Summary of Evidence





    Evidence Base For Anti-Hypertension Drugs

    All drugs that lower blood pressure do not equally reduce cardiovascular risk.

    • JNC - Joint National Committee (came together in 1972)
      • Every 4 years report came out.
    • JNC7 came out in 2003
      • Had concept of pre-hypertension (lower target for DMII and Renal Disease)
      • Observed: Systolic BP correlates better than diastolic for heart disease.
      • Indicated that diuretics lead to better outcomes (Established First Line)
    • Old Studies:
      • 10 year follow-up with pts. to have untreated hypertension  (Unethical now).
      • Virtually all treatments of HTN, show greater reduction in stroke events than CVD.
      • Whitecoat hypertension is NOT normal, it is pre-hypertension. (Highly labile)
        • Illustrated in study (1400 pts followed 10 years, 16% - BP elevated in office, normal @home)
        • In follow-up 10 yrs: Ones with whitecoat HTN --> 43% progressed to HTN (14% of normotensive)
        • Cannot rely on home pressures.
        • RISK ONLY goes up when they develop true HTN (not whitecoat HTN).


    • Secondary Causes of Hypertension (aka "Identifiable Causes")
      • Most common: OSA (does not respond to therapy).
      • Second most common (Much less so) : Renal Artery Stenosis.
    • Cochrane Review 2009 - Compared first-line Anti-HTN therapy of 4 major drug classes (each against placebo)
      • Conclusions:
        • Low-dose Thiazide: mortality benefit, coronary heart disease (CHD) events, 
        • High-dose Thiazide: no CHD event reduction.
        • B-Blocker: less benefit in reducing stroke, CV Events, and CHD than low-dose thiazides.
          • However, 4/5 trials used atenolol.
        • ACEi: Similar mortality benefit to low-dose thiazides, but wider confidence intervals at all outcomes. 
        • CCB: Not enough data:  confidence intervals are too wide. 
      • Low Dose thiazide means:
        • HCTZ < 50mg
        • Chlothalidone < 50mg
        • Indapamide < 5mg
      • NOTE:
        • CHD - Coronary Heart Disease events (fatal and non-fatal MI, Sudden/rapid cardiac death).
        • Cardiovascular Events - Total stroke, total CHD, hospitalization, or death from CHF, aneurisms etc... Excludes angina, TIAs)





    All drugs that lower blood pressure do not equally reduce cardiovascular risk.


    Bottom Line:

    • GREAT data for thiazide diuretics.
    • Good data for ACEi and CCB (CCB more data in combination).
    • Mixed data for ARBs.
    • Inferior Data: Do not use Beta Blockers and A1 blockers.
    • No evidence on renin inhibitor.
    • Other way to put this:
      • 1st line: Diuretics, ACEi, CCB.
        • If no reason to pick other two, start with thiazide.
      • 2nd line: ARB, renin inhibitor.
      • 3rd line: Labetalol, Hydralazine



    Thiazide Diuretics


    • JNC7/CHEP Hypertension Guidelines support diuretics as first line therapy for HTN.
    • MOST Robust data.
    • ↓ K+ (monitor Lytes), especially careful if longer QT interval
    • Effect dose dependent:
      • Dose 12.5-25mg --> Vasodilation
      • Dose 25mg + --> Diuresis (+ side effects)
    • Types:
      • Hydrochlorthiazide
      • Cholthalidone  (Better than Hydrochorthiazide)
    • Evidence:
      • More effective than other agents in African-American populations and elderly with isolated systolic hypertension. 
      • ALL-HAT Trial (JAMA-2002)
        • Multi-center trial (like real life)
        • Pts >55 randomized to:
          • CCB, Thiazide, A-blocker, ACEi, Followed by 5 years.
          • Can compare:
            • Chorthalidone vs. amlodipine
              • Chorthalidone equally effective to amlodipine for mortality endpoint.
              • HF outcomes: favours chlorthalidone (less new-onset HF).
            • Chlorthalidone to Lisinopril.
              • All-cause mortality: NO DIFFERENCE.
              • Chlorthalidone favoured to ACEi for new-onset HF (smaller difference)
              • Chlorthalidone favoured to ACEi for stroke prevention.
      • Preventing new onset heart failure meta-analysis:
        • Relative risk for new-onset HF was lowest for pts treated with diuretics.
      • MR-FIT Trial
        • HCTZ vs. Chlorthalidone (Not head-to-head, but has data)
          • Very poor data, but one trial (MR-FIT trial) use data to make indirect comparisons.
          • Event-free probability favoured (HR=0.79) favouring chlorthalidone.
          • MrFittrial.png
          • Chlorthalidone is twice as potent (not twice as effective)
            • (12.5mg = 25mg of HCTZ)
          • Chlorthalidone has longer half-life (1 day).  More effective in lowering night-time BP (Suggested is important marker for CV risk).
          • Most trials used chlorthalidone.
          • Chlorthalidone: Start with 12.5mg and go no higher than 25mg.
          • Chlorthalidone: Slightly higher rate of hypokalemia.
            • Bring back in 2 weeks and check K+, and may need replacement.  (Almost always occurs in first 2 weeks.)

