CONSIDERATION OF COEXISTING CONDITIONS IN ANTIHYPERTENSIVE THERAPY


Asthma and other COPD
Benign Prostatic Hyperplasia
Chronic Renal Disease
Congestive Heart Failure
Coronary Artery Disease
Demographics
Depression
Diabetes Mellitus
Dyslipidemias
Dysrhythmias
Gout
Hepatic Disease
Left Ventricular Hypertrophy
Migraine
NSAID use
Osteoporosis
Peripheral Arterial Disease
Pregnancy

I. Demographics

  1. If high renin (likely so in young, white, male): ACEIs, Beta-blockers are likely to be effective at reducing BP
  2. If low renin (likely so in old, black, female): drugs which don't change renin are likely to be effective at reducing BP, e.g. Ca-blockers, diuretics
  1. Race
    1. Some studies have suggested that African-Americans have less BP reduction with ACEIs than whites; diuretics have been shown to be more effective monotherapy for BP reduction in African-Americans than beta-blockers or ACEIs
    2. In African-Americans with hypertensive nephropathy-ACEIs better at reducing adverse renal events than Ca-blockers or Beta-blockers (See ACEI section for details)
    3. In a subgroup analysis of ALLHAT, in which 33,357 pts > 55yo with HTN and at least one other cardiovascular risk factor were randomized to amlodipine, lisinopril, or chlorthalidone, the primary outcome of (fatal CAD or nonfatal MI) was not sig. diff. among the treatments in either blacks or non-blacks, but among both black and non-black patients, the outcome of heart failure incidence was sig. higher in amlodipine vs. chlorthalidone recipients (RR 1.37) (JAMA 293:1595, 2005--abst)
  1. Elderly
    1. Target BP should be < 140/90
    2. Check BP in standing and either supine or sitting positions b/c of increased prevalence of orthostatic hypotension
    3. Start w/lower doses than in younger people
    4. JAMA 279:1903, 1998
      1. A meta-analysis of 10 randomized trials of > 1y (avg. f/u 5y) duration in 16,000 pts > 60yo.
      2. Beta-blockers (atenolol & others) were worse than diuretics (hydrochlorothiazide +/- triamterine or amiloride, thiazide, or chlorthalidone) in efficacy as monotherapy as well as reduction in clinical endpoints: cerebrovascular events, fatal CVA, CAD, CV mortality, and all-cause mortality. In face, in all outcomes except the first, beta-blocker monotherapy was associated with non-statistically significant alterations in incidence c/w placebo (95% CI's or RR crossed 1.0)
      3. Note that this involved comparison between groups of trials; only one trial, the "Medical Research Council" trial BMJ 304:405, 1992--didn't read that paper), included comparative outcomes data on diuretics vs. beta-blockers.
    5. Avoid agents that cause orthostatic hypotension (vasodilators, alpha-blockers) and those that cause cognitive dysfunction (centrally-acting agents)

II. Dyslipidemias

  1. Contrary to popular belief, low-dose thiazides don't alter lipids (JAMA 275:1549, 1996)--Doses equivalent to > 50mg/d HCTZ may produce modest elevations in total cholesterol, of questionable clinical significance
  2. Beta-blockers may produce slight increase in TG and decrease HDL; less so for cardioselective beta-blockers
  3. Alpha-blockers may increase HDL and decrease LDL slightly
  4. Ca-blockers, and ACEIs have no effect

