Long-term safety of antihypertensive therapy

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  • Long-Term Safety ofAntihypertensive Therapy

    Ehud Grossman and Franz H. Messerli

    Lowering blood pressure (BP) in hypertensivepatients reduces morbidity and mortality. Howeverthe long-term safety of some antihypertensiveagents was a matter of concern. Diuretic, the goldstandard treatment in hypertension may impairglucose tolerance and thereby accelerate the de-velopment of diabetes mellitus. It was also asso-ciated with increased cardiovascular mortality indiabetic patients. However, recent evidenceshowed that low-medium dose of thiazide diureticespecially when given in combination with potassi-um sparing agent is effective in reducing BP andcardiovascular morbidity and mortality. Beta block-ers are less effective than other antihypertensiveagents in the elderly. Therefore they may beappropriate as a first choice in young and middle-age hypertensives, and in those with fast heart rate,but they should not be considered appropriate asthe first-line therapy in the elderly with uncompli-cated hypertension. Several years ago a plethora ofpublications showed that short-acting calciumantagonists may increase the risk for myocardialinfarction and cancer. A few years ago two studiesshowed that calcium antagonists are less effectivethan angiotensin converting enzyme inhibitors inpreventing cardiovascular events in diabetic hyper-tensive patients. However, recent results from largeprospective randomized studies showed that calci-um antagonists reduce cardiovascular morbidityand mortality in diabetic and non-diabetic hyper-tensive patients. Some investigators have sug-gested that angiotensin receptor blockers (ARBs)may increase the risk of myocardial infarction

    in hypertensive patients. However, recent metaanalyses refuted this conclusions and showed thatARBs are probably as effective as other antihyper-tensive agents in prevention of myocardial infarc-tion. Despite the concern that has been raisedregarding the long-term safety of some antihyper-tensive agents, it is clear that lowering BP is safeand beneficial.n 2006 Elsevier Inc. All rights reserved.

    Hypertension is one of the major risk factorsfor cardiovascular morbidity and mortality.It is clear that lowering blood pressure is ben-

    eficial1-5; however, there are still some doubts

    regarding the long-term safety of antihyperten-

    sive therapy. We will discuss some of the doubts

    and show what is clearly safe and what is still

    open to debate.


    Numerous prospective studies attested to the

    safety and efficacy of thiazide diuretics in reducing

    morbidity and mortality in hypertensive pa-

    tients.1,2 However, the safety of diuretics in diabetic

    hypertensive patients has been questioned.

    Fifteen years ago, Warram et al6 showed that

    in diabetic hypertensive patients, the risk ofcardiovascular mortality was 3.8-fold higher in

    those treated with diuretics than in those who

    were not treated. In contrast later, prospective

    studies showed that diuretics reduced cardiovas-

    cular morbidity and mortality in elderly diabetic

    hypertensive patients.7-9 The old belief that di-

    uretics may paradoxically increase cardiovascu-

    lar morbidity and mortality can be put to rest inview of the recent evidence of clear benefit. In

    the past, a high dose of diuretic was used, which

    may account for lack of benefit, whereas in more

    recent studies, a low- to medium-dose diuretic

    with or without potassium-sparing agents was

    used. It is well accepted that the low to medium

    dose of diuretic is effective in lowering blood

    Progress in Cardiovascular Diseases, Vol. 49, No. 1 (July/August), 2006: pp 16-2516

    From the Internal Medicine D and Hypertension Unit,

    The Chaim Sheba Medical Center, Tel-Hashomer, Affil-iated to the Sackler School of Medicine Tel-Aviv

    University, Israel, and Division of Cardiology, St. Lukes-

    Roosevelt Hospital, NY.

    Address reprint requests to Ehud Grossman, InternalMedicine D and Hypertension Unit, The Chaim Sheba

    Medical Center, Tel-Hashomer, 52621 Israel.

