- Email: [email protected]
Misconceptions and Facts About Treating Hypertension
REVIEW
Misconceptions and Facts About Treating Hypertension Edgar Argulian, MD, MPH,a Ehud Grossman, MD,b Franz H. Messerli, MDa a
Mt Sinai St Luke’s and Roosevelt Hospitals, New York, NY; bThe Chaim Sheba Medical Center, Tel Hashomer, Israel.
ABSTRACT Hypertension is a powerful risk factor strongly linked to adverse cardiovascular outcomes. Because of its high prevalence, health care providers at many levels are involved in treating hypertension. Distinct progress has been made in improving the rates of hypertension awareness and treatment over years, but the overall control of hypertension remains inadequate. Several recent guidelines from different sources have been put forward in an attempt to bridge the gap between existing evidence and clinical practice. Despite this effort, several misconceptions about treating hypertensive cardiovascular disease continue to persist among clinicians. This review highlights some of the misconceptions regarding antihypertensive therapy. Ó 2015 Elsevier Inc. All rights reserved. The American Journal of Medicine (2015) 128, 450-455 KEYWORDS: Antihypertensive therapy; Hypertension; J-curve
It is difficult to overestimate the benefits of widespread adequate hypertension control on cardiovascular morbidity and mortality at the population level.1 The overall prevalence of hypertension is high and likely to increase with the aging population and increasing prevalence of obesity and other risk factors.2,3 Despite this, the benefits of antihypertensive therapy have been established by a solid bulk of evidence.3 The rates of hypertension awareness, treatment, and control have been improving over recent decades but are still far from adequate.2 Moreover, several misconceptions persist among practicing clinicians, commonly in the areas in which evidence is scarce or misinterpreted.
MISCONCEPTION #1: HYDROCHLOROTHIAZIDE IS THE MOST USEFUL AND VERSATILE THIAZIDE DIURETIC Facts Hydrochlorothiazide remains by far the most commonly prescribed antihypertensive agent in the United States and Funding: None. Conflict of Interest: FHM is a consultant or has advisory relationships with Daiichi, Sankyo, Pfizer, Takeda, Abbott, AbbVie, Servier, Medtronic, Inc, and Ipca Laboratories. Authorship: All authors had access to the data and played a role in writing this manuscript. Requests for reprints should be addressed to Edgar Argulian, MD, MPH, Division of Cardiology, Mt Sinai St Luke’s and Roosevelt Hospitals, Mt Sinai Health System, 1111 Amsterdam Ave, New York, NY 10025. E-mail address: [email protected] or [email protected] 0002-9343/$ -see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2014.11.015
worldwide.4 This is not surprising since starting with Joint National Committee (JNC) I, every subsequent JNC advocated “thiazides” for the first-line therapy for hypertension by stating that thiazides should be preferred over other drugs because they had been shown to reduce morbidity and mortality.3 The authors of the various JNCs thereby tacitly implied that thiazides were synonymous with hydrochlorothiazide. Before we continue to subscribe to such wisdom, we should consider the following simple facts: 1. Hydrochlorothiazide is one of the weakest antihypertensive agents available. In head-to-head comparison by 24-hour ambulatory monitoring, the antihypertensive efficacy was shown to be inferior to other drug classes, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and calcium channel blockers.5 Moreover, hydrochlorothiazide’s antihypertensive effect does not last 24 hours, thereby leaving the critical early morning hours unprotected.5-7 2. Hydrochlorothiazide in its usual dose of 12.5 to 25 mg per day has never been shown to reduce the risk of myocardial infarction, stroke, or death.4 In fact, higher doses have been shown to increase the risk of sudden cardiac death in a dose-dependent fashion.8 3. Even in combination with an angiotensin-converting enzyme inhibitor, hydrochlorothiazide has been shown to be inferior to a calcium channel blocker, such as amlodipine. In the Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension
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trial, despite identical blood pressure reduction, the dose every 4 weeks if the blood pressure remained amlodipine-based combination reduced cardiovascular elevated.17 Twelve subjects completed the 12-week treatevents by 20% better than the hydrochlorothiazide combiment period, and the 24-hour ambulatory blood pressure, nation, a fact that led to a premature termination of the study.9 which was 143.1/75.1 mm Hg at baseline, was reduced by 10.5/3.1 mm Hg (P ¼ .01/P ¼ .17). Adverse events, such as 4. All efficacy and outcome data for thiazides are solely hypokalemia, hyperuricemia, hyponatremia, and transient derived from chlorthalidone and indapamide. Antihycreatinine elevations, were surpertensive therapy based on prisingly common; clearly, paboth of these drugs have been CLINICAL SIGNIFICANCE tients should be closely monitored shown repeatedly to decrease for these.17 the risk of heart attack, stroke, Hydrochlorothiazide should be avoided, heart failure, and even death in particularly as the first-line therapy for several prospective randomhypertension. When diuretics are used in MISCONCEPTION #3: ized trials, such as Systolic hypertension, chlorthalidone or indapaADRENERGIC ACTIVITY IS Hypertension in the Elderly mide should be preferred. A MAJOR TARGET IN Program, Antihypertensive and Lipid-Lowering Treatment to There is little if any evidence that blood TREATING PRIMARY Prevent Heart Attack Trial pressure lowering by decreasing sympaHYPERTENSION (ALLHAT), Hypertension in thetic activity translates into reduction Facts the Very Elderly Trial, and of meaningful clinical outcomes in unPerin-dopril Protection against This seemingly attractive statecomplicated hypertension. Recurrent Stroke Study.10-13 ment is supported by the current Combination therapy with