In anyone with any type of cardiac condition BB remain THE first line drug of choice. In uncomplicated HTN (if such a term exists!), there are many drugs that have cemented
Beta Blockers in HTN
In the name of Allah, Most Gracious, Most Merciful
B E T A B L OCK E R S - I N H Y P E R T E NS I ON - Dr. Mohammed Sadiq Azam First yr. PG M-I
HISTORY• 1948: Ahlquist classified adrenergic receptors into α and β receptors.• 1958: Dichloroisoprenaline (DCI) – First BB• 1963: Therapeutic breakthrough, Propronolol introduced by J.W.Black• 1980: BB become the most popular antiHTNs after diuretics. Practolol – First β1 selective.• 2003: BB become the most controversial antiHTNs!!• 2010: ??????
CLASSIFICATION OF β BLOCKERS GENERATION CLASS COMPOUND First Non selective Propronolol Second Selective Metoprolol Third Beta blocker - vasodilator Carvedilol Bucindolol Nebivolol(Ref: Braunwald, Drugs in treatment of Heart Failure, Heart Disease, p590:t23-11,7e:2005)
PHARMACODYNAMICS (Prototype: Propronlol)• On Heart: – ↓ HR, ↓ Force of contraction, ↓ Cardiac Output – ↑ systole by ↓ conduction (↓ synergy of fibres) – Cardiac work, O2 consumption: ↓ – Total coronary flow: ↓ • Restricted to subepicardial region, subendocardial region is not affected. – Overall Effect : ↑ O2 supply/demand status & exercise tolerance. – ↓ Refractory period & automaticity - ↓ rate of DP in ectopic foci – AV conduction : Delayed – ↑ ↑ doses: membrane stabilisation & direct depressant (Quinidine like) effect. – Blocks cardiac stimulatory action of adrenergic drugs but NOT Digoxin, Ca, Methyl xanthines, glucagon.
PHARMACODYNAMICS (Prototype: Propronlol)• On Blood vessels: – Inhibits VD & ↓ BP caused by Isoprenaline – Augments ↑ BP caused by Adrenaline – Re-reversal of vasomotor reversal seen after α-blockade (Reverse Dale) – No direct effect on blood vessels => little acute change in BP – Prolonged use: BP ↓ in hypertensive subjects but NOT in normotensives.
PHARMACODYNAMICS (Prototype: Propronlol)• Mechanisms of Anti Hypertensive action: – Initially: TPR ↑ and C.O ↓ (15-20%) => little change in BP • Chronic use: resistance vessels adapt – TPR ↓, CO ↓ => BP ↓ 2. ↓ NA release from sympathetic terminals due to blockade of β-mediated release. 3. ↓ β 1 mediated renin release from kidney (upto 60% in BB with ISA - ) 4. Central action ↓ sympathetic outflow
PHARMACOKINETICS (Prototype: Propronlol)• Oral absorption: Good• Low Bioavailability (due to↑ FP metabolism in Liver)• Oral:Parental dose ratio = 40:1• Interindividual variation in extent of FPM +• Lipophilic, easily crosses BBB• Liver metabolism depends on HBF ( ↓ on chronic use)• BA ↑ with meals as food ↓ FPM• Metabolism is saturatable. BA ↑ with ↑ doses• Plasma protein binding > 90%• Excretion in urine as Glucronides
DRUG INTERACTION (Prototype: Propronlol)• Additive depression of SA node and AV conduction with digitalis and verapamil .• Delayed recovery from hypoglycemia• Unopposed α action - ↑ TPR• Indomethacin/NSAIDs- Attenuate anti HTN action• Cimitidine inhibits Ppnl metabolism.• Ppnl ↓ metabolism by ↓ HBF• Ppnl ↑ BA of CPZ by ↓ FPM
ADR & CONTRA INDICATIONS (Prototype: Propronlol)• Fatigue - MC ADR• ↑↑ Myocardial insufficiency – C/I in severe HF• Bradycardia - ↑↑ in patients with SSS• ↑ variant angina – unopposed α mediated coronary VC• Impairment of carbohydrate tolerance in pre diabetics.• Altered plasma lipid profile - ↑ TGL , LDL - ↓ HDL• Sudden withdrawal – rebound HTN, ↑ angina, sudden death• ↓ exercise capacity – β2 mediated VD to skeletal muscle ↓• Worsening of PVD
ADR & CONTRA INDICATIONS (Prototype: Propronlol)• Non selective BBs can precipitate life threatening AE of BA• C/I in partial/ complete heart block – can ppt arrest• C/I in pheochromocytoma – can ppt a severe HTN crisis.• Sexual dysfunction in males• ?? Effect on depression – reported ↑ r/o suicide compared to CCB/ACEI• Caution in DM, elderly, pregnancy (esp. non specific BB)
COCHRANE ON BB in HTN (Prototype: Atenolol)• The review, published online January 24, 2007, bases this conclusion on "the relatively weak effect of beta blockers to reduce stroke and the absence of an effect on coronary heart disease when compared with placebo or no treatment" and "the trend toward worse outcomes in comparison with calcium-channel blockers, renin-angiotensin-system inhibitors, and thiazide diuretics.“• Most of the evidence for these conclusions comes from trials where atenolol was the beta blocker used, and it is not known at present whether there are differences between the different subtypes of beta blockers or whether beta blockers have differential effects on younger and elderly patients.
