European Heart Journal (1992) 13 {Supplement G), 92-95
Diuretics in hypertension: clinical experiences V. PAPADEMETRIOU
Department of Veterans Affairs Medical Center, Washington DC, U.S.A. KEY WORDS: Hypertension, diuretics, efficacy, side effects.
Early experience Chlorothiazide first became available for clinical evaluation in 1956 and its beneficial effects in lowering blood pressure were quickly recognized'11. In patients with mild or moderate hypertension, chlorothiazide was effective as monotherapy and in patients with more elevated blood pressure it was found to combine efficaciously with ganglion-blocking drugs, reserpine and hydralazine. These early studies led to one of thefirstmajor clinical trials devoted to evaluation of the influence of blood pressurelowering drugs on morbidity and mortality in hypertensive patients12*31. In this placebo-controlled study, a major reduction in cardiovascular events was observed in the patients with diastolic blood pressure (DBP) in the range 115-129 mmHg. In patients with DBP 105-114mmHgat entry, there was a statistically significant reduction in the incidence of major cardiovascular complications in those receiving active antihypertensive treatment compared to those receiving placebo. However, in patients with entry DBP 90-104 mmHg, there was no significant reduction in major cardiovascular events or improvement in survival over the average of 3-3 years of follow-up. This early landmark study firmly established that reduction in blood pressure in the hypertensive patient is clinically worthwhile, particuarly at the higher levels of blood pressure. It has been succeeded by numerous trials with a variety of other antihypertensive drugs in an attempt to establish similar benefits on the increased cardiovascular event rate, particularly in patients with mild hypertension.
developed, none have been demonstrated to be superior to diuretics when used either as monotherapy or in combination with other antihypertensive compounds. The thiazide diuretics hold a number of major advantages in the long-term treatment of hypertension. They are effective in controlling blood pressure in more than 50% of patients with mild or moderate hypertension when used alone and in potentiating the antihypertensive activity of all other currently available agents. Their dose-response relationship is relatively flat, so that the control of blood pressure is possible with relatively few side-effects. They are well tolerated, particularly in low doses, by the majority of patients, including the elderly, and their side effect profile is amongst the most favoured of antihypertensive drugs. They are unique amongst these agents in their ability to prevent fluid retention. These clinical advantages of the diuretics are significantly enhanced by their low cost compared to other antihypertensive drugs; this may be of crucial importance in a disease syndrome requiring continued administration of medication, sometimes over decades. There are three potential disadvantages in the use of these diuretics. They may precipitate gout or uncover diabetes mellitus in patients with a predisposition to these syndromes. Impotence in male patients appears as a side effect in 10-15% of patients receiving chronic treatment and in some this does not revert on discontinuing the drug. However, these side effects do not preclude the use of the diuretics in the majority of hypertensive patients.
Current experiences Although a wide variety of antihypertensive drugs with widely differing pharmacodynamic activities have been
Efficacy of diuretics
Correspondence: Vasilios Papademetnou, MD, Department of Veterans Affairs Medical Center, 50 Irving Si, NW, Washington, DC 20422, U.S.A. 0195-668X/92/0G0O92 + 04 $08.00/0
In addition to the early morbidity/mortality studies'2-31, a number of other studies have emanated from the Veterans Administration (VA) Group confirming the overall efficacy of diuretics in antihypertensive therapy. © 1992 The European Society of Cardiology
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on January 21, 2016
Diuretics have long been used in the treatment ofhypertension and are outstandingly efficacious when used either alone or in combination with other antihypet tensive compounds. Blood pressure is controlled with diuretics alone in over 50% of patients and in over 80% in combination with other drugs. Thiazide diuretics were used singly and in combination in the early VA Co-operative studies that demonstrated decrease in cardiovascular morbidity with blood pressure control. Subsequent studies have confirmed these earlyfindingsand clearly demonstrated that the thiazide diuretics are as effective in lowering blood pressure as other currently available antihypertensive compounds. Diuretics, like all other antihypertensives, have side effects, of which the most important ones are hypokalaemia, alterations of the plasma lipid profile, hyperuricaemia and glucose intolerance. Diuretic-induced hypokalaemia may be hazardous in the presence of digitalis, but does not appear to have any inherent propensity to induce life-threatening arrhythmias. Diuretics remain amongstfirst-linedrugs in the treatment ofhigh bloodpressure due to their efficacy, especially in blacks and the elderly, the potentiation of the antihypertensive efficacy of other compounds, their low side effect profile and their low cost.