angiotensinunderstanding of basic physiHowever, both of these drugs, ology. Adrenergic activity has a chlorthalidone and indapamide, converting inhibitors has been demonmajor influence on both cardiac are distinctly different from strated to reduce calcium channel and vascular mechanisms of the hydrochlorothiazide and have blocker-induced peripheral edema. blood pressure control.18 Also, it been documented to exert The optimal blood pressure targets for a pleiotropic effects that may is intimately related to other wide range of hypertensive patients are account for their superior important hormonal and metabolic still debated. efficacy.4,14 regulatory mechanisms, such as renin-angiotensin system, insulin It is clear that hydrochlorothiresistance, glucose, and fat metaazide should be avoided as the first-line therapy for hyperbolism. Understandably, modulation of adrenergic activity tension. If a thiazide is deemed to be appropriate, our choice was considered a seminal target for hypertension research should be chlorthalidone or indapamide, as is stated in the for decades. Unfortunately, this resulted in rounds of frusBritish National Institute for Health and Clinical Excellence tration. Selective alpha1-adrenergic blocker doxazosin was 15 guidelines. studied in a large ALLHAT trial; the doxazosin arm was terminated prematurely because of a higher risk of heart failure.19 No outcome data are available for centrally acting MISCONCEPTION #2: THIAZIDES ARE NOT agents suppressing sympathetic activity, such as clonidine, and these drugs have significant adverse effects that make EFFECTIVE FOR HYPERTENSION IN ADVANCED them unsuitable for common use. Beta-blockers were once RENAL DISEASE considered a first-line therapy for primary hypertension, but Facts their cardiovascular protective effect failed when used in uncomplicated hypertension.20 Several meta-analyses Hypertension commonly begets chronic kidney disease and becomes increasingly difficult to treat as renal disease proshowed that beta-blockers (atenolol being most commonly gresses. It is a common notion of many nephrologists that studied) confer lower protection against stroke and may be thiazide diuretics are ineffective antihypertensive agents in associated with higher all-cause mortality compared with moderate to advanced renal disease.16 Of note, the evidence other antihypertensive agents.21 In addition, beta-blockers base for this recommendation that was made into several are associated with an increased risk of new-onset diabetes guidelines is unknown. On the contrary, observational data mellitus and may worsen glycemic control in patients with and small randomized studies suggest that thiazide diuretics established diabetes.22 Vasodilating beta-blockers, such as can result in meaningful blood pressure reduction in these carvedilol and nebivolol, do not seem to carry adverse patients (for review, see Agarwal and Sinha16). Most metabolic or hemodynamic effects, but so far no outcome data have been put forward in hypertension. Therefore, betarecently, in a small study of patients with chronic kidney blockers as a class should not be considered for initial disease (estimated glomerular filtration rate of 20-45 mL/ therapy of hypertension unless another indication for their min/1.73 m2), Agarwal et al17 added chlorthalidone to use is present. Finally, catheter-based radiofrequency existing medications in a dose of 25 mg/day and doubled the
452 ablation of renal sympathetic nerves showed highly promising results in several unblinded observations, but a properly designed randomized clinical trial failed to show any significant antihypertensive efficacy.23,24 The question is not whether decreasing sympathetic/adrenergic activity lowers blood pressure; there is ample evidence that it does. The question is whether blood pressure lowering by decreasing sympathetic/adrenergic activity will translate into a reduction of meaningful clinical outcomes, and there is little if any evidence for that.
MISCONCEPTION #4: THE MORE COMPLETE RENIN-ANGIOTENSIN SYSTEM BLOCKADE THE GREATER THE BENEFITS Facts The concept of dual renin-angiotensin system blockade originated from the elegant animal model created by Menard et al,25 purporting to show a “synergistic” effect between angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. It was hoped that combining the 2 drug classes would be a way to avoid the escape phenomenon occurring because of incomplete blockade of the renin-angiotensin system with monotherapy of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker.26 Dual renin-angiotensin blockade was promptly accepted primarily by nephrologists and even became increasingly popular among practicing cardiologists.27 The concept seemed so logical and appealing that “benefits” in surrogate end points, such as blood pressure, proteinuria, and endothelial dysfunction, became accepted as a free pass for this combination having cardioprotective and nephroprotective effects.27 Despite a lack of solid evidence on safety and efficacy, dual renin-angiotensin system blockade found entrance into several sets of recent guidelines.28,29 Unfortunately, trials based on clinically meaningful outcomes were disappointing. A meta-analysis of dual renin-angiotensin system blockage of 33 randomized controlled trials with 68,405 patients showed no reduction in mortality but an excessive risk of adverse events, such as hyperkalemia, hypotension, and renal failure compared with monotherapy.30 In this study, the risk to benefit ratio argued against the use of dual reninangiotensin system blockade in hypertension and heart failure alike. Hopefully, these data will convince physicians that such therapy was merely a fad whose time has come and gone. The sobering data evolving from studies with dual renin-angiotensin blockade should remind us that surrogate end point failure is not uncommon and that leapfrogging from surrogate data cannot substitute for patient exposure in clinical outcome studies.27 In contrast to dual renin-angiotensin system blockade, the addition of aldosterone antagonists to an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker has been shown to be beneficial in congestive heart failure and seems to be effective in lowering blood pressure.31-33
