Long-term safety of antihypertensive therapy

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<ul><li><p>Long-Term Safety ofAntihypertensive Therapy</p><p>Ehud Grossman and Franz H. Messerli</p><p>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</p><p>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.</p><p>Hypertension is one of the major risk factorsfor cardiovascular morbidity and mortality.It is clear that lowering blood pressure is ben-</p><p>eficial1-5; however, there are still some doubts</p><p>regarding the long-term safety of antihyperten-</p><p>sive therapy. We will discuss some of the doubts</p><p>and show what is clearly safe and what is still</p><p>open to debate.</p><p>Diuretics</p><p>Numerous prospective studies attested to the</p><p>safety and efficacy of thiazide diuretics in reducing</p><p>morbidity and mortality in hypertensive pa-</p><p>tients.1,2 However, the safety of diuretics in diabetic</p><p>hypertensive patients has been questioned.</p><p>Fifteen years ago, Warram et al6 showed that</p><p>in diabetic hypertensive patients, the risk ofcardiovascular mortality was 3.8-fold higher in</p><p>those treated with diuretics than in those who</p><p>were not treated. In contrast later, prospective</p><p>studies showed that diuretics reduced cardiovas-</p><p>cular morbidity and mortality in elderly diabetic</p><p>hypertensive patients.7-9 The old belief that di-</p><p>uretics may paradoxically increase cardiovascu-</p><p>lar morbidity and mortality can be put to rest inview of the recent evidence of clear benefit. In</p><p>the past, a high dose of diuretic was used, which</p><p>may account for lack of benefit, whereas in more</p><p>recent studies, a low- to medium-dose diuretic</p><p>with or without potassium-sparing agents was</p><p>used. It is well accepted that the low to medium</p><p>dose of diuretic is effective in lowering blood</p><p>Progress in Cardiovascular Diseases, Vol. 49, No. 1 (July/August), 2006: pp 16-2516</p><p>From the Internal Medicine D and Hypertension Unit,</p><p>The Chaim Sheba Medical Center, Tel-Hashomer, Affil-iated to the Sackler School of Medicine Tel-Aviv</p><p>University, Israel, and Division of Cardiology, St. Lukes-</p><p>Roosevelt Hospital, NY.</p><p>Address reprint requests to Ehud Grossman, InternalMedicine D and Hypertension Unit, The Chaim Sheba</p><p>Medical Center, Tel-Hashomer, 52621 Israel.</p><p>E-mail: gross-e@zahav.net.il</p><p>0033-0620/$ - see front mattern 2006 Elsevier Inc. All rights reserved.doi:10.1016/j.pcad.2006.06.002</p></li><li><p>pressure with minimal side effects. Increasing</p><p>the dose adds very little to the control of blood</p><p>pressure, whereas it increases substantially the</p><p>rate of side effects such as hypokalemia, hypo-</p><p>natremia, hyperuricemia, hypercholesterolemia,</p><p>and so on.10 Similarly, the risk of sudden cardiacdeath was low in diuretic users when the dose</p><p>was low and a potassium-sparing agent was</p><p>added.11 The rationale of adding a potassium-</p><p>sparing agent to a thiazide is supported by the</p><p>recent evidence that addition of aldosterone</p><p>antagonists to optimal treatment reduces cardio-</p><p>vascular morbidity and mortality in patients with</p><p>congestive heart failure.12,13 It seems that thecontroversy regarding the long-term efficacy and</p><p>safety of diuretics in hypertension has been</p><p>resolved by using a low- to medium-dose</p><p>diuretic with the option of adding a potassium-</p><p>sparing agent. Recently, aldosterone antagonist</p><p>has been included in the regimen of resistant</p><p>hypertension.14 The combination of thiazide with</p><p>an aldosterone antagonist may be very effectivein lowering blood pressure and reducing the risk</p><p>of hypokalemia and sudden death.15 However,</p><p>this combination, particularly when given with</p><p>an angiotensin-converting enzyme (ACE) inhib-</p><p>itor, may expose patients to hyperkalemia.16</p><p>Thus, close follow-up of serum potassium levels</p><p>may increase the safety of diuretics.</p><p>Diuretics may impair glucose tolerance anddecrease insulin sensitivity and thereby acceler-</p><p>ate the development of diabetes mellitus.17 This</p><p>deleterious effect of diuretic may take time and</p><p>can be blunted by the combination with an ACE</p><p>inhibitor.18 Most prospective randomized trials</p><p>in hypertension last 4 to 6 years and therefore</p><p>provide little if any information as to long-term</p><p>safety of diuretics. Many patients are exposed toblood pressurelowering drugs for many de-</p><p>cades, and drug-induced changes could be</p><p>cumulative. This is potentially true with the</p><p>adverse metabolic effects that are seen with the</p><p>diuretics.19 Clearly, the increased risk of new</p><p>onset diabetes with diuretics, single or in</p><p>combination, will not translate into