Diuretic still remains the first line therapy in uncomplicated hypertension?
BACKGROUND :
Since the time primary hypertension (uncomplicated hypertension) was identified as a contributor of morbidity and mortality and required to be treated, diuretics have emerged as the first line antihypertensive therapy. Time after time several trials have demonstrated not only morbidity but mortality benefit with diuretic therapy in uncomplicated hypertension. Several JNC Guidelines have identified diuretics as the gold-standard for management of hypertension. As a matter of fact no individual can be labeled as resistant hypertension unless a concurrent use of 3 antihypertensive agents of different classes, of which at least one of them is a diuretic, has been prescribed at optimal doses. Interestingly, in real world practice, despite this robust clinical data, the use of diuretics has actually continued to decline. The reason of-course is because not only availability of newer, both effective and safe drugs but also linked to number of misconceptions prevailing about use of diuretics in ‘garden variety’ of hypertension such as:
- Diuretics are not as effective as other anti-hypertensive agents.
- Diuretics are less safe.
- Diuretics are less convenient to administer/ poorly tolerated.
- The use of diuretics is associated with significant adverse metabolic effects (increased lipid levels, adverse effects on glucose metabolism, effects on arrhythmias, etc.).
- Newer diuretics could be costly
EFFICACY :
In hypertension all the five major classes of drugs (low-dose diuretics, calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACE – I) or angiotensin receptor blockers (ARBs) and beta-blockers (BB) are effective in reducing blood pressure (BP) and cardiovascular (CVS) events. Furthermore, it is the tight control of BP which leads to reduction of CVS morbidity and mortality rather than class of drug used. However, the early landmark trials in treatment of hypertension did reveal a significant reduction of stroke, CVS morbidity and mortality when diuretics particularly thiazide diuretics were used. Even the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), which undertook head-to-head comparison between different anti-hypertensive agents, revealed that chlorthalidone was superior to other agents in preventing one or more major forms of CV disease. Several subsequent trials and meta-analysis revealed same. Overall, it was estimated that use of diuretics could prevented 15 strokes, 24 major CVS and 8 deaths for every 1000 patients treated for 5 years (with number needed to treat of 67, 41 and 118, respectively).
SAFETY AND TOLERABILITY :
Concerns about safety of diuretics have been a major reason for limiting their use. However, the available data reveals that diuretics either do not interfere with, or may actually improve, quality of life in hypertensive patients. In particular, low-dose diuretic treatment is a well-tolerated and could be an excellent initial choice for hypertensive patients, even elderly. A deeper insight may be obtained if the studies in which patients have had to stop their treatment because of adverse effects are analyzed. A meta-analysis involving 190 mono-therapy treatment trials in patients with primary hypertension revealed that discontinuations due to adverse events were rather more common with CCBs (7%) compared with ARBs or diuretics (3%) shattering the myth that diuretics are unsafe compared to some newer anti-hypertensives.
METABOLIC EFFECTS :
There is a small extra risk of type 2 diabetes with the long-term use of thiazide diuretics but that risk may be more linked to use of hydrochlorothiazide. The data with use of low dose chlorthalidone or low dose newer diuretics like indapamide may be more promising (daily doses of chlorthalidone and indapamide not exceeding 12.5 mg and 1.5 mg respectively). Low dose diuretics are also safer in patients with renal dysfunction and electrolyte imbalance, however it would still be prudent to record serum potassium, urea / creatinine, uric acid and fasting glucose before initiating the therapy and avoiding it in case of manifest dysfunction.
CONVINIENCE OF ADMINISTRATION :
Diuretics can generally be used in once daily dose but should be preferably administered in the morning (to avoid increased nocturnal micturition).
COST ANALYSIS :
Cost of therapy is always a major factor in choice of the therapy in particular when there are no major differences in efficacy, safety and convenience. Several analysis have revealed that a diuretic based therapy is the cheapest among all the anti-hypertensive agents.
WHICH DIURETIC TO USE :
High dose hydrochlorothiazide is equivalent in efficacy to any other first line anti-hypertensive drugs but do have safety and tolerability concerns particularly metabolic side-effects. Lose dose hydrochlorothiazide is generally safer but they lose their efficacy as well.
Most data with thiazide diuretics is available with chlorthalidone (versus hydrochlorothiazide) which is much safer than hydrochlorothiazide especially at low doses. Furthermore, unlike hydrochlorothiazide the efficacy still persists with low dose chlorthalidone ( ≤ 12.5 mg).
Indapamide is another diuretic which is equivalent in efficacy to any other standard anti-hypertensive agent even at low dose (1.5 mg) but has very few side effects or tolerability issues at this dose. One of the reasons for the beneficial effect of indapamide could be by virtue of its predominantly vascular effect, which minimizes the risk of diuretic related side effects like electrolytic or metabolic disturbances.