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MISCONCEPTION #5: PERIPHERAL EDEMA, A COMMON ADVERSE EFFECT OF CALCIUM CHANNEL BLOCKERS, CAN BE MOST EFFECTIVELY MITIGATED BY CONCOMITANT DIURETIC THERAPY Facts Peripheral edema is the most common side effect of dihydropyridine calcium channel blockers, which is dosedependent and may exceed 80% with very high doses.34 Although it seems logical that diuretic therapy should mitigate this uncomfortable adverse effect, one should realize that this is not primarily a volume-retention phenomenon and therefore may not be very responsive to diuretics. In fact, calcium channel blockers have been shown to have a natriuretic effect.35 Peripheral edema is best explained by the vasodilatory effect of calcium channel blockers on precapillary sphincters, causing capillary hypertension during upright posture. Of note, combination therapy with renin-angiotensin system antagonists (angiotensin-converting enzyme inhibitors more than angiotensin receptor blockers) has been demonstrated to reduce calcium channel blockereinduced peripheral edema, probably by venodilation thereby decreasing capillary hypertension.36 As discussed earlier, the combination of a calcium channel blocker and an angiotensin-converting enzyme inhibitor has been shown to be superior to the combination of the same angiotensin-converting enzyme inhibitor with hydrochlorothiazide in improving cardiovascular outcomes.9
MISCONCEPTION #6: ANTIHYPERTENSIVE THERAPY CAUSES ERECTILE DYSFUNCTION Facts Indeed, erectile dysfunction is common in treated hypertensive men. However, this is a complex issue because patients with hypertension are more likely to have erectile dysfunction than normotensive subjects, and patients with erectile dysfunction are more likely to have hypertension than those without erectile dysfunction.37,38 Hypertension may affect erectile function through structural and functional alterations in the penile vasculature, similar to those induced in other vascular beds.39 Therefore, erectile dysfunction often precedes hypertensive target organ disease, such as clinically overt coronary artery disease, by several years.40 In a given patient, this brings about a simple clinical question: Is the erectile dysfunction due to hypertension per se, the antihypertensive regimen, or a combination of both?38 The following points should be considered: 1. Acute abrupt lowering of blood pressure or too low a blood pressure can impede erectile function for obvious reasons. This would indicate that any antihypertensive regimen when excessive can be associated with erectile dysfunction. However, this form of erectile dysfunction
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is blood pressure dependent and therefore often transient. Once the vascular system has adjusted to the new lower blood pressure level, erectile function recovers. 2. Antihypertensive agents that lead to volume depletion, such as the thiazide diuretics, are more likely to cause erectile dysfunction than other drugs that predominantly act by vasodilation.41 3. Beta-blockers (unlike alpha-blockers) are also prone to cause erectile dysfunction, but the risk appears to be small.42 A notable exception is the beta-blocker nebivolol, in which the nitric oxide release seems to compensate for the negative effect of beta-blockade per se.43 4. Some small studies have indicated that angiotensin receptor blockers, if anything, improve erectile function, possibly by enhancing blood flow in the penile vasculature.44 Other vasodilating agents, such as angiotensinconverting enzyme inhibitors and calcium channel blockers, are considered “neutral” in the absence of convincing evidence.44 Of note, data from randomized studies on erectile dysfunction and antihypertensive therapy are limited; as of today, the issue remains an evidence-free zone.45 However, the good news is that the addition of phosphodiesterase 5 inhibitors to the most common antihypertensive drugs (diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers) often results in a small ancillary decrease in blood pressure without an increase in adverse events.46
MISCONCEPTION #7: THE LOWER THE ACHIEVED BLOOD PRESSURE GOAL THE BETTER A linear relationship between blood pressure (systolic and diastolic) and heart attack, stroke, and death has been found in several landmark studies. This, together with the observation that blood pressure is a powerful risk factor even within the normotensive range, has led to the notion of “the lower, the better.”47-49 However, the systolic and diastolic blood pressure pattern while treating hypertensive patients has been documented to follow a J-shaped curve in relation to cardiovascular outcomes.50,51 Setting the target blood pressure range too high will result in excess outcome events due to damaging effects of hypertension. Setting the goal too low may also result in adverse events, probably mediated by episodes of hypotension and organ hypoperfusion. This J-shaped relationship has been demonstrated on post hoc analysis of many randomized trials (although none of the trials aimed primarily at investigating the J-curve relationship).50 Although most of the studies point to the range of 130 to 139 mm Hg for systolic blood pressure and 70 to 85 mm Hg for diastolic blood pressure, the optimal blood pressure target is still debated.52 Moreover, there may not be a single optimal target for all patients because the relationship is possibly modified by different covariates (Figure).50 Age could be a major modifier for this relationship because elderly patients are more susceptible to both deleterious
453
Figure The concept of J-curve in treating hypertension. CAD ¼ coronary artery disease; CKD ¼ chronic kidney disease; DM ¼ diabetes mellitus; LV ¼ left ventricle.