    ACE Inhibitors


    • First line agents in select patients.  CAD/CHF or Diabetes
    • Many trials: ACEi are effective!
    • Reduce CV risk to about same extent as the diuretics.
    • Side Effects:
      • Angioedema
      • ↑ K+
      • cough
    • Combination:
      • Can combine Thiazide + ACEi (Synergistic)
      • Can combine CCB + ACEi (Based on ACCOMPLISH trial)
    • Evidence:
      • Do not reduce CVD events in patients who had a stroke.


    Angiotensin Receptor Blockers (ARB)


    • 2nd Line therapy for HTN treatment due to evidence:
    • Evidence:
      • TRANSCEND Trial
        • 6000 high-risk pts, with existing heart disease and DM (Secondary prevention), intolerant to ACEi (Cough)
          • Customary switch to ARBs.  
        • Randomly assigned to telmisartan (fixed dose) vs. placebo.  
        • Two lines are superimposable. 
        • NO BETTER than placebo at reducing CVD risk in high risk patients. 
        • TrascendTrial.png
      • 2010 NEJM trial:
        • Enrolled pts impaired fasting glucose (3/4 had HTN), high risk due to DM or HTN.
        • Valsartan (fixed dose) vs. Placebo
        • Hazard ratio 0.99 (two lines superimposible).
        • ARBs do not reduce CBD risk in high risk pts.
      • ON-TARGET Trial
        • Randomly assigned to Telmisartan, Ramipril, or combination.
        • Maximally inhibiting the RAAS.
        • No difference in CVD risk reduction (dual therapy compared to either drug alone).
        • Telmisartan NON-Inferior to ACE inhibitors, but combination was no better.
        • Dual therapy: More adverse effects (Hypotension, syncope, renal dysfunction).
        • Do not use ACEi and ARBs together for HTN mgmt.
      • Trial: DO NOT reduce cardiovascular events in people who had a stroke. j
      • Hence: 2nd line.




    • S/E: Orthostatic hypotension!!  (4rth/5th line).
    • Bottom Line: DO NOT USE.
    • ALL-HAT Trial:
      • Used Doxazosin (along with other combination agents - see Thiazide Diuretics Section)
      • Increased CV event rate for Doxazosin.
      • Removed alpha-blocker arm from the trial.




    • Standard of HTN treatment for a long time (along with thiazides).
    • New evidence moved using B-blockers for HTN out of favour (not even 2nd line)
    • Evidence:
      • At least 4 different meta-analyses came to same conclusion.
      • Most recent: Cochrane meta-analysis: 2009, published in 2012
        • B-Blocker vs. placebo
          • B-blocker on Mortality in HTN patients: NO BENEFIT (Risk Ratio 0.99)
          • B-blocker on Coronary Events in HTN patients: NO BENEFIT
          • B-blocker on Stroke risk in HTN patients: MODEST BENEFIT, Risk ratio: 0.80 (smaller the better)
            • Hence: 20% risk reduction. This is less than most other drug classes.  Most reduce by (30-40%).
      • Forest plots: Each box represents an individual study, size of box indicates number of subjects.  Vertical line: line of unity (no difference). Left favours B-Blocker, Right favours placebo.  Diamond: summary estimate.