COCHRANE ON BB in HTN (Prototype: Atenolol)• Results showed that the risk of all-cause mortality was not different between first- line beta blockers and placebo, diuretics, or inhibitors of the renin angiotensin system but was higher for beta blockers compared with calcium blockers. Comparative drug RR of all-cause mortality 95% CI for beta blockers Placebo 0.99 0.88-1.11 Diuretics 1.04 0.91-1.19 ACE inhibitors/ARBs 1.10 0.98-1.24 Calcium blockers 1.07 1.00-1.14
COCHRANE ON BB in HTN (Prototype: Atenolol)• The risk of total cardiovascular disease was lower for first-line beta blockers compared with placebo but was significantly worse for beta blockers compared with calcium blockers. There was no significant difference in this end point with beta blockers when compared with either diuretics or ACE inhibitors/ARBs. Comparative drug RR of total CV disease for 95% CI beta blockers Placebo 0.88 0.79-0.97 Diuretics 1.13 0.99-1.13 ACE inhibitors/ARBs 1.00 0.72-1.38 Calcium blockers 1.18 1.08-1.29
COCHRANE ON BB in HTN (Prototype: Atenolol)• The lower risk of total cardiovascular disease with beta blockers compared with placebo was primarily a reflection of the significant decrease Comparative RR of stroke 95% CI drug for beta in stroke, whereas coronary heart disease (CHD) blockers risk was not significantly different between beta blockers and placebo. Placebo 0.80 0.66-0.96• Similarly, the increase in total cardiovascular disease with beta blockers compared with Diuretics 1.17 0.65-2.09 calcium blockers was due to an increase in stroke with the beta blockers. ACE 1.30 1.11-1.53 inhibitors/• There was also an increase in stroke with beta ARBs blockers as compared with inhibitors of the renin angiotensin system. CHD was not Calcium 1.24 1.11-1.40 blockers significantly different between beta blockers and diuretics, calcium blockers, or renin- angiotensin-system inhibitors.
COCHRANE ON BB in HTN (Prototype: Atenolol)• The authors conclude that "beta blockers are inferior to various calcium-channel blockers for all-cause mortality, stroke, and total cardiovascular events and to renin-angiotensin-system inhibition for stroke."• Is age important? Noting that a previous meta-analysis (by Khan and McAlister) found beta blockers to be inferior to all other therapies only in elderly patients, they point out that this claim relies heavily on the Medical Research Council trial in elderly hypertensive patients, in which the dropout rate was 25%. They say: "At present, there are insufficient data to make a valid comparison of beta-blocker effects on younger vs elderly patients, although this is an important hypothesis."
COCHRANE ON BB in HTN (Prototype: Atenolol)• Are there differences between beta blockers? They point out that of the 40,245 participants using beta blockers in this review, atenolol was used by 30,150 (75%). "Due to the paucity of data using beta blockers other than atenolol, it is not possible to say whether the effectiveness (or lack thereof) and (in)tolerability of beta blockers seen here is a property of atenolol or is a class effect of beta blockers across the board.“• The authors note that the information reported in the trials considered in this review was insufficient to explore the effect of race or ethnicity, as most trial participants were white.
ASCOT-BPLA TRIAL (Prototype: Atenolol)• Anglo-Scandinavian Cardiac Outcomes Trial—Blood Pressure Lowering Arm (ASCOT-BPLA) trial have confirmed preliminary findings showing that an antihypertensive strategy based on amlodipine, with perindopril added as required, significantly reduced all-cause mortality and other cardiovascular end points, including stroke, compared with an atenolol-based strategy, with the diuretic bendroflumethiazide added as required.• A 10% reduction in nonfatal MI and fatal coronary heart disease (CHD), the primary end point of the trial, did not reach statistical significance, a finding that the researchers attribute to the early stop of the trial.• A reduction in all-cause mortality seen with the amlodipine/perindopril strategy caused the trial to be stopped in November 2004.