effects of hypertension and iatrogenic hypotension. The 2014 Eighth JNC panel recommendation of a systolic blood pressure threshold for initiation of drug therapy and a therapeutic target of <150 mm Hg in those aged more than 60 years has triggered a controversy.3,53 The effect of various agents on the target window and the slope of the curve is largely unknown. Major comorbidities, such as diabetes mellitus, chronic kidney disease, and coronary artery disease, also may affect the curve. It was speculated that diabetic patients may benefit from a tighter blood pressure control, although the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, which randomized diabetic patients to an intensive goal of systolic blood pressure <120 mm Hg versus the traditional <140 mm Hg, did not show any overall benefit for combined cardiovascular events with intensive therapy.54 Moreover, post hoc analysis of the International Verapamil-Trandolapril Study showed an increased mortality in diabetic patients with treated systolic blood pressure <115 mm Hg.55 Finally, there may be target organ heterogeneity in that the nadir of the J-curve may differ from one cardiovascular outcome to another, that is, the optimal blood pressure for prevention of stroke may be lower than the one for prevention of coronary artery disease. For instance, in the same ACCORD trial, although there was no overall benefit for intensive antihypertensive therapy, patients in the intensive arm had a lower incidence of stroke.54 Further clinical trials, such as the Systolic Blood Pressure Intervention Trial, should help to define the optimal blood pressure treatment for the wide range of hypertensive patients.56
CONCLUSIONS Currently, many treatment options are available for hypertension, but despite this variety there are areas in which evidence is scarce or misinterpreted. Adequate control of hypertension using the best available evidence offers a large
454 potential impact on cardiovascular morbidity and mortality at the population level.
References 1. Ford ES. Trends in mortality from all causes and cardiovascular disease among hypertensive and nonhypertensive adults in the United States. Circulation. 2011;123:1737-1744. 2. Egan BM, Zhao Y, Axon RN. US trends in prevalence, awareness, treatment, and control of hypertension, 1988-2008. JAMA. 2010;303: 2043-2050. 3. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311:507-520. 4. Messerli FH, Bangalore S. Half a century of hydrochlorothiazide: facts, fads, fiction, and follies. Am J Med. 2011;124:896-899. 5. Messerli FH, Makani H, Benjo A, et al. Antihypertensive efficacy of hydrochlorothiazide as evaluated by ambulatory blood pressure monitoring: a meta-analysis of randomized trials. J Am Coll Cardiol. 2011;57:590-600. 6. Carter BL, Ernst ME, Cohen JD. Hydrochlorothiazide versus chlorthalidone: evidence supporting their interchangeability. Hypertension. 2004;43:4-9. 7. Finkielman JD, Schwartz GL, Chapman AB, et al. Lack of agreement between office and ambulatory blood pressure responses to hydrochlorothiazide. Am J Hypertens. 2005;18:398-402. 8. Siscovick DS, Raghunathan TE, Psaty BM, et al. Diuretic therapy for hypertension and the risk of primary cardiac arrest. N Engl J Med. 1994;330:1852-1857. 9. Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008;359:2417-2428. 10. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group. JAMA. 1991;265:3255-3264. 11. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288:2981-2997. 12. Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;358:1887-1898. 13. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001;358:1033-1041. 14. Woodman R, Brown C, Lockette W. Chlorthalidone decreases platelet aggregation and vascular permeability and promotes angiogenesis. Hypertension. 2010;56:463-470. 15. Krause T, Lovibond K, Caulfield M, et al. Management of hypertension: summary of NICE guidance. BMJ. 2011;343:d4891. 16. Agarwal R, Sinha AD. Thiazide diuretics in advanced chronic kidney disease. J Am Soc Hypertens. 2012;6:299-308. 17. Agarwal R, Sinha AD, Pappas MK, Ammous F. Chlorthalidone for poorly controlled hypertension in chronic kidney disease: an interventional pilot study. Am J Nephrol. 2014;39:171-182. 18. Esler M, Lambert E, Schlaich M. Point: chronic activation of the sympathetic nervous system is the dominant contributor to systemic hypertension. J Appl Physiol (1985). 2010;109:1996-1998, discussion 2016. 19. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). ALLHAT Collaborative Research Group. JAMA. 2000;283:1967-1975. 20. Lavie CJ, Messerli FH, Milani RV. Beta-blockers as first-line antihypertensive therapy the crumbling continues. J Am Coll Cardiol. 2009;54:1162-1164.
