Table of contents
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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)
- Conclusions:
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
- 1st line: Diuretics, ACEi, CCB.
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.
- Chorthalidone vs. amlodipine
- 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.)
- HCTZ vs. Chlorthalidone (Not head-to-head, but has data)
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
- 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%).
- B-Blocker vs. placebo
- 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)
- Amlodipine (CCB) + benazepril (ACEi) vs. HCTZ (Thiazide) + benazepril (ACEi)
- Isolated Systolic Hypertension - good data for use of CCB.
- ASCOT Trial (2006)
- Conclusion:
- Conflicting data.
- ASCOT: better than atenolol.
- ALL-HAT: Worse than Thiazides
- ACCOMPLISH: Better in combination.
- Monotherapy: No data available.
- Conflicting data.
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
- Labetalol (Advised by Expert)
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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