Clinical experience with diuretics in hypertension 93
and concentrations less than 3 mEq. L ' are rarely encountered. The major clinical concern of diureticinduced hypokalaemia is its potential to precipitate cardiac arrhythmias, particularly in the presence of digitalis. While such an hazardous association is undoubted, the majority of patients with high blood pressure are not in heart failure, do not have atrial fibrillation and, therefore, do not receive digitalis. For this reason, potassium supplements have been widely used in patients taking diuretics, despite scepticism concerning the value of such supplements'91. A few studies suggested that, diuretics may lower the serum potassium concentration and precipitate ventricular ectopic beats'101, but many other studies failed to demonstrate such an BENDROFLUMETHIAZIDE VS NADOLOL(61 1 151 This comparison was undertaken in 365 hypertensive association "" . male patients (DBP 95-114 mmHg). Nadolol was titrated It has also been suggested that patients with left venfrom 80-240 mg o.d. and bendroflumethiazide from tricular hypertrophy (LVH) have more propensity to 5-10 mg o.d. The reduction in DBP was similar between develop ventricular arrhythmias and thus may be more the two drugs, although systolic blood pressure reduction susceptible to reduction in the serum potassium conwas greater with the diuretic than the beta-blocking drug. centration1'51. This was directly addressed in a study Again, black patients responded better to diuretic therapy in 44 hypertensive patients of whom 28 had echothan their white counterparts. cardiographic evidence of LVH; all were monitored for 48 h before and after administration of HCTZ. As expected, diuretics decreased systolic and diastolic blood HYDROCHLOROTHIAZIDE VS CAPTOPRIL171 The antihypertensive efficacy of the ACE-inhibitor, pressure as well as serum potassium concentration captopril, was evaluated with or without HCTZ in 475 ( — 0-57 mEq . L^') (Table 1). There was no significant hypertensive patients with DBP 92-109 mmHg. Patients change in the number of ventricular ectopic beats, were randomly assigned to receive either captopril 12-5, couplets or runs of ventricular tachycardia after diuretic 25 or 50 mg t.i.d. or 37-5 mg b.d. or placebo. After 7 weeks therapy and there was no significant difference between of captopril or placebo therapy, HCTZ 25 mg b.d. was HCTZ and placebo. It was concluded that short-term added in two-thirds of the patients receiving captopril administration of HCTZ did not increase ventricular and in all of the patients receiving placebo, and treatment arrhythmias in hypertensive patients with LVH. A review then continued for a total period of 10 months. In these of studies directed to this issue confirms this conclusion patients, the dose-response to captopril was relatively (Table 2). flat, but the addition of HCTZ substantially enhanced the It is also reasonable to argue that if, indeed, hypoblood pressure-lowering effects of the ACE-inhibitor. kalaemia was a cause of ventricular arrhythmias in Overall evaluation of these studies from the VA group hypertensive patients, correction of the serum potassium clearly showed that diuretics were effective in lowering concentration should result in a disappearance, or at least blood pressure, when used alone, in at least 50% of male a decrease, in such arrhythmias. Unfortunately, inforpatients with mild or moderate hypertension, were more mation on this aspect is limited. In one study, ventricular effective in older than in younger patients, were more ectopic beat activity during hypokalaemia was reduced 10 effective in black than in white subjects and, without after potassium repletion' '. In contrast, in another study exception, enhanced the hypotensive effects of other in 16 hypertensive patients with hypokalaemia (serum potassium 2-8 mEg . L~'), correction of the hypokalaemia currently used antihypertensive compounds. did not improve the arrhythmia'171. A further aspect of the problem relates to the possibility Risk profile of the diuretics that diuretic-induced hypokalaemia and hypomagnesThe most frequent and important metabolic adverse aemia may precipitate ventricular arrhythmias during effects of the diuretics are alterations of lipid profile and strenuous dynamic exercise. Such exercise stress results glucose tolerance and the induction of hypokalaemia and in ingress of potassium and magnesium into the cardiac hyperuricaemia. Fortunately, these sides effects are rela- cell, due to adrenalin-induced beta-2 adrenoceptor stimu81 tively infrequent, rarely of sufficient severity to necessitate lation by circulating adrenalin" . It has also been demonstopping treatment, only rarely persist when the diuretics strated that diuretic-treated patients have an exaggerated 1 are discontinued and none have been shown to be of response in this regard to adrenalin infusion'" . It is intriguing, therefore, and of direct therapeutic interest clinical significance in increasing cardiovascular risk. that, although HCTZ may decrease the serum potassium and magnesium concentrations, such changes appear to DIURETIC-INDUCED HYPOKALAEMIA AND CARDIAC have no significant affect on the induction of cardiac ARRHYTHMIAS after exercise in patients with The serum potassium concentration is reduced in 20- arrhythmias either during or 201 uncomplicated hypertension' . 40% of patients taking diuretics, but is usually mild HYDROCHLOROTH1AZIDE VS PROPRANOLOLH1
Six hundred and eighty-three hypertensive male patients (DBP 95-114 mmHg) were randomized doubleblind to receive either hydrochlorothiazide (HCTZ) or propranolol, with the goal of reducing DBP to below 90 mmHg or titrated to a maximum drug dose (HCTZ 200 mg daily; propanolol 640 mg daily). HCTZ was more effective in lowering both systolic and diastolic blood pressures than propanolol, particularly in black patients; propanolol was more effective than diuretics in the white patients. These effects were maintained over the 12-months duration of the study151.
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on January 21, 2016
94
V. Papademetriou
Table 1 Ventricular ectopy in patients with or without left ventricular hypertrophy before and after hvdrochlorothiaztde
No LVH (n = 16)
LVH (n = 28)
Variable
LVPWT BW PK PVC.h-' Total couplets Total VT episodes
Baseline
Diuretic
Baseline
l-39±014 86-3 ±14-7 406±0-23 16-6 ±49-8 123 5
85-4±14-7' 3-39±0-45* 101 ±22-9 15 3
103±007 9O0±20-8 410±0-32 21 ±50 6 2
Diuretic
88-1 ±20-6* 3-33 ±0-43* 30±5-9 3 0
' = /"< 0-001; compare values before and after diuretic; LVPWT = left ventricular posterior wall thickness; BW = body weight; PK = plasma potassium; PVC = premature ventricular contractions; VT = ventricular tachycardia. (Reproduced with permission11").
Table 2
Hypokalaemia and ventricular ectopy in patients with uncomplicated hypertension
Holland et al. Papademetriou Leifif/a/. Madias et al. Medical Research Council Narayan et al.