The American Journal of Medicine, Vol 128, No 5, May 2015 21. Bangalore S, Messerli FH, Kostis JB, Pepine CJ. Cardiovascular protection using beta-blockers: a critical review of the evidence. J Am Coll Cardiol. 2007;50:563-572. 22. Bangalore S, Parkar S, Grossman E, Messerli FH. A meta-analysis of 94,492 patients with hypertension treated with beta blockers to determine the risk of new-onset diabetes mellitus. Am J Cardiol. 2007;100: 1254-1262. 23. Bhatt DL, Kandzari DE, O’Neill WW, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014;370: 1393-1401. 24. Messerli FH, Bangalore S. Renal denervation for resistant hypertension? N Engl J Med. 2014;370:1454-1457. 25. Menard J, Campbell DJ, Azizi M, Gonzales MF. Synergistic effects of ACE inhibition and Ang II antagonism on blood pressure, cardiac weight, and renin in spontaneously hypertensive rats. Circulation. 1997;96:3072-3078. 26. Givertz MM. Manipulation of the renin-angiotensin system. Circulation. 2001;104:E14-E18. 27. Messerli FH, Staessen JA, Zannad F. Of fads, fashion, surrogate endpoints and dual RAS blockade. Eur Heart J. 2010;31:2205-2208. 28. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2012;33:1787-1847. 29. Standards of medical care in diabetese2012. Diabetes Care. 2012;35(Suppl 1):S11-S63. 30. Makani H, Bangalore S, Desouza KA, et al. Efficacy and safety of dual blockade of the renin-angiotensin system: meta-analysis of randomised trials. BMJ. 2013;346:f360. 31. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341:709-717. 32. Shlomai G, Sella T, Sharabi Y, et al. Serum potassium levels predict blood pressure response to aldosterone antagonists in resistant hypertension. Hypertens Res. 2014;37:1037-1041. 33. Bangalore S, Kumar S, Messerli FH. When conventional heart failure therapy is not enough: angiotensin receptor blocker, direct renin inhibitor, or aldosterone antagonist? Congest Heart Fail. 2013;19: 107-115. 34. Messerli FH. Vasodilatory edema: a common side effect of antihypertensive therapy. Curr Cardiol Rep. 2002;4:479-482. 35. Weir MR, Rosenberger C, Fink JC. Pilot study to evaluate a water displacement technique to compare effects of diuretics and ACE inhibitors to alleviate lower extremity edema due to dihydropyridine calcium antagonists. Am J Hypertens. 2001;14(9 Pt 1):963-968. 36. Makani H, Bangalore S, Romero J, et al. Effect of renin-angiotensin system blockade on calcium channel blocker-associated peripheral edema. Am J Med. 2011;124:128-135. 37. Nunes KP, Labazi H, Webb RC. New insights into hypertensionassociated erectile dysfunction. Curr Opin Nephrol Hypertens. 2012;21:163-170. 38. Kloner R. Erectile dysfunction and hypertension. Int J Impot Res. 2007;19:296-302. 39. Costa C, Virag R. The endothelial-erectile dysfunction connection: an essential update. J Sex Med. 2009;6:2390-2404. 40. Thompson IM, Tangen CM, Goodman PJ, et al. Erectile dysfunction and subsequent cardiovascular disease. JAMA. 2005;294:2996-3002. 41. Grimm RH Jr, Grandits GA, Prineas RJ, et al. Long-term effects on sexual function of five antihypertensive drugs and nutritional hygienic treatment in hypertensive men and women. Treatment of Mild Hypertension Study (TOMHS). Hypertension. 1997;29(1 Pt 1):8-14. 42. Ko DT, Hebert PR, Coffey CS, et al. Beta-blocker therapy and symptoms of depression, fatigue, and sexual dysfunction. JAMA. 2002;288:351-357.
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43. Brixius K, Middeke M, Lichtenthal A, et al. Nitric oxide, erectile dysfunction and beta-blocker treatment (MR NOED study): benefit of nebivolol versus metoprolol in hypertensive men. Clin Exp Pharmacol Physiol. 2007;34:327-331. 44. Doumas M, Douma S. The effect of antihypertensive drugs on erectile function: a proposed management algorithm. J Clin Hypertens (Greenwich). 2006;8:359-364. 45. Doumas M, Viigimaa M, Papademetriou V. Combined antihypertensive therapy and sexual dysfunction: terra incognita. Cardiology. 2013;125:232-234. 46. Kloner RA, Brown M, Prisant LM, Collins M. Effect of sildenafil in patients with erectile dysfunction taking antihypertensive therapy. Sildenafil Study Group. Am J Hypertens. 2001;14:70-73. 47. Panjrath GS, Chaudhari S, Messerli FH. The j-point phenomenon in aggressive therapy of hypertension: new insights. Curr Atheroscler Rep. 2012;14:124-129. 48. Messerli FH, Mancia G, Conti CR, et al. Dogma disputed: can aggressively lowering blood pressure in hypertensive patients with coronary artery disease be dangerous? Ann Intern Med. 2006;144:884-893. 49. Vasan RS, Larson MG, Leip EP, et al. Impact of high-normal blood pressure on the risk of cardiovascular disease. N Engl J Med. 2001;345:1291-1297.
455 50. Banach M, Aronow WS. Blood pressure j-curve: current concepts. Curr Hypertens Rep. 2012;14:556-566. 51. Kaplan NM. The diastolic J curve: alive and threatening. Hypertension. 2011;58:751-753. 52. Zanchetti A. Blood pressure targets of antihypertensive treatment: up and down the J-shaped curve. Eur Heart J. 2010;31:2837-2840. 53. Bangalore S, Gong Y, Cooper-DeHoff RM, et al. 2014 Eighth Joint National Committee Panel Recommendation for Blood Pressure Targets Revisited: Results From the INVEST Study. J Am Coll Cardiol. 2014;64:784-793. 54. Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362:1575-1585. 55. Cooper-DeHoff RM, Gong Y, Handberg EM, et al. Tight blood pressure control and cardiovascular outcomes among hypertensive patients with diabetes and coronary artery disease. JAMA. 2010;304: 61-68. 56. Ambrosius WT, Sink KM, Foy CG, et al. The design and rationale of a multicenter clinical trial comparing two strategies for control of systolic blood pressure: The Systolic Blood Pressure Intervention Trial (SPRINT). Clin Trials. 2014;11:532-546.
Misconceptions and Facts About Treating Hypertension Edgar Argulian, MD, MPH,a Ehud Grossman, MD,b Franz H. Messerli, MDa a
Mt Sinai St Luke’s and Roosevelt Hospitals, New York, NY; bThe Chaim Sheba Medical Center, Tel Hashomer, Israel.