increased</p><p>morbidity and mortality in a study lasting 4 to6 years.9 After decades, however, sustained dia-</p><p>betes may have an important impact on cardio-</p><p>vascular morbidity and mortality.20</p><p>Long-term treatment with thiazide diuretics</p><p>may increase the risk for renal cell carcinoma.21</p><p>The risk is higher in women than in men and</p><p>seems to increase in parallel with the duration of</p><p>diuretic exposure.21 This risk of carcinogenicity</p><p>is unlikely to be discovered in short-term</p><p>(4-6 years) prospective, randomized trials be-</p><p>cause similar to other carcinogenic substances(tobacco), the exposure needed exceeds 2 dec-</p><p>ades. Diuretics have the longest track record of</p><p>any antihypertensive drug class and therefore</p><p>have been intensively scrutinized. The benefit of</p><p>lowering blood pressure should therefore be</p><p>weighed against the potential long-term adverse</p><p>effects of diuretics.</p><p>bbb-Blockers in the Treatmentof Hypertension</p><p>Until the recent publication of the Joint National</p><p>Committee 7 (JNC 7), diuretics and b-blockerswere both recommended as the drug of choice for</p><p>essential hypertension.22 Although numerous</p><p>epidemiologic studies attest to the safety andefficacy of diuretics in this regard, the data for</p><p>b-blockers are sketchy and unconvincing. In fact,the available data suggest that the clinical benefits</p><p>of b-blockers are poorly documented and thatb-blockers may be inefficacious in the elderly,who account for a large segment of the hyperten-</p><p>sive population.23 Monotherapy with a b-blockerin the elderly does not reduce morbidity andmortality compared with placebo. The British</p><p>Medical Research Council 2 Trial, a randomized,</p><p>placebo-controlled, single-blinded study in</p><p>patients aged 65 to 74 years, clearly documented</p><p>that although blood pressure was lowered effec-</p><p>tively by the cardioselective b-blocker atenolol,morbidity and mortality of the b-blocker groupdid not differ from that of the placebo group.2</p><p>Moreover, patients who received the combination</p><p>of b-blockers and diuretics fared consistentlyworse than those receiving diuretics alone.24 In</p><p>a previous meta-analysis, we showed that</p><p>b-blockerbased therapy does not reduce cardio-vascular disease, coronary heart disease, and total</p><p>mortality in elderly hypertensive patients.23 The</p><p>Losartan Intervention For Endpoint reduction inhypertension study showed that atenolol-based</p><p>therapy is inferior to losartan-based therapy in</p><p>elderly hypertensive patients with electrocardio-</p><p>gram-documented left ventricular hypertro-</p><p>phy.25,26 In the recent Anglo-Scandinavian</p><p>LONG-TERM SAFETY OF ANTIHYPERTENSIVE THERAPY 17</p></li><li><p>Cardiac Outcomes Trial-Blood Pressure Lower-</p><p>ing Arm, atenolol-based regimen was less effec-</p><p>tive in preventing cardiovascular events and</p><p>induced more diabetes mellitus than amlodi-</p><p>pine-based regimen.27,28 In a recent meta-analy-</p><p>sis that compared treatment with b-blockers toother antihypertensive drugs, the relative risk of</p><p>stroke was 16% higher for b-blockers than forother drugs.29,30 Thus, despite their having a</p><p>beneficial effect on the surrogate end point, that</p><p>is, blood pressure, b-blocker therapy failed tofavorably affect the real end point, that is, strokes</p><p>and cardiac events in elderly.</p><p>Similarly, in a large case control study, the riskof sudden cardiac death was distinctly higher in</p><p>elderly patients receiving either b-blocker asmonotherapy or in combination with a thiazide</p><p>diuretic than in patients receiving other therapy</p><p>(calcium antagonists, ACE inhibitors, potassium-</p><p>sparing diuretics).31 This would indicate that</p><p>b-blocker therapy does needlessly exposemillions of elderly hypertensive patients to ad-verse effects and cost while not conferring any</p><p>benefit whatsoever. In all studies in the geriatric</p><p>population, wherein b-blockers were implied toreduce morbidity and mortality, they were used in</p><p>combination with a diuretic. Thus, in the Swedish</p><p>STOP Trial,3 more than two thirds of the patients</p><p>were receiving combination therapy, and no</p><p>information was available regarding the effectsof b-blocker monotherapy. In the Systolic Hyper-tension in the Elderly Program Study, only 32%</p><p>of patients were receiving atenolol (or reserpine),</p><p>all of these in combination with a diuretic.1 A</p><p>subanalysis by Kostis et al32 did not identify any</p><p>additional benefits attributable to atenolol (or</p><p>reserpine) that were independent of the ones</p><p>conferred by the diuretic. In the study of Coopeand Warrender,33 which demonstrated a signifi-</p><p>cant reduction in the rate of strokes, 70% of</p><p>patients in the treatment group were receiving</p><p>atenolol, and 60% were receiving bendrofluazide.