Plasma K
No of patients
Basal
Diuretic
ECG monitoring
Hours of
Arrhythmic change
7 14 27 17 13 20 16 45
40 3-9 40 4-2 40 4-4 4-2 4-2
30 30 30 3-8 30 30 3-6 3-6
24 24 48 48 48 24 24 48
Increase No change No change No change No change No change No change No change
DIURETICS AND PLASMA URIC ACID
Hypertensive patients have a higher incidence of hyperuricaemia and it has been suggested that this may incur an increased mortality risk. Since diuretic therapy frequently produces a modest increase in serum uric acid concentration, the possibility exists that thiazide-induced hyperuricaemia would worsen the patient's prognosis. Fortunately, a major study dispells such fears. The interaction of thiazides, serum uric acid and creatinine concentrations were examined in 3693 hypertensive patients in the HDFP study12'1. Thiazides increased the plasma concentration of both uric acid and creatinine. These increases were greatest in patients with low serum uric acid concentration and least in those with higher concentrations. Patients who received uric acid-lowering agents had the same increase in serum creatinine concentration as those who did not receive such agents, suggesting the lack of a causal relationship between serum uric acid and creatinine elevations. Changes in serum uric acid concentration after one year of diuretic treatment were inversely correlated with mortality risk in these hypertensive males. Only 15 episodes of clinical gout were reported amongst the 3693 participants over the 5-year period of the study. The authors concluded that diuretic-induced changes in serum uric acid concentration are probably benign and there was no clinical reason to reduce serum uric acid by pharmacologic means in treated hypertensive patients
unless they presented with gout, which was a rare occurrence. Conclusion Experience of the hypertension research clinic of the Veterans Administration Medical Center with diuretics in the treatment of high blood pressure has been extensive and concurs with that of many other clinics. Diuretics have been shown to be efficacious, both as monotherapy and in combination with other antihypertensive drugs and have, without qualification, been shown to be safe and with a high degree of patient tolerability. They are effective in the majority of subgroups of hypertensive patients and, importantly, are outstandingly efficacious in black patients and the more elderly. From the risk viewpoint, diuretic-induced hypokalaemia does not appear to be of sinister clinical significance and in the absence of digitalis does not appear to be proarrhythmic. The changes in the plasma lipid profile, glucose/insulin metabolism and uric acid mobilization have no clinically sinister portends in the majority of hypertensive patients; they are important only in the subsets of patients in whom these abnormalities aggravate a predisposing metabolic disorder. For these reasons, the diuretics continue to constitute the cornerstone of drug therapy for hypertension in the VA Hypertension Research and Treatment Clinic.
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on January 21, 2016
Report
Clinical experience with diuretics in hypertension
References
[11] Papademetriou V. Diuretics hypokalemia, and cardiac arrhythmias: a critical analysis. Am Heart J 1986; 111: 1217-24. [12] Papademetriou V, Bums JF, Notargiacomo A, Fletcher RD, Freis ED. Thiazide therapy is not a cause of arrhythmia in patients with systemic hypertension. Arch Int Med 1988; 148: 1272-6. [ 13] Leif PD, Beligon I, Mates J et al. Diuretic-induced hypokalemia does not cause ventricular ectopy in uncomplicated essential hypertension, abstracted. Kidney Int 1984; 25: 203. [14] Madias Je, Madias NE, Gavras HP. Non-arrhythmogenicity of diuretic-induced hypokalemia. Arch Int Med 1984; 144: 2171-6. [15] Papademetriou V, Price M, Notargiacomo A el al. Effect of diuretic therapy on ventricular arrhythmias in hypertensive patients with or without left ventricular hypertrophy. Am Heart J1985; 110:595-9. [16] Narayan P, Colleran J, Kokkinos P, Notargiacomo A, Freis ED, Papademetrious V. Hydrochlorothiazide therapy and ventricular arrhythmias in hypertensive patients with advanced left ventricular hypertrophy. JACC March 1, 1992; 19: 196A. [17] Papademetriou V, Fletcher RD, Khatri IM, Freis ED. Diureticinduced hypokalemia in uncomplicated hypertension: effect of plasma potassium correction on cardiac arrhythmias. AJC 1983; 52: 1017-22. [18] Brown MJ, Brown DC, Murphy MD. Hypokalemia from B2 receptor stimulation by circulating epinephrine. NEJM 1983; 309: 1414-19. [19] Struthers AD, Whitesmith R, Reid JL. Prior thiazide diuretic treatment increases adrenaline-induced hypokalemia. Lancet 1983; 1: 1358-61. [20] Papademetriou V, Notargiacomo A, Heine D, Fletcher RD, Freis ED. Effects of diuretic therapy and exercise-related arrhythmias in systemic hypertension. AJC 1989; 64: 1152-6. [21] Langford HG et al. Is thiazide produced uric acid elevation harmful? Analysis of data from the Hypertension Detection and Follow-up Program. Arch Int Med 1987; 147: 645.
