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.
        • IN NONE OF THE COMPARISONS WAS THIAZIDE INFERIOR.
  • 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.
      • 
      • 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. 
    • 
  • 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.

Alpha-Blockers

• 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.

B-Blockers

• 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.

Aliskiren

• 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. 

Spironolactone

• 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.