LEGEND: Clinical insights for hypertension Patrick Ryan, Martijn Schuemie, Marc Suchard on behalf of the LEGEND team OHDSI Symposium 12 October 2018 Current knowledge base for hypertension Head-to-head antihypertensive drug comparisons co − amilozide hydralazine minoxidil guanfacine methyldopa chlorthalidone hydrochlorothiazide bendroflumethiazide clonidine indapamide metolazone terazosin benazepril prazosin captopril Driven primarily by ALLHAT doxazosin enalapril fosinopril Aliskiren I just 3 individual drugs lisinopril labetalol moexipril carvedilol perindopril pindolol Focus: efficacy safety quinapril penbutolol ramipril carteolol trandolapril acebutolol azilsartan propranolol candesartan Can LEGEND provide nadolol eprosartan irbesartan nebivolol 1. reliable – concordant w/ RCTs losartan metoprolol olmesartan bisoprolol telmisartan 2. rich – across “all” comparators betaxolol valsartan atenolol amlodipine felodipine spironolactone isradipine 3. relevant – inform practice epleronone nicardipine nifedipine triamterene nisoldipine amiloride lacidipine diltiazem torsemide furosemide verapamil evidence? bumetanide Trials: 40 N = 102 [1148] 33K − − LEGEND knowledge base for hypertension Head-to-head HTN drug comparisons co co − − amilozide amilozide hydralazine hydralazine minoxidil minoxidil guanfacine guanfacine methyldopa methyldopa chlorthalidone chlorthalidone hydrochlorothiazide hydrochlorothiazide bendroflumethiazide bendroflumethiazide clonidine indapamide clonidine indapamide metolazone metolazone terazosin terazosin benazepril benazepril prazosin captopril prazosin captopril doxazosin enalapril doxazosin enalapril fosinopril fosinopril Aliskiren Aliskiren lisinopril lisinopril labetalol labetalol moexipril moexipril carvedilol carvedilol perindopril perindopril pindolol pindolol quinapril quinapril penbutolol penbutolol ramipril ramipril carteolol carteolol trandolapril trandolapril acebutolol azilsartan acebutolol azilsartan propranolol candesartan propranolol candesartan nadolol eprosartan nadolol eprosartan irbesartan irbesartan nebivolol nebivolol losartan losartan metoprolol metoprolol olmesartan olmesartan bisoprolol bisoprolol telmisartan telmisartan betaxolol betaxolol valsartan valsartan atenolol atenolol amlodipine amlodipine felodipine felodipine spironolactone isradipine spironolactone isradipine epleronone nicardipine epleronone nicardipine nifedipine nifedipine triamterene triamterene nisoldipine nisoldipine amiloride lacidipine amiloride lacidipine diltiazem diltiazem torsemide torsemide furosemide furosemide verapamil verapamil bumetanide bumetanide Trials: 40 Comparisons: 10, 278 N = 102 [1148] 33K N = 3502 [212K] 1.9M − − − − e168 Whelton et al. JACC VOL. 71, NO. 19, 2018 2017 High Blood Pressure Clinical Practice Guideline MAY 15, 2018:e127– 248 2. The treatment of patients with hypertension without decreases CVD morbidity and mortality. The clinical elevated risk has been systematically understudied trial evidence is strongest for a target BP of 140/90 because lower-risk groupswouldrequireprolonged mm Hg in this population. However, observational follow-up to have a sufficient number of clinical events studies suggest that these individuals often have a high to provide useful information. Although there is clin- lifetime risk and would benefitfromBPcontrolearlier ical trial evidence that both drug and nondrug therapy in life (S8.1.5-19,S8.1.5-20). willFirst-line interrupt the progressive agents course of hypertension (S8.1.5-6),thereisnotrialevidencethatthistreatment 8.1.6. Choice of Initial Medication Recommendation for Choice of Initial Medication 2017References ACC/AHA that support theGuidelines recommendation are summarized in Online Data Supplement 27 and Systematic Review Report. COR LOE RECOMMENDATION 1. For initiation of antihypertensive drug therapy, first-line agents include thiazide diuretics, CCBs, and ACE SR IA inhibitors or ARBs. (S8.1.6-1,S8.1.6-2) SR indicates systematic review. “In particular, there is inadequate evidence to support the initial use of beta blockersSynopsis for hypertension in the absence of specificeffective for cardiovascular prevention of CVDcomorbidities.” than other first-step The overwhelming majority of persons with BP suffi- agents, such as thiazide diuretics (S8.1.6-3,S8.1.6-10). ciently elevated to warrant pharmacological therapy may Recommendation-SpecificSupportiveText be best treated initially with 2 agents (see Section 8.1.6.1). When initiation of pharmacological therapy with a single 1. The overall goal of treatment should be reduction in BP, 2018medication ESC/ESH is appropriate, Guidelines: primary consideration Class should I, Levelin A the context of underlying CVD risk. Five drug classes be given to comorbid conditions (e.g., HF, CKD) for which