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on January 21, 2016
[1] Freis ED, Wanko A, Wilson IM, Parish AE. Chlorothiazide in hypertensive and normotensive patients. Ann NY Acad Science 1958; 71:450-5. [2] Veterans Administration Cooperative Study Group on Antihypertensive Agents: Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 mmHg. JAMA 1967; 202: 1028-34. [3] Veterans Administration Cooperative Study Group: Effects of treatment on morbidity in hypertension: III. Influence of age, diastolic pressure and prior cardiovascular disease. Circulation 1972:45:991-1004. [4] Veterans Administration Cooperative Study Group on Antihypertensive Agents: Comparison of propranolol and hydrochlorothiazide for the initial treatment of hypertension. I. Results of short-term titration with emphasis on racial differences in response. JAMA 1982; 248: 1996. [5] Veterans Administration Cooperative Study Group on Antihypertensive Agents: Comparison of propranolol and hydrochlorothiazide for the initial treatment of hypertension. II. Results of long-term treatment. JAMA 1982; 248: 2004. [6] Freis ED. Veterans Administration Study Group on Nadolol as monotherapy and in combination with a diuretic. Am Heart J 1984; 108: 1087-91. [7] Veterans Administration Cooperative Study Group. Captopril: evaluation of low doses, twice daily and the addition of diuretic for the treatment of mild to moderate hypertension. Clin Science 1982; 63: 4435-51. [8] Freis ED. Age and antihypertensive drugs (hydrocholorothiazide, bendroflumethiazide, nadolol and captopril). AJC 1988; 61:117-21. [9] Harrington JT, Isner JM, Kassirer JP. Our national obsession with potassium. Am J Med 1982; 73: 155. [10] Holland OB, Nixon JV, Kuhnert I. Diuretic induced ventricular ectopic activity. Am J Med 1981; 70: 762.
95
Diuretics in hypertension: clinical experiences V. PAPADEMETRIOU
Department of Veterans Affairs Medical Center, Washington DC, U.S.A. KEY WORDS: Hypertension, diuretics, efficacy, side effects.
Early experience Chlorothiazide first became available for clinical evaluation in 1956 and its beneficial effects in lowering blood pressure were quickly recognized'11. In patients with mild or moderate hypertension, chlorothiazide was effective as monotherapy and in patients with more elevated blood pressure it was found to combine efficaciously with ganglion-blocking drugs, reserpine and hydralazine. These early studies led to one of thefirstmajor clinical trials devoted to evaluation of the influence of blood pressurelowering drugs on morbidity and mortality in hypertensive patients12*31. In this placebo-controlled study, a major reduction in cardiovascular events was observed in the patients with diastolic blood pressure (DBP) in the range 115-129 mmHg. In patients with DBP 105-114mmHgat entry, there was a statistically significant reduction in the incidence of major cardiovascular complications in those receiving active antihypertensive treatment compared to those receiving placebo. However, in patients with entry DBP 90-104 mmHg, there was no significant reduction in major cardiovascular events or improvement in survival over the average of 3-3 years of follow-up. This early landmark study firmly established that reduction in blood pressure in the hypertensive patient is clinically worthwhile, particuarly at the higher levels of blood pressure. It has been succeeded by numerous trials with a variety of other antihypertensive drugs in an attempt to establish similar benefits on the increased cardiovascular event rate, particularly in patients with mild hypertension.