III. Coronary artery disease

  1. Note-see section on  Treatment of Stable Coronary Artery Disease for information on use of certain antihypertensive medications to alter cardiovascular outcomes in non-hypertensive patients with coronary disease.
  2. CAD patients in general-Verapamil & Atenolol for treatment of HTN ass'd with similar outcomes
    1. In a trial of 22,576 pts > 50yo with HTN and CAD randomized to sustained-release verapamil vs. atenolol, with trandolapril and/or hydrochlorothiazide added as needed to achieve JNC VI target BP levels, over mean 2.7y f/u, overall BP control and incidence of (death, nonfatal MI, or nonfatal CVA) were not sig. diff. in the two groups (International Verapamil-Trandolapril Study ("INVEST")--JAMA 290:2805, 2003--abst, JW)
  3. Stable angina
    1. Beta-blockers and Ca-channel blockers can both decrease sx but
    2. Avoid short-acting Ca-channel blockers, which in case-control studies have been associated with increased mortality from cardiac events
  4. Post-MI
    1. Beta-blockers (without intrinsic sympathomimetic activity) are DRUGS OF CHOICE, even if reduced LVEF!
    2. Non-dihydropyridine Ca-channel blockers if can't use beta-blockers, but Ca-blockers are BAD if LVEF < 50% (increase mortality)
    3. Diuretics may increase mortality ("Cooperative Cardiovascular Project," a nonrandomized prospective cohort study of 159,000 post-MI pts followed x 30mos; diuretic users had RR 1.77 of death; higher for those with LVEF < 50%; only 60% of the sample was hypertensive--so why were they on diuretics, I wonder...--presented at Int. Soc. on HTN in Blacks meeting 1998, reported in Family Practice News)

IV. Diabetes Mellitus

  1. Target BP should be 130/80 per JNC VII--See section on Diabetes Management for review of data on target BP's in diabetics
  2. Note that ACEIs and ARBs slow progression of diabetic nephropathy (see section on Diabetic Nephropathy for details)
  3. Comparisons of different antihypertensives in diabetic patients
Note--One important source of data for such comparisons is the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack ("ALLHAT") study (JAMA 288:2981, 2002).  The following is a description of the study; data from relevant secondary analyses is incorporated in the sections below:

33,357 pts > 55yo with HTN and at least 1 other CAD risk factor (prior MI or CVA, other atherosclerotic disease, LVH on ECG or echo, type 2 DM, cigarette use, or HDL < 35) randomized to the following with tx to target BP < 140/90 (additional drugs could be added if neeed, including atenolol, clonidine, and reserpine): Chlorthalidone 12.5-25mg/d, amlodipine 2.5-10mg/d, or lisinopril 10-40mg/d (a doxazosin arm was dropped early b/c of sig. higher incidence of main endpoint c/w chlorthalidone).  Over mean 4.9y f/u, incidence of (nonfatal MI or coronary death) and all-cause mortality were not sig. diff. between any of the treatments.  However, analysis of secondary endpoints did show some differences (see below).