ABSTRACT Hypertension is a powerful risk factor strongly linked to adverse cardiovascular outcomes. Because of its high prevalence, health care providers at many levels are involved in treating hypertension. Distinct progress has been made in improving the rates of hypertension awareness and treatment over years, but the overall control of hypertension remains inadequate. Several recent guidelines from different sources have been put forward in an attempt to bridge the gap between existing evidence and clinical practice. Despite this effort, several misconceptions about treating hypertensive cardiovascular disease continue to persist among clinicians. This review highlights some of the misconceptions regarding antihypertensive therapy. Ó 2015 Elsevier Inc. All rights reserved. The American Journal of Medicine (2015) 128, 450-455 KEYWORDS: Antihypertensive therapy; Hypertension; J-curve
It is difficult to overestimate the benefits of widespread adequate hypertension control on cardiovascular morbidity and mortality at the population level.1 The overall prevalence of hypertension is high and likely to increase with the aging population and increasing prevalence of obesity and other risk factors.2,3 Despite this, the benefits of antihypertensive therapy have been established by a solid bulk of evidence.3 The rates of hypertension awareness, treatment, and control have been improving over recent decades but are still far from adequate.2 Moreover, several misconceptions persist among practicing clinicians, commonly in the areas in which evidence is scarce or misinterpreted.
MISCONCEPTION #1: HYDROCHLOROTHIAZIDE IS THE MOST USEFUL AND VERSATILE THIAZIDE DIURETIC Facts Hydrochlorothiazide remains by far the most commonly prescribed antihypertensive agent in the United States and Funding: None. Conflict of Interest: FHM is a consultant or has advisory relationships with Daiichi, Sankyo, Pfizer, Takeda, Abbott, AbbVie, Servier, Medtronic, Inc, and Ipca Laboratories. Authorship: All authors had access to the data and played a role in writing this manuscript. Requests for reprints should be addressed to Edgar Argulian, MD, MPH, Division of Cardiology, Mt Sinai St Luke’s and Roosevelt Hospitals, Mt Sinai Health System, 1111 Amsterdam Ave, New York, NY 10025. E-mail address: [email protected] or [email protected] 0002-9343/$ -see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2014.11.015
worldwide.4 This is not surprising since starting with Joint National Committee (JNC) I, every subsequent JNC advocated “thiazides” for the first-line therapy for hypertension by stating that thiazides should be preferred over other drugs because they had been shown to reduce morbidity and mortality.3 The authors of the various JNCs thereby tacitly implied that thiazides were synonymous with hydrochlorothiazide. Before we continue to subscribe to such wisdom, we should consider the following simple facts: 1. Hydrochlorothiazide is one of the weakest antihypertensive agents available. In head-to-head comparison by 24-hour ambulatory monitoring, the antihypertensive efficacy was shown to be inferior to other drug classes, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and calcium channel blockers.5 Moreover, hydrochlorothiazide’s antihypertensive effect does not last 24 hours, thereby leaving the critical early morning hours unprotected.5-7 2. Hydrochlorothiazide in its usual dose of 12.5 to 25 mg per day has never been shown to reduce the risk of myocardial infarction, stroke, or death.4 In fact, higher doses have been shown to increase the risk of sudden cardiac death in a dose-dependent fashion.8 3. Even in combination with an angiotensin-converting enzyme inhibitor, hydrochlorothiazide has been shown to be inferior to a calcium channel blocker, such as amlodipine. In the Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension
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trial, despite identical blood pressure reduction, the dose every 4 weeks if the blood pressure remained amlodipine-based combination reduced cardiovascular elevated.17 Twelve subjects completed the 12-week treatevents by 20% better than the hydrochlorothiazide combiment period, and the 24-hour ambulatory blood pressure, nation, a fact that led to a premature termination of the study.9 which was 143.1/75.1 mm Hg at baseline, was reduced by 10.5/3.1 mm Hg (P ¼ .01/P ¼ .17). Adverse events, such as 4. All efficacy and outcome data for thiazides are solely hypokalemia, hyperuricemia, hyponatremia, and transient derived from chlorthalidone and indapamide. Antihycreatinine elevations, were surpertensive therapy based on prisingly common; clearly, paboth of these drugs have been CLINICAL SIGNIFICANCE tients should be closely monitored shown repeatedly to decrease for these.17 the risk of heart attack, stroke, Hydrochlorothiazide should be avoided, heart failure, and even death in particularly as the first-line therapy for several prospective randomhypertension. When diuretics are used in MISCONCEPTION #3: ized trials, such as Systolic hypertension, chlorthalidone or indapaADRENERGIC ACTIVITY IS Hypertension in the Elderly mide should be preferred. A MAJOR TARGET IN Program, Antihypertensive and Lipid-Lowering Treatment to There is little if any evidence that blood TREATING PRIMARY Prevent Heart Attack Trial pressure lowering by decreasing sympaHYPERTENSION (ALLHAT), Hypertension in thetic activity translates into reduction Facts the Very Elderly Trial, and of meaningful clinical outcomes in unPerin-dopril Protection against This seemingly attractive statecomplicated hypertension. Recurrent Stroke Study.10-13 ment is supported by the current Combination therapy with angiotensinunderstanding of basic physiHowever, both of these drugs, ology. Adrenergic activity has a chlorthalidone and indapamide, converting inhibitors has been demonmajor influence on both cardiac are distinctly different from strated to reduce calcium channel and vascular mechanisms of the hydrochlorothiazide and have blocker-induced peripheral edema. blood pressure control.18 Also, it been documented to exert The optimal blood pressure targets for a pleiotropic effects that may is intimately related to other wide range of hypertensive patients are account for their superior important hormonal and metabolic still debated. efficacy.4,14 regulatory mechanisms, such as renin-angiotensin system, insulin It is clear that hydrochlorothiresistance, glucose, and fat metaazide should be avoided as the first-line therapy for hyperbolism. Understandably, modulation of adrenergic activity tension. If a