    E-mail: gross-e@zahav.net.il

    0033-0620/$ - see front mattern 2006 Elsevier Inc. All rights reserved.doi:10.1016/j.pcad.2006.06.002

  • pressure with minimal side effects. Increasing

    the dose adds very little to the control of blood

    pressure, whereas it increases substantially the

    rate of side effects such as hypokalemia, hypo-

    natremia, hyperuricemia, hypercholesterolemia,

    and so on.10 Similarly, the risk of sudden cardiacdeath was low in diuretic users when the dose

    was low and a potassium-sparing agent was

    added.11 The rationale of adding a potassium-

    sparing agent to a thiazide is supported by the

    recent evidence that addition of aldosterone

    antagonists to optimal treatment reduces cardio-

    vascular morbidity and mortality in patients with

    congestive heart failure.12,13 It seems that thecontroversy regarding the long-term efficacy and

    safety of diuretics in hypertension has been

    resolved by using a low- to medium-dose

    diuretic with the option of adding a potassium-

    sparing agent. Recently, aldosterone antagonist

    has been included in the regimen of resistant

    hypertension.14 The combination of thiazide with

    an aldosterone antagonist may be very effectivein lowering blood pressure and reducing the risk

    of hypokalemia and sudden death.15 However,

    this combination, particularly when given with

    an angiotensin-converting enzyme (ACE) inhib-

    itor, may expose patients to hyperkalemia.16

    Thus, close follow-up of serum potassium levels

    may increase the safety of diuretics.

    Diuretics may impair glucose tolerance anddecrease insulin sensitivity and thereby acceler-

    ate the development of diabetes mellitus.17 This

    deleterious effect of diuretic may take time and

    can be blunted by the combination with an ACE

    inhibitor.18 Most prospective randomized trials

    in hypertension last 4 to 6 years and therefore

    provide little if any information as to long-term

    safety of diuretics. Many patients are exposed toblood pressurelowering drugs for many de-

    cades, and drug-induced changes could be

    cumulative. This is potentially true with the

    adverse metabolic effects that are seen with the

    diuretics.19 Clearly, the increased risk of new

    onset diabetes with diuretics, single or in

    combination, will not translate into increased

    morbidity and mortality in a study lasting 4 to6 years.9 After decades, however, sustained dia-

    betes may have an important impact on cardio-

    vascular morbidity and mortality.20

    Long-term treatment with thiazide diuretics

    may increase the risk for renal cell carcinoma.21

    The risk is higher in women than in men and

    seems to increase in parallel with the duration of

    diuretic exposure.21 This risk of carcinogenicity

    is unlikely to be discovered in short-term

    (4-6 years) prospective, randomized trials be-

    cause similar to other carcinogenic substances(tobacco), the exposure needed exceeds 2 dec-

    ades. Diuretics have the longest track record of

    any antihypertensive drug class and therefore

    have been intensively scrutinized. The benefit of

    lowering blood pressure should therefore be

    weighed against the potential long-term adverse

    effects of diuretics.

    bbb-Blockers in the Treatmentof Hypertension

    Until the recent publication of the Joint National

    Committee 7 (JNC 7), diuretics and b-blockerswere both recommended as the drug of choice for

    essential hypertension.22 Although numerous

    epidemiologic studies attest to the safety andefficacy of diuretics in this regard, the data for

    b-blockers are sketchy and unconvincing. In fact,the available data suggest that the clinical benefits

    of b-blockers are poorly documented and thatb-blockers may be inefficacious in the elderly,who account for a large segment of the hyperten-

    sive population.23 Monotherapy with a b-blockerin the elderly does not reduce morbidity andmortality compared with placebo. The British

    Medical Research Council 2 Trial, a randomized,

    placebo-controlled, single-blinded study in

    patients aged 65 to 74 years, clearly documented

    that although blood pressure was lowered effec-

    tively by the cardioselective b-blocker atenolol,morbidity and mortality of the b-blocker groupdid not differ from that of the placebo group.2

    Moreover, patients who received the combination

    of b-blockers and diuretics fared consistentlyworse than those receiving diuretics alone.24 In

    a previous meta-analysis, we showed that

    b-blockerbased therapy does not reduce cardio-vascular disease, coronary heart disease, and total

    mortality in elderly hypertensive patients.23 The

    Losartan Intervention For Endpoint reduction inhypertension study showed that atenolol-based

    therapy is inferior to losartan-based therapy in

    elderly hypertensive patients with electrocardio-

    gram-documented left ventricular hypertro-

    phy.25,26 In the recent Anglo-Scandinavian


  • Cardiac Outcomes Trial-Blood Pressure Lower-

    ing Arm, atenolol-based regimen was less effec-

    tive in preventing cardiovascular events and

    induced more diabetes mellitus than amlodi-

    pine-based regimen.27,28 In a recent meta-analy-

    sis that compared treatment with b-blockers toother antihypertensive drugs, the relative risk of

    stroke was 16% higher for b-blockers than forother drugs.29,30 Thus, despite their having a

    beneficial effect on the surrogate e