  1. Diuretics vs. ACEIs-Diuretics better
    1. In ALLHAT (op. cit.),  lisinopril group had sig. higher 6y incidence of combined CV events (33.3% vs. 30.9%, RR 1.10), CVA (6.3% vs. 5.6%, RR 1.15), and heart failure (8.7% vs. 7.7%, RR 1.19) than chlorthalidone; these differences were maintained in analysis of the subgroup with DM.
  2. Diuretics vs. Ca-blockers-Diuretics better
    1. In ALLHAT (op. cit.), amlodipine tx was ass'd with sig. higher 6y incidence of heart failure than chlorthalidone (10.2% vs. 7.7%; RR 1.38); these differences were maintained in analysis of the subgroup with DM.
  3. ACEIs vs. Ca-blockers-ACEIs better
    1. 470 Pts w/DM randomized to nisoldipine vs. enalapril; over 5y f/u, no diff. in BP reduction but in intention-to-treat analyses, MI incidence was sig. higher in nisoldipine group (RR 5.5) (Substudy of Appropriate Blood Pressure Control in Diabetes ("ABCD") study--NEJM 338:645, 1998)
    2. 380 pts w/type 2 DM randomized to fosinopril vs. amlodipine; pts assigned to the latter had sig. greater SBP but not DBP reductions; incidence of CV events was sig. lower in fosinopril (RR 0.49); no diff. in all-cause mortality (Fosinopril vs. Amlodipine Cardiovascular Events Trial ("FACET") study--Diab. Care 21:597, 1998)
    3. 6614 pts 70-84yo (719 of whom had DM) randomized to (diuretics or beta-blockers), Ca-blockers, or ACEIs.  In DM subgroup, no diff. in BP reductions among the groups; no sig. diff. in incidence of CV mortality but MI incidence was sig. lower in those randomized to ACEI c/w Ca-blockers (RR 0.51). ( Swedish Trial in Old Patients with Hypertension-2 ("STOP-2")--J. Hypertens. 18:1671, 2000)
  4. ACEIs vs. beta-blockers-ACEIs probably better
    1. 10,985 pts w/HTN (11% had DM) randomized to captopril or "conventional tx" (diuretics and/or beta-blockers); no sig. diff. in BP reduction but captopril group had sig. lower all-cause mortality (RR 0.54), incidence of  (combined MI, CVA, or cardiovascular death) (RR 0.59), and MI (RR 0.34).  Has been criticized b/c of unbalanced randomization and post-hoc subgroup analyses (Captopril Prevention Project ("CAPPP")--Lancet 353:611, 1999)
    2. 400 pts w/DM randomized to captopril or atenolol; over 9y f/u, with no sig. diff. in BP reduction and no sig. diff. in total mortality or macrovascular events (UK Prospective Diabetes Study "UKPDS 39" (BMJ 317:713, 1998)
  5. ARBs vs. beta-blockers-ARBs better (if LVH present)
    1. 9193 pts w/HTN (BP 160-200/95-115) and LVH on ECG randomized to losartan or atenolol titrated to BP < 140/90; hydrochlorothiazide added if needed.  Over mean 4.8y f/u, among the subgroup of pts w/DM, no sig. diff. in BP reductions but losartan group had sig. lower , incidence of (MI, CVA, or CV death) (RR 0.76) and all-cause mortality (RR 0.61) (Losartan Intervention for Endpoint Reduction ("LIFE") study--Lancet 359:1004, 2002)
  1. Beta-blockers in Diabetes
    1. Concern has been raised that they may increase risk for hypoglycemia by blunting sx of same; this has not been borne out in observational studies (click link for details)
  2. Diuretics in Diabetes
    1. Thought to possibly increase glucose intolerance; However, in a 6y [prospective trial of 12,550 nondiabetic pts with hypertension, use of thiazides was not ass'd with increased risk of a new dx of DM (NEJM 342:905, 2000--JW)

V. Dysrhythmias

  1. Supraventricular tachyarrhythmias
    1. Beta-blockers and non-dihydropyridine Ca-channel blockers may help control ventricular rate
    2. Nifedipine may cause reflex tachycardia so should be avoided
  2. Heart Block (2nd or 3rd degree)
    1. Avoid beta-blockers and non-dihydropyridine Ca-channel blockers

VI. Congestive Heart Failure

  1. If LVEF is below low
    1. ACEIs are drugs of choice (reduce mortality even if no HTN)
    2. ACE receptor blockers, e.g. Losartan, may be alternative
    3. Carvedilol, may also be helpful but avoid other beta-blockers
  1. Ca-blockers are contraindicated (except those which has no effect on contractility, e.g. amlodipine & felodipine)
  2. Few studies have looked at HTN therapy in HTN with CHF with nl LVEF

VII. Asthma and other COPD--Beta-blockers may worsen bronchoconstriction

VIII. Left Ventricular Hypertrophy

  1. ACEIs/ARBs
    1. Captopril, Enalapril, & Lisinopril all reduce LVH (Circ. 70:271, 1984, Am.J.Hypertens 1:214S, 1988; Am.J.Cardiol. 63:1093, 1989)
    2. ACEI/diuretic combination seems particularly powerful and reducing LVH (Circ. 95:2007, 1997--JNC rvw.)
    3. 9,193 pts with moderate HTN and LVH on ECG randomized to losartan vs. atenolol as first-line tx for HTN. Over mean 4.8y f/u, losartan gropu had sig. lower incidence of adverse cardiovascular events. Severity of LVH on treatment was ass'd with risk of cardiovascular morbidity & mortality independent of randomized treatment, severity of baseline LVH, and baseline & on-treatment BP ("LIFE" study, JAMA 292:2343, 2004--JW)
  2. Ca-blockers--reduce LVH; may be better than diuretics or Beta-blockers (Arch.Int.Med. 149:1263, 1989; NEJM 322:1350, 1990, respectively)
  3. Centrally acting agents (e.g. methyldopa) decrease LV mass
  4. Beta-blockers--Controversial results
  5. Diuretics--NO change in LVH
  6. Vasodilators (e.g. hydralazine, minoxidil) are BAD--increase LVH through reflex stim. of symp. NS and increase in renin-angiotensin