</p><p>None of these studies allows us to conclude that</p><p>either b-blocker alone or b-blocker with thediuretic regimen did indeed significantly and</p><p>independently impact morbidity and mortality.Nevertheless, some indirect evidence suggests</p><p>that b-blockers may have benefits in middle-aged and younger patients. In all 3 trials</p><p>(Medical Research Council, International Pro-</p><p>spective Primary Prevention Study in Hyperten-</p><p>sion, and Heart Attack Primary prevention in</p><p>Hypertension),34-36 the rate of myocardial in-</p><p>farction (MI), stroke, and cardiovascular death</p><p>was not very different in a b-blocker regimenthan with a diuretic regimen. A meta-analysis</p><p>analyzing the 3 studies showed a decreasingtrend in total cardiovascular mortality in men by</p><p>14% and an increasing trend in women by 16%</p><p>in the b-blocker group when compared with thenonb-blocker group.37 Thus, there is still doubtwhether a b-blocker is adequate as one of thefirst drugs of choice for hypertension.</p><p>The use of b-blockers became even more of aquestion in diabetic hypertensive patients. TheNational High Blood Pressure Education Program</p><p>Working Group38 recommended in 1994 to avoid</p><p>the use of b-blockers in diabetic hypertensivepatients because they can have adverse effects on</p><p>peripheral blood flow and mask symptoms of</p><p>hypoglycemia. However, the results from the UK</p><p>Prospective Diabetes Study39 showed that block-</p><p>ers are as effective as ACE inhibitors in reducingcardiovascular events in diabetic hypertensive</p><p>patients. It seems that b-blockers may be appro-priate as a first choice treatment in young and</p><p>middle-age hypertensives and in those with fast</p><p>heart rate, but it should not be considered</p><p>appropriate as the first-line therapy in the elderly</p><p>with uncomplicated hypertension.</p><p>The class of b-blockers is heterogeneous, and ithas been debated whether all the drugs in the</p><p>class are the same. It has been shown that</p><p>metoprolol and carvedilol are effective in con-</p><p>gestive heart failure. Nonetheless, the recent</p><p>Carvedilol or Metoprolol European Trial showed</p><p>a superiority of carvedilol over metoprolol in</p><p>patients with congestive heart failure.40 However,</p><p>the design of the study does not allow one toconclude that carvedilol is superior because</p><p>blood pressure levels were lower in the carvedi-</p><p>lol-treated group and metoprolol was used in</p><p>a subtherapeutic dose. In addition, in the re-</p><p>cent Glycemic Effects in Diabetes Mellitus:</p><p>Carvedilol-Metoprolol Comparison in Hyper-</p><p>tensives Study in diabetic hypertensive patients</p><p>who were treated with a blocker of the reninangiotensin system, carvedilol had a less detri-</p><p>mental effect on glycemic indices than did</p><p>metoprolol.41 Similarly, nebivolol may differ</p><p>from other b-blockers because of its vasodilatingproperties. Thus, the question whether the</p><p>GROSSMAN AND MESSERLI18</p></li><li><p>efficacy and safety of all b-blockers are equal isstill pertinent, and only a well designed head-to-</p><p>head comparative study with 2 b-blockers will beable to resolve the uncertainty.</p><p>Calcium Antagonists</p><p>Calcium antagonists are widely used as antihy-</p><p>pertensive agents. They are liked by physicians</p><p>and patients because of their efficacy, metabolic</p><p>neutrality, and clean side-effect profile. Several</p><p>years ago, a plethora of publications showed that</p><p>hypertensive patients treated with short-acting</p><p>calcium antagonists are at increased risk for MIand have a higher mortality rate compared with</p><p>patients treated with other antihypertensive</p><p>drugs.42-45 Moreover, calcium antagonists have</p><p>been accused of increasing the risk of cancer</p><p>among hypertensive patients.46,47 Because these</p><p>studies were uncritically extrapolated to all</p><p>calcium antagonists as a class, they cast doubt</p><p>on the safety and efficacy of these drugs, alarmedpatients, and frustrated physicians. Recent pro-</p><p>spective randomized studies attested to the</p><p>safety of calcium antagonists.9,27,48-51 Moreover,</p><p>they showed clearly that calcium antagonists</p><p>are beneficial in reducing cardiovascular mor-</p><p>bidity and mortality.4,9,27,48-50,52 Calcium antag-</p><p>onists are less effective than diuretics and ACE</p><p>inhibitors in preventing congestive heart fail-ure9,50,52 and less effective than blockers of the</p><p>renin angiotensin system in preventing renal</p><p>failure.53,54 However, they are equally effective</p><p>as renin angiotensin syste...</p></li></ul>

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