thiazide is deemed to be appropriate, our choice was considered a seminal target for hypertension research should be chlorthalidone or indapamide, as is stated in the for decades. Unfortunately, this resulted in rounds of frusBritish National Institute for Health and Clinical Excellence tration. Selective alpha1-adrenergic blocker doxazosin was 15 guidelines. studied in a large ALLHAT trial; the doxazosin arm was terminated prematurely because of a higher risk of heart failure.19 No outcome data are available for centrally acting MISCONCEPTION #2: THIAZIDES ARE NOT agents suppressing sympathetic activity, such as clonidine, and these drugs have significant adverse effects that make EFFECTIVE FOR HYPERTENSION IN ADVANCED them unsuitable for common use. Beta-blockers were once RENAL DISEASE considered a first-line therapy for primary hypertension, but Facts their cardiovascular protective effect failed when used in uncomplicated hypertension.20 Several meta-analyses Hypertension commonly begets chronic kidney disease and becomes increasingly difficult to treat as renal disease proshowed that beta-blockers (atenolol being most commonly gresses. It is a common notion of many nephrologists that studied) confer lower protection against stroke and may be thiazide diuretics are ineffective antihypertensive agents in associated with higher all-cause mortality compared with moderate to advanced renal disease.16 Of note, the evidence other antihypertensive agents.21 In addition, beta-blockers base for this recommendation that was made into several are associated with an increased risk of new-onset diabetes guidelines is unknown. On the contrary, observational data mellitus and may worsen glycemic control in patients with and small randomized studies suggest that thiazide diuretics established diabetes.22 Vasodilating beta-blockers, such as can result in meaningful blood pressure reduction in these carvedilol and nebivolol, do not seem to carry adverse patients (for review, see Agarwal and Sinha16). Most metabolic or hemodynamic effects, but so far no outcome data have been put forward in hypertension. Therefore, betarecently, in a small study of patients with chronic kidney blockers as a class should not be considered for initial disease (estimated glomerular filtration rate of 20-45 mL/ therapy of hypertension unless another indication for their min/1.73 m2), Agarwal et al17 added chlorthalidone to use is present. Finally, catheter-based radiofrequency existing medications in a dose of 25 mg/day and doubled the
452 ablation of renal sympathetic nerves showed highly promising results in several unblinded observations, but a properly designed randomized clinical trial failed to show any significant antihypertensive efficacy.23,24 The question is not whether decreasing sympathetic/adrenergic activity lowers blood pressure; there is ample evidence that it does. The question is whether blood pressure lowering by decreasing sympathetic/adrenergic activity will translate into a reduction of meaningful clinical outcomes, and there is little if any evidence for that.
MISCONCEPTION #4: THE MORE COMPLETE RENIN-ANGIOTENSIN SYSTEM BLOCKADE THE GREATER THE BENEFITS Facts The concept of dual renin-angiotensin system blockade originated from the elegant animal model created by Menard et al,25 purporting to show a “synergistic” effect between angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. It was hoped that combining the 2 drug classes would be a way to avoid the escape phenomenon occurring because of incomplete blockade of the renin-angiotensin system with monotherapy of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker.26 Dual renin-angiotensin blockade was promptly accepted primarily by nephrologists and even became increasingly popular among practicing cardiologists.27 The concept seemed so logical and appealing that “benefits” in surrogate end points, such as blood pressure, proteinuria, and endothelial dysfunction, became accepted as a free pass for this combination having cardioprotective and nephroprotective effects.27 Despite a lack of solid evidence on safety and efficacy, dual renin-angiotensin system blockade found entrance into several sets of recent guidelines.28,29 Unfortunately, trials based on clinically meaningful outcomes were disappointing. A meta-analysis of dual renin-angiotensin system blockage of 33 randomized controlled trials with 68,405 patients showed no reduction in mortality but an excessive risk of adverse events, such as hyperkalemia, hypotension, and renal failure compared with monotherapy.30 In this study, the risk to benefit ratio argued against the use of dual reninangiotensin system blockade in hypertension and heart failure alike. Hopefully, these data will convince physicians that such therapy was merely a fad whose time has come and gone. The sobering data evolving from studies with dual renin-angiotensin blockade should remind us that surrogate end point failure is not uncommon and that leapfrogging from surrogate data cannot substitute for patient exposure in clinical outcome studies.27 In contrast to dual renin-angiotensin system blockade, the addition of aldosterone antagonists to an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker has been shown to be beneficial in congestive heart failure and seems to be effective in lowering blood pressure.31-33
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MISCONCEPTION #5: PERIPHERAL EDEMA, A COMMON ADVERSE EFFECT OF CALCIUM CHANNEL BLOCKERS, CAN BE MOST EFFECTIVELY MITIGATED BY CONCOMITANT DIURETIC THERAPY Facts Peripheral edema is the most common side effect of dihydropyridine calcium channel blockers, which is dosedependent and may exceed 80% with very high doses.34 Although it seems logical that diuretic therapy should mitigate this uncomfortable adverse effect, one should realize that this is not primarily a volume-retention phenomenon and therefore may not be very responsive to diuretics. In fact, calcium channel blockers have been shown to have a natriuretic effect.35 Peripheral edema is best explained by the vasodilatory effect of calcium channel blockers on precapillary sphincters, causing capillary hypertension during upright posture. Of note, combination therapy with renin-angiotensin system antagonists (angiotensin-converting enzyme inhibitors more than angiotensin receptor blockers) has been demonstrated to reduce calcium channel blockereinduced peripheral edema, probably by venodilation thereby decreasing capillary hypertension.36 As discussed earlier, the combination of a calcium channel blocker and an angiotensin-converting enzyme inhibitor has been shown to be superior to the combination of the same angiotensin-converting enzyme inhibitor with hydrochlorothiazide in improving cardiovascular outcomes.9
MISCONCEPTION #6: ANTIHYPERTENSIVE THERAPY CAUSES ERECTILE DYSFUNCTION Facts Indeed, erectile dysfunction is common in treated hypertensive men. However, this is a complex issue because patients with hypertension are more likely to have erectile dysfunction than normotensive subjects, and patients with erectile dysfunction are more likely to have hypertension than those without erectile dysfunction.37,38 Hypertension may affect erectile function through structural and functional alterations in the penile vasculature, similar to those induced in other vascular beds.39 Therefore, erectile dysfunction often precedes hypertensive target organ disease, such as clinically overt coronary artery disease, by several years.40 In a given patient, this brings about a simple clinical question: Is the erectile dysfunction due to hypertension per se, the antihypertensive regimen, or a combination of both?38 The following points should be considered: 1. Acute abrupt lowering of blood pressure or too low a blood pressure can impede erectile function for obvious reasons. This would indicate that any antihypertensive regimen when excessive can be associated with erectile dysfunction. However, this form of erectile dysfunction
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is blood pressure dependent and therefore often transient. Once the vascular system has adjusted to the new lower blood pressure level, erectile function recovers. 2. Antihypertensive agents that lead to volume depletion, such as the thiazide diuretics, are more likely to cause erectile dysfunction than other drugs that predominantly act by vasodilation.41 3. Beta-blockers (unlike alpha-blockers) are also prone to cause erectile dysfunction, but the risk appears to be small.42 A notable exception is the beta-blocker nebivolol, in which the nitric oxide release seems to compensate for the negative effect of beta-blockade per se.43 4. Some small studies have indicated that angiotensin receptor blockers, if anything, improve erectile function, possibly by enhancing blood flow in the penile vasculature.44 Other vasodilating agents, such as angiotensinconverting enzyme inhibitors and calcium channel blockers, are considered “neutral” in the absence of convincing evidence.44 Of note, data from randomized studies on erectile dysfunction and antihypertensive therapy are limited; as of today, the issue remains an evidence-free zone.45 However, the good news is that the addition of phosphodiesterase 5 inhibitors to the most common antihypertensive drugs (diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers) often results in a small ancillary decrease in blood pressure without an increase in adverse events.46
MISCONCEPTION #7: THE LOWER THE ACHIEVED BLOOD PRESSURE GOAL THE BETTER A linear relationship between blood pressure (systolic and diastolic) and heart attack, stroke, and death has been found in several landmark studies. This, together with the observation that blood pressure is a powerful risk factor even within the normotensive range, has led to the notion of “the lower, the better.”47-49 However, the systolic and diastolic blood pressure pattern while treating hypertensive patients has been documented to follow a J-shaped curve in relation to cardiovascular outcomes.50,51 Setting the target blood pressure range too high will result in excess outcome events due to damaging effects of hypertension. Setting the goal too low may also result in adverse events, probably mediated by episodes of hypotension and organ hypoperfusion. This J-shaped relationship has been demonstrated on post hoc analysis of many randomized trials (although none of the trials aimed primarily at investigating the J-curve relationship).50 Although most of the studies point to the range of 130 to 139 mm Hg for systolic blood pressure and 70 to 85 mm Hg for diastolic blood pressure, the optimal blood pressure target is still debated.52 Moreover, there may not be a single optimal target for all patients because the relationship is possibly modified by different covariates (Figure).50 Age could be a major modifier for this relationship because elderly patients are more susceptible to both deleterious
453
Figure The concept of J-curve in treating hypertension. CAD ¼ coronary artery disease; CKD ¼ chronic kidney disease; DM ¼ diabetes mellitus; LV ¼ left ventricle.
effects of hypertension and iatrogenic hypotension. The 2014 Eighth JNC panel recommendation of a systolic blood pressure threshold for initiation of drug therapy and a therapeutic target of <150 mm Hg in those aged more than 60 years has triggered a controversy.3,53 The effect of various agents on the target window and the slope of the curve is largely unknown. Major comorbidities, such as diabetes mellitus, chronic kidney disease, and coronary artery disease, also may affect the curve. It was speculated that diabetic patients may benefit from a tighter blood pressure control, although the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, which randomized diabetic patients to an intensive goal of systolic blood pressure <120 mm Hg versus the traditional <140 mm Hg, did not show any overall benefit for combined cardiovascular events with intensive therapy.54 Moreover, post hoc analysis of the International Verapamil-Trandolapril Study showed an increased mortality in diabetic patients with treated systolic blood pressure <115 mm Hg.55 Finally, there may be target organ heterogeneity in that the nadir of the J-curve may differ from one cardiovascular outcome to another, that is, the optimal blood pressure for prevention of stroke may be lower than the one for prevention of coronary artery disease. For instance, in the same ACCORD trial, although there was no overall benefit for intensive antihypertensive therapy, patients in the intensive arm had a lower incidence of stroke.54 Further clinical trials, such as the Systolic Blood Pressure Intervention Trial, should help to define the optimal blood pressure treatment for the wide range of hypertensive patients.56
CONCLUSIONS Currently, many treatment options are available for hypertension, but despite this variety there are areas in which evidence is scarce or misinterpreted. Adequate control of hypertension using the best available evidence offers a large
454 potential impact on cardiovascular morbidity and mortality at the population level.
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