IX. Benign Prostatic Hyperplasia--Alpha-blockers can reduce symptoms

X. Hepatic disease--Avoid central agents (hepatically metabolized)

XI. Chronic Renal Disease

  1. Target BP for patients with chroici renal disease
    1. In a meta-analysis of 11 randomized trials of antihypertensive medications for pts with predominantly nondiabetic renal disease, risk of progression of renal disease (doubling of baseline serum Cr level or onset of renal failure) was lowest for pts with SBP 110-129 during treatment.
    2. In a study in 1,094 African-American with HTN-related chronic kidney disease but no DM randomized to antihypertensive treatment with standard vs. intensive BP control (with mean BPs 130/78 vs. 141/86), there was no sig. diff in 4y incidence of (50% reduction in GFR, end-stage renal disease, or death)  ("African-American Study of Kidney Disease and Hypertension" ("AASK"); JAMA 288:2421, 2002-JW)
    3. In a follow-up to the African-American Study of Kidney Disease and Hypertension (AASK) trial, in which pts were followed for 6y after end of the initial phase of the trial, during which the target BP was < 130/80 and all pts received ramipril, there was no sig. diff. in the incidence of (doubling of serum Cr, end-stage renal disease, or death), though in the subgroup of pts in whom baseline urine protein-to-creatinine ratio was > .22, intensive BP control was associated with sig. lower incidence of that endpoint (HR 0.73) (NEJM 363:918, 2010-JW)
  2. ACEIs may slow progression
    1. Use with caution if Cr > 3.0
    2. Monitor serum Cr & d/c if rises > 1.0 above baseline (& remains high when reassessed after several days)
    3. In a meta-analysis of 127 randomized trials comparing the impact of different antihypertensive regimens on renal outcomes, use of an ACEI or ARB was associated with sig. lower risk for progression to end-stage renal disease (RR 0.87) despite lack of sig. diff. in BP changes (Lancet 366:2026, 2005--JW)
  3. Thiazides usually ineffective when Cr > 2.5
  4. Avoid K-sparing diuretics b/c of risk of hyperkalemia

XII. Migraine--Beta-blockers and Ca-channel blockers may help

XIII. Depression--Beta-blockers generally avoided, though no association in large case-control studies (JAMA 267:1783, 1992; Drugs 40:792, 1990; cited in Archives Rev'w)

XIV. Osteoporosis--Diuretics may help maintain bone mineral density

XV. Gout

  1. Ca-channel blockers and losartan and are associated with reduced risk of gout in pts with hypertension; Diurectics, beta-blockers, ACEIs, and ARBs other than losartan are associated with increased risk of gout in pts with hypertension (BMJ 344:d8190, 2012-JW)

XVI. On NSAIDS--Reduces efficacy of diuretics and ACEIs

XVII. Pregnancy

  1. Only agents proven to be safe are alpha-methyldopa and hydralazine
  2. Beta-blockers ass'd with IUGR if used in 1st trimester but otherwise ok (atenolol & metoprolol)
  3. Avoid ACEIs and angiotensin receptor-blockers because of teratogenicity per JNC VII
  4. See also "Hypertensive Diseases in Pregnancy"

XVIII. Peripheral Arterial Disease

  1. Beta-blockers traditionally thought to be risky because of peripheral vasoconstriction, but probably safe (NEJM 344:1607, 2001)

(Sources include The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blod Pressure--JAMA 289:2560, 2003)