    • Real mechanistic effect, not just epiphenomenon:
      • Among trials of patients getting B-blockers for HTN, those with lower heart rates (more B-blocked) had increased CV events.  This means that this relationship is TRUE.
      • Likely a class-effect, but most of the trials looked at atenolol.
    • Conclusions:
      • No benefit in: mortality, CV events, and the stroke benefit is much less than other drugs.
      • Only use if don't have many choices.
      • Keep in mind: This is for PRIMARY PREVENTION in HYPERTENSIVE patients.
      • Lots of roles of B-blockers post-MI, heart failure, etc.
    • S/E:
      • Exacerbate asthma
      • ↓ HR



    • Calcium Channel Blockers
      • Dihydropyridine CCB (vasodilation, reflex tachycardia)
      • Non-dihydropyridine CCBs (act like B-blockers, mostly bradycardia, little effect on BP)
        • Diltiazem
        • Verapamil
      • S/E: Edema
    • Nitrates
    • Hydralazine (if pregnant)
    • Also consider Statins and ASA if >50yo

    Calcium Channel Blockers


    • JNC8/CHEP - Can be first line without any compelling indications for other agents
    • S/E: Constipation, Headache, Fluid retention
    • Evidence:
      • ASCOT Trial (2006)
        • Amlodipine vs. Atenolol
        • CVD events lower with amlodipine.
        • Controversy: Atenalol is inferiour drug in general, selected an inferior agent.
      • ACCOMPLISH Trial  (2008)
        • Looked at combinations.
        • Physicians selected from drugs in non-randomized fashion.
        • Combinations:
          • Amlodipine (CCB) + benazepril (ACEi) vs. HCTZ (Thiazide) + benazepril (ACEi)
            • Lower CV event risk in CCB + ACEi group
          • Hence: In combination, CCBs have a role.  Have not yet been duplicated in other trials (as of 2008)
      • Isolated Systolic Hypertension - good data for use of CCB.
    • Conclusion:
      • Conflicting data.
        • ASCOT: better than atenolol.
        • ALL-HAT: Worse than Thiazides
        • ACCOMPLISH: Better in combination.
        • Monotherapy: No data available.



    • New drug: Direct renin inhibitor.
    • (Mitchell 2007) Not inferior or superior to other agents to reduce blood pressure.
    • However no trials to show that it reduces cardiovascular risk. (as of 2013)
      • NOT first line because does not show decreases cardiovascular risk.
      • Use only when no other options available.
      • (Captopril was first ACE inhibitor --> showed reduced HTN, but did not show CVD benefits until 10 years later, but took on faith.  Nowadays good drugs exist, cannot take this on faith).
    • ALTITUDE Trial - Adding aliskiren to ACEi or ARB associated with trend towards increased risk of CV events in pts with Type II DM, most of whom had CKD and proteinuria. 



    • Indication for resistant hypertension.
    • Retrospective study of spironolactone in pts with resistant HTN (look at data with some suspicion)
      • 170/90 on study entry (fit resistant HTN definition).
    • Adding spironolactone to regimen --> BP reduction of 25 mmHg systolic and 10 mmHg diastolic, and 50% reached target 140/90. 
    • Mechanism: Many ppl with resistant hypertension have inappropriately high levels of aldosterone.


    Other Highly Potent Drugs (3rd line)


    • No data on any of them regarding mortality benefits, CV events, CHF etc....
    • However, they are highly effective in reducing BP
    • Examples:
      • Labetalol (Advised by Expert)
        • Highly effective, can get BP down in most patients.
        • Easier to use.
      • Hydralazine & Minoxidil
        • Pts report salt retention, reflex tachycardia, feel unwell.
      • Carvedilol
      • Spironolactone



    Special Considerations


    • African Americans and elderly with isolated systolic hypertension have different response to antihypertensives.
      • Much more salt sensitive.  Dietary salt restriction and diuretics and MUCH more effective in these populations. 
      • ACEinhibitors, B-Blockers and ARBs are not as effective.
      • Diuretics make a lot of difference (work better).
      • CCBs + Thiazides tend to work better.
      • Start: Chlorthalidone and add amlodipine.
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