developed, none have been demonstrated to be superior to diuretics when used either as monotherapy or in combination with other antihypertensive compounds. The thiazide diuretics hold a number of major advantages in the long-term treatment of hypertension. They are effective in controlling blood pressure in more than 50% of patients with mild or moderate hypertension when used alone and in potentiating the antihypertensive activity of all other currently available agents. Their dose-response relationship is relatively flat, so that the control of blood pressure is possible with relatively few side-effects. They are well tolerated, particularly in low doses, by the majority of patients, including the elderly, and their side effect profile is amongst the most favoured of antihypertensive drugs. They are unique amongst these agents in their ability to prevent fluid retention. These clinical advantages of the diuretics are significantly enhanced by their low cost compared to other antihypertensive drugs; this may be of crucial importance in a disease syndrome requiring continued administration of medication, sometimes over decades. There are three potential disadvantages in the use of these diuretics. They may precipitate gout or uncover diabetes mellitus in patients with a predisposition to these syndromes. Impotence in male patients appears as a side effect in 10-15% of patients receiving chronic treatment and in some this does not revert on discontinuing the drug. However, these side effects do not preclude the use of the diuretics in the majority of hypertensive patients.
Current experiences Although a wide variety of antihypertensive drugs with widely differing pharmacodynamic activities have been
Efficacy of diuretics
Correspondence: Vasilios Papademetnou, MD, Department of Veterans Affairs Medical Center, 50 Irving Si, NW, Washington, DC 20422, U.S.A. 0195-668X/92/0G0O92 + 04 $08.00/0
In addition to the early morbidity/mortality studies'2-31, a number of other studies have emanated from the Veterans Administration (VA) Group confirming the overall efficacy of diuretics in antihypertensive therapy. © 1992 The European Society of Cardiology
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on January 21, 2016
Diuretics have long been used in the treatment ofhypertension and are outstandingly efficacious when used either alone or in combination with other antihypet tensive compounds. Blood pressure is controlled with diuretics alone in over 50% of patients and in over 80% in combination with other drugs. Thiazide diuretics were used singly and in combination in the early VA Co-operative studies that demonstrated decrease in cardiovascular morbidity with blood pressure control. Subsequent studies have confirmed these earlyfindingsand clearly demonstrated that the thiazide diuretics are as effective in lowering blood pressure as other currently available antihypertensive compounds. Diuretics, like all other antihypertensives, have side effects, of which the most important ones are hypokalaemia, alterations of the plasma lipid profile, hyperuricaemia and glucose intolerance. Diuretic-induced hypokalaemia may be hazardous in the presence of digitalis, but does not appear to have any inherent propensity to induce life-threatening arrhythmias. Diuretics remain amongstfirst-linedrugs in the treatment ofhigh bloodpressure due to their efficacy, especially in blacks and the elderly, the potentiation of the antihypertensive efficacy of other compounds, their low side effect profile and their low cost.
Clinical experience with diuretics in hypertension 93
and concentrations less than 3 mEq. L ' are rarely encountered. The major clinical concern of diureticinduced hypokalaemia is its potential to precipitate cardiac arrhythmias, particularly in the presence of digitalis. While such an hazardous association is undoubted, the majority of patients with high blood pressure are not in heart failure, do not have atrial fibrillation and, therefore, do not receive digitalis. For this reason, potassium supplements have been widely used in patients taking diuretics, despite scepticism concerning the value of such supplements'91. A few studies suggested that, diuretics may lower the serum potassium concentration and precipitate ventricular ectopic beats'101, but many other studies failed to demonstrate such an BENDROFLUMETHIAZIDE VS NADOLOL(61 1 151 This comparison was undertaken in 365 hypertensive association "" . male patients (DBP 95-114 mmHg). Nadolol was titrated It has also been suggested that patients with left venfrom 80-240 mg o.d. and bendroflumethiazide from tricular hypertrophy (LVH) have more propensity to 5-10 mg o.d. The reduction in DBP was similar between develop ventricular arrhythmias and thus may be more the two drugs, although systolic blood pressure reduction susceptible to reduction in the serum potassium conwas greater with the diuretic than the beta-blocking drug. centration1'51. This was directly addressed in a study Again, black patients responded better to diuretic therapy in 44 hypertensive patients of whom 28 had echothan their white counterparts. cardiographic evidence of LVH; all were monitored for 48 h before and after administration of HCTZ. As expected, diuretics decreased systolic and diastolic blood HYDROCHLOROTHIAZIDE VS CAPTOPRIL171 The antihypertensive efficacy of the ACE-inhibitor, pressure as well as serum potassium concentration captopril, was evaluated with or without HCTZ in 475 ( — 0-57 mEq . L^') (Table 1). There was no significant hypertensive patients with DBP 92-109 mmHg. Patients change in the number of ventricular ectopic beats, were randomly assigned to receive either captopril 12-5, couplets or runs of ventricular tachycardia after diuretic 25 or 50 mg t.i.d. or 37-5 mg b.d. or placebo. After 7 weeks therapy and there was no significant difference between of captopril or placebo therapy, HCTZ 25 mg b.d. was HCTZ and placebo. It was concluded that short-term added in two-thirds of the patients receiving captopril administration of HCTZ did not increase ventricular and in all of the patients receiving placebo, and treatment arrhythmias in hypertensive patients with LVH. A review then continued for a total period of 10 months. In these of studies directed to this issue confirms this conclusion patients, the dose-response to captopril was relatively (Table 2). flat, but the addition of HCTZ substantially enhanced the It is also reasonable to argue that if, indeed, hypoblood pressure-lowering effects of the ACE-inhibitor. kalaemia was a cause of ventricular arrhythmias in Overall evaluation of these studies from the VA group hypertensive patients, correction of the serum potassium clearly showed that diuretics were effective in lowering concentration should result in a disappearance, or at least blood pressure, when used alone, in at least 50% of male a decrease, in such arrhythmias. Unfortunately, inforpatients with mild or moderate hypertension, were more mation on this aspect is limited. In one study, ventricular effective in older than in younger patients, were more ectopic beat activity during hypokalaemia was reduced 10 effective in black than in white subjects and, without after potassium repletion' '. In contrast, in another study exception, enhanced the hypotensive effects of other in 16 hypertensive patients with hypokalaemia (serum potassium 2-8 mEg . L~'), correction of the hypokalaemia currently used antihypertensive compounds. did not improve the arrhythmia'171. A further aspect of the problem relates to the possibility Risk profile of the diuretics that diuretic-induced hypokalaemia and hypomagnesThe most frequent and important metabolic adverse aemia may precipitate ventricular arrhythmias during effects of the diuretics are alterations of lipid profile and strenuous dynamic exercise. Such exercise stress results glucose tolerance and the induction of hypokalaemia and in ingress of potassium and magnesium into the cardiac hyperuricaemia. Fortunately, these sides effects are rela- cell, due to adrenalin-induced beta-2 adrenoceptor stimu81 tively infrequent, rarely of sufficient severity to necessitate lation by circulating adrenalin" . It has also been demonstopping treatment, only rarely persist when the diuretics strated that diuretic-treated patients have an exaggerated 1 are discontinued and none have been shown to be of response in this regard to adrenalin infusion'" . It is intriguing, therefore, and of direct therapeutic interest clinical significance in increasing cardiovascular risk. that, although HCTZ may decrease the serum potassium and magnesium concentrations, such changes appear to DIURETIC-INDUCED HYPOKALAEMIA AND CARDIAC have no significant affect on the induction of cardiac ARRHYTHMIAS after exercise in patients with The serum potassium concentration is reduced in 20- arrhythmias either during or 201 uncomplicated hypertension' . 40% of patients taking diuretics, but is usually mild HYDROCHLOROTH1AZIDE VS PROPRANOLOLH1
Six hundred and eighty-three hypertensive male patients (DBP 95-114 mmHg) were randomized doubleblind to receive either hydrochlorothiazide (HCTZ) or propranolol, with the goal of reducing DBP to below 90 mmHg or titrated to a maximum drug dose (HCTZ 200 mg daily; propanolol 640 mg daily). HCTZ was more effective in lowering both systolic and diastolic blood pressures than propanolol, particularly in black patients; propanolol was more effective than diuretics in the white patients. These effects were maintained over the 12-months duration of the study151.
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on January 21, 2016
94
V. Papademetriou
Table 1 Ventricular ectopy in patients with or without left ventricular hypertrophy before and after hvdrochlorothiaztde
No LVH (n = 16)
LVH (n = 28)
Variable
LVPWT BW PK PVC.h-' Total couplets Total VT episodes
Baseline
Diuretic
Baseline
l-39±014 86-3 ±14-7 406±0-23 16-6 ±49-8 123 5
85-4±14-7' 3-39±0-45* 101 ±22-9 15 3
103±007 9O0±20-8 410±0-32 21 ±50 6 2
Diuretic
88-1 ±20-6* 3-33 ±0-43* 30±5-9 3 0
' = /"< 0-001; compare values before and after diuretic; LVPWT = left ventricular posterior wall thickness; BW = body weight; PK = plasma potassium; PVC = premature ventricular contractions; VT = ventricular tachycardia. (Reproduced with permission11").
Table 2
Hypokalaemia and ventricular ectopy in patients with uncomplicated hypertension
Holland et al. Papademetriou Leifif/a/. Madias et al. Medical Research Council Narayan et al.
Plasma K
No of patients
Basal
Diuretic
ECG monitoring
Hours of
Arrhythmic change
7 14 27 17 13 20 16 45
40 3-9 40 4-2 40 4-4 4-2 4-2
30 30 30 3-8 30 30 3-6 3-6
24 24 48 48 48 24 24 48
Increase No change No change No change No change No change No change No change
DIURETICS AND PLASMA URIC ACID
Hypertensive patients have a higher incidence of hyperuricaemia and it has been suggested that this may incur an increased mortality risk. Since diuretic therapy frequently produces a modest increase in serum uric acid concentration, the possibility exists that thiazide-induced hyperuricaemia would worsen the patient's prognosis. Fortunately, a major study dispells such fears. The interaction of thiazides, serum uric acid and creatinine concentrations were examined in 3693 hypertensive patients in the HDFP study12'1. Thiazides increased the plasma concentration of both uric acid and creatinine. These increases were greatest in patients with low serum uric acid concentration and least in those with higher concentrations. Patients who received uric acid-lowering agents had the same increase in serum creatinine concentration as those who did not receive such agents, suggesting the lack of a causal relationship between serum uric acid and creatinine elevations. Changes in serum uric acid concentration after one year of diuretic treatment were inversely correlated with mortality risk in these hypertensive males. Only 15 episodes of clinical gout were reported amongst the 3693 participants over the 5-year period of the study. The authors concluded that diuretic-induced changes in serum uric acid concentration are probably benign and there was no clinical reason to reduce serum uric acid by pharmacologic means in treated hypertensive patients
unless they presented with gout, which was a rare occurrence. Conclusion Experience of the hypertension research clinic of the Veterans Administration Medical Center with diuretics in the treatment of high blood pressure has been extensive and concurs with that of many other clinics. Diuretics have been shown to be efficacious, both as monotherapy and in combination with other antihypertensive drugs and have, without qualification, been shown to be safe and with a high degree of patient tolerability. They are effective in the majority of subgroups of hypertensive patients and, importantly, are outstandingly efficacious in black patients and the more elderly. From the risk viewpoint, diuretic-induced hypokalaemia does not appear to be of sinister clinical significance and in the absence of digitalis does not appear to be proarrhythmic. The changes in the plasma lipid profile, glucose/insulin metabolism and uric acid mobilization have no clinically sinister portends in the majority of hypertensive patients; they are important only in the subsets of patients in whom these abnormalities aggravate a predisposing metabolic disorder. For these reasons, the diuretics continue to constitute the cornerstone of drug therapy for hypertension in the VA Hypertension Research and Treatment Clinic.
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on January 21, 2016
Report
Clinical experience with diuretics in hypertension
References
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