have been shown, in high-quality RCTs, to prevent CVD “Amongspecifi allcclassesofBP-loweringmedicationareindicated antihypertensive drugs, ACE inhibitors,as compared ARBs, with beta-blockers, placebo (diuretics, ACE CCBs, inhibitors, (see Section 9) (S8.1.6-1).Inthelargesthead-to-head ARBs, CCBs, and beta blockers) (S8.1.6-11,S8.1.6-12).In and [thiazide]comparison of diureticsfirst-step drug . therapy have for demonstrated hypertension effectivehead-to-head reduction comparisons of of BPfirst-step andCV therapy, events(S8.1.6-3) in RCTs,,thethiazide-typediureticchlorthalidonewas and thus are indicated as thedifferent basis drug of classesantihypertensive have been reported treat- to provide superior to the CCB amlodipine and the ACE inhibitor somewhat divergent capacity to prevent specificCVD mentlisinopril strategies.” in preventing “. beta-blockers HF,aBP-relatedoutcomeof are usuallyevents. equivalent Interpretation in preventing ofmeta-analysescomparing major CV increasing importance in the growing population of older agents from different drug classes is challenging events,persons except with hypertension for less(S8.1.6-4 effective—S8.1.6-7) prevention.Addition- of strokebecause the . relevant . ” RCTs were conducted in different ally, ACE inhibitors were less effective than thiazide di- time periods, during which concurrent antihyperten- uretics and CCBs in lowering BP and in prevention of sive therapy was less or more common, and the efficacy stroke. For black patients, ACE inhibitors were also of agents from certain drug classes may have changed. notably less effective than CCBs in preventing HF (S8.1.6- In recognition of this, some (S8.1.6-2) but not all (S8.1.6- 8) and in the prevention of stroke (S8.1.6-9) (see Section 11,S8.1.6-12) meta-analyses, as well as the largest indi- 10.1). ARBs may be better tolerated than ACE inhibitors vidual RCT that compared first-step agents (S8.1.6-3), in black patients, with less cough and angioedema, but have suggested that diuretics, especially the long-acting according to the limited available experience they offer no thiazide-type agent chlorthalidone, may provide an proven advantage over ACE inhibitors in preventing optimal choice for first-step drug therapy of hyperten- stroke or CVD in this population, making thiazide diuretics sion. In contrast, some meta-analyses have suggested (especially chlorthalidone) or CCBs the best initial choice that beta blockers may be less effective, especially for for single-drug therapy. For stroke, in the general popu- stroke prevention in older adults, but interpretation is lation, beta blockers were less effective than CCBs (36% hampered by inclusion of RCTs that used beta blockers lower risk) and thiazide diuretics (30% lower risk). CCBs that are now considered to be inferior for prevention of have been shown to be as effective as diuretics for CVD (S8.1.6-13,S8.1.6-14).Inasystematicreview reducing all CVD events other than HF, and CCBs are a and network meta-analysis conducted for the good alternative choice for initial therapy when thiazide present guideline, beta blockers were significantly diuretics are not tolerated. Alpha blockers are not used as less effective than diuretics for prevention of stroke first-line therapy for hypertension because they are less and cardiovascular events (S8.1.6-1).Diureticswerealso First-line agents: comparisons from RCTs RCT − AMI Efficacy outcomes: myocardial infarction, heart failure, stroke Figure 3.3 Network of clinical trials of antihypertensive drug classes in which myocardial infarction was reported (N=29). * ACE Target ACEIs CI overlap full ● ARBs ● ALPINE THZ partial ARB 0.41 (0.01-5.6) ● ● cBBs ● ● ● ● ● dCCBs ● ● ● ● ● ● ● ASCOT-BPLA, ELSA CCB BB TZDs ● ● ● ● 0.89 (0.55-1.5) *The trials included in each pair-wise comparison are labeled above the arrow. Summary of relative risk (RR) and 95% CIs for the direct comparisons are shown below the arrow. For each pair-wise comparison, the line starts at the reference group and points towards the comparison group. Thus, the arrowhead points to a class of antihypertensive drugs for which a higher RR would signify an increased risk of myocardial infarction. Comparator cBBs TZDs ARBs Figure 3.4. Network of clinical trials of antihypertensive drug classes in which heart failure was reported (N=21). ACEIs dCCBs © 2017 by the28 American /College 30 of Cardiology estimates Foundation and the American Heart are Association, concordant Inc. (discordant59 in BBs for HF) First-line agents: comparisons from LEGEND RCT − AMI Acute myocardial infarction Meta−analysis Efficacy outcome: myocardial infarction, heart failure, stroke RCTs LEGEND ACEIs ACEIs ARBs ARBs cBBs cBBs dCCBs dCCBs TZDs TZDs cBBs cBBs TZDs TZDs ARBs ARBs ACEIs ACEIs dCCBs dCCBs Data source: