure could be quite high. Our aim should be to keep the standing blood pressure to near-normal.
Thiazide diuretics may be avoided in diabetics, and if inevitable, careful monitoring of blood sugar and serum potassium should be done. Potassium supplement should be given with caution in diabetes and in patients with renal failure as both these conditions might be associated with hypokalaemia. Even spironolactone should be given with caution to diabetics as many of the diabetics have an inherent hypoaldosteronism. Potassium supplement should be given with caution in old age. Recent JNC V report has recommended diuretics as the first choice.

BETA-BLOCKERS:
Were first recommended for initial antihypertensive therapy in the III Joint National Committee report in 1984. Nine beta-blockers were listed in the IV JNC. Oxprenolol was deleted and Acebutalol and Perbuterol were added.
Several beta-blockers have been shown to reduce sudden death after Myocardial infarct. Beta-blockers are particularly effective in young hypertensives with "hyper-kinetic" circulation.
Age and beta-blocking effect have an inverse relationship, i.e., they are less effective in older age groups. However, even elderly patients with associated myocardial infarct may benefit from beta-blockade.
Beta-blockers on short term might adversely affect the fat profile but in the long run they get corrected. Beta-blockers have anti-atherosclerotic properties in animals but not proven in man. Fatigue, lethargy, depression, insomnia and hallucinations occur less ofter with hydrophilic beta-blockers (acebutolol, atenolol, nadolol) but can occur with any of these drugs.
Dyspnoea, bronchospasm, Raynaud’s phenomenon (rare in India) may also occur. Gout and impotence are not rare either.
Presence of heart block greater that 1st degree, congestive failure and/or bronchial asthma are contra-indications. Interestingly, hypertensives who have early diastolic dysfunction resulting in a clinical picture of left ventricular failure where the systolic function of the left ventricle is very good, respond very well to beta-blockers.

Calcium Channel Blockers
This class of smooth muscle relaxants produce a fall in the arterial pressure. Newer generation calcium channel blockers are in the pipe line and they may not have the usual side effects of the presently available drugs like Nifedipine which gave rise to tachycardia ankle oedema and flushing. Calcium channel blockers occasionally give rise to adverse skin reactions of all known types.
All calcium channel blockers have negative inotropic effect and should be used with caution in patients with congestive failure. These are antianginal agents as well. They are under a cloud at the time and we may know more about them in the very near future.

ACE inhibitors
The first orally-active angiotensin converting enzyme (ACE) inhibitor was the sulphydryl-containing drug, captopril. The second agent in this class, without sulphydryl group, was enalapril. For enalapril to produce its effect it must first be activated by metabolic cleavage in the liver to the di-acid enalaprilat. This active molecule is too hydrophilic to be well absorbed from the G.I. tract: enalapril therefore acts as a pro-drug to facilitate absorption. Lisinopril is the lysine analogue of enalaprilat. The presence of lysine residue makes the molecule less hydrophilic and the active drug is absorbed as such.
Unlike beta-blockers and calcium channel blockers, ACE inhibitors are useful in treating associated congestive failure. They can be used alone or with diuretics.
They are well tolerated but may cause renal failure in patients with renal artery stenosis. Hyperkalaemia in the presence of renal failure, skin rash, cough, angioneurotic oedema and taste disturbance have been reported. Since hypertension is characterised by increasing peripheral vascular tone and abnormal water and sodium excretion, it makes sense to use, captopril, and its analogue enalapril, which prevent the conversion of angiotensin I to angiotensin II. They may also have effects such as inhibition of degradation of the vasodilator peptide bradykinin, and stimulation by the accumulated angiotensin I of a vasodilator metabolite of prostaglandin PGE2 called PGE2-M, which is a powerful vasodilator. Enalapril is less toxic without the SH group and is longer acting but it is a prodrug and, as such is poorly absorbed. These drugs are very effective in certain subsets of patients with hypertension like renal hypertension, diuretic treated patients and those patients with malignant hypertension who are resistant to treatment.
The sulphydryl group in captopril may have a vital role of ‘free radical scavenging’ when used in acute myocardial infarction where free radicals are supposed to do a lot of damage.
Profound hyportension may occur sometimes with atenolol or even captopril. This may happen in patients with low renin hypertension. It is always advisable to use very small doses of these drugs in the beginning and see the response before increasing the dose as otherwise the profound fall may damage the brain or lead to other catastrophic eventualities.
Recent JNC report in 1988 has modified the step-care treatment, as also the 1993 JNC V report.

Follow up:
While on drug therapy patients must be regularly followed up both to check efficacy of control and also to monitor the side effects of drugs. If the patients are being tried on non-pharmacologic methods, the blood pressure can be checked at least once in 3 months. Those on drug therapy should also have periodic blood chemistry studies done. Since the risk of vascular disease is very high in hypertensives who are also diabetics, an attempt must be made to control their diabetes effectively.

REFERENCE

1. Hegde BM. Hypertension - The Other side of the coin. J Assoc Phys India 1988;36:271-77.
2. Shushrutha Samhita: Chapter 45. Verse:34.
3. Folkow B. Physiologic aspects of primary Hypertension. Physiol. Rev:1982;62:347-504.
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11. Kitlar JA, Mc Mohan SW, and Furburg CD Controlled trials and hypertension. Hypertension. Hypertension 1989:13 (suppl 1):36-44.
12. Bonita R and Beaglehole AR. Drug treatment of mild hypertension. Hypertension 1989;13 (suppl 1):69-73.
13. Anonymous Dangerous antihypertensive treatment (editorial), Br Med J. 1979:II:228-229.
14. Hegde BM. Should we treat hypertension ? Bull. VHS, Madras 1984;54:4-8
15. 1988 Report of JNC on detection and treatment of hypertension. Arch Intern Med 1988;148:1023-1038.
16. Kaplan NM. Therapy of mild hypertension - an overview. Am. J Cardiol 1984;53(Suppl A):2A-8A.
17. Moser M. Diuretic dilemma and the management of hypertension. J Clin.
18. Ledingham J.G.G. Early assessment of organ involvement in hypertension. J.Hypertens 1985;3 (Suppl 2):S33-35.
19. Hypertension Detection and Follow-up Program Group. Five year findings of the hypertension detection and follow-up program: I. Reduction in mortality of persons with high blood pressure, including mild hypertension. JAMA 1979;242:2562-2571.
20. Hegde BM. Postural hypertension. An indicator of significane J.Assoc.Phys.Ind.1989;37:127.
21. Working Party:British Hypertension Society. Treating mild hypertension. Br. Med. J. 1989;298:325-329.
22. Hegde BM. Rao AC.Bhat EK and Rao Raghunandan. Cardiovasc Drugs and Ther. 1987;1:310.

Prof. B.M.Hegde,
MD., FRCP(Lond).,FRCP(Edinb)., FRCP(Glasg.) FACC.,
Dean,
Kasturba Medical College, Mangalore 575 001.
INDIA

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