ASCOT-BPLA: PRIMARY AND SECONDARY END POINTS (Prototype: Atenolol) End point Amlodipine- Atenolol-based Unadjusted hazard p based regimen regimen ratio (95% CI)Primary end point 429 474 0.90 (0.79-1.02) 0.1052 (n)Fatal and nonfatal 327 422 0.77 (0.66-0.89) 0.0003 stroke (n)Total CV events and 1362 1602 0.84 (0.78-0.90) <0.0001 procedures (n)All-cause mortality 738 820 0.89 (0.81-0.99) 0.025 (n)
ASCOT-BPLA:PRIMARY AND SECONDARY END POINTS (Prototype: Atenolol) End point Amlodipine- Atenolol-based Unadjusted p based regimen regimen hazard ratio (95% CI) New-onset 567 799 0.70 (0.63-0.78) <0.0001 diabetes
CAFE TRIAL (Prototype: Atenolol)• Conduit Artery Function Evaluation (CAFE), a sub- study of the ASCOT, which compared the BB atenolol +/- a diuretic with a regimen based on amlodipine +/- without the ACEI, perindopril.• CAFE findings showed substantial reductions in central aortic BP with amlodipine + perindopril over atenolol + diuretic, despite very similar brachial BPs between the groups.
CAFE TRIAL (Prototype: Atenolol)• The greater vasodilation seen with amlodipine-based treatment might translate into a reduction in the strength of the reflected wave velocity from the periphery, thereby reducing central arterial pressures.• Williams pointed out that a 3- to 4-mm-Hg difference in BP seen between groups in central aortic pressures translates into roughly a 25% difference in stroke risk— (similar to the 27% reduction in stroke risk seen in ASCOT in the amlodipine/perindopril arm, supporting the possibility that this difference in central pressures may explain the differences seen in outcomes between groups).
CAFE TRIAL (Prototype: Atenolol)Measure Amlodipine-based 95% CI p vs Atenolol-based regimen (mm Hg)Brachial systolic BP 0.7 -0.4 to 1.7 0.2Central aortic 4.3 3.3 to 5.4 <0.0001systolic BPCentral aortic pulse 3.0 2.1 to 3.9 <0.0001pressure
WHAT THE ESC/ESH SAYS…BB vs CCB:• In support of ASCOT-BPLA• INVEST trial: also showed equal incidence of CV events in patients with CAD in whom treatment was started with a CCB (verapamil, often + ACE I) or with a BB (atenolol often + D)
WHAT THE ESC/ESH SAYS…BB vs ARB:• In the LIFE study in more than 9000 hypertensive patients with electrocardiographic left ventricular hypertrophy mean blood pressure was reduced to the same degree in the groups in which treatment was initiated with either losartan or the b- blocker atenolol.• Over the about 5 years of follow-up losartan-treated patients showed a significant 13% reduction in major cardiovascular events (the primary end point) with no difference in the incidence of myocardial infarction, but a 25% difference in the incidence of stroke.
WHAT THE ESC/ESH SAYS…• The LIFE study and the ASCOT study, both of which showed superiority of an ARB, and, respectively, a CCB over therapy initiated by a BB as far as stroke (LIFE) or stroke and mortality (ASCOT) were concerned.• These two large trials have strongly influenced a recent meta- analysis which concluded that BB initiated therapy is inferior to others in stroke prevention, but not in prevention of myocardial infarction and reduction in mortality.• On the basis of a similar meta-analysis, the National Institute for Health and Clinical Excellence (NICE) in the United Kingdom has advised the use of b-blockers only as fourth line antihypertensive agents.
THE VERDICT• ↓ efficacy on CV endpoints (esp. Stroke) 1,3,4• Metabolically unfriendly - ↑ r/o New onset DM 1• Least cost effective 2• No significant difference in all cause mortality compared to A or D but higher than with CCB 3• Risk for CV disease worse with BB compared to CCB 3• Should be used as 4th line drugs in HTN 2 Source: 1 – ASCOT-BPLA trial, LIFE study 2 – NICE guidelines – CG34:Hypertension 3 – Cochrane Review: BB should not be fist line for HTN , Jan 24, 2007 4 – CAFE trial: Circulation, Mar 2006; CACHET trial: Stroke 2006
The future looks bleak for Beta Blockers..BUT, IS IT SO??? LETS LOOK BACK…
COCHRANE ON BB in HTN (Prototype: Atenolol)Comparative drug RR of all-cause mortality for 95% CI beta blockersPlacebo 0.99 0.88-1.11Diuretics 1.04 0.91-1.19 OL Comparative drug RR of total CV disease for beta 95% CI OL blockersACE inhibitors/ARBs 1.10 0.98-1.24 EN Comparative RR of stroke for 95% CI Placebo 0.88 0.79-0.97 ATCalcium blockers 1.07 1.00-1.14 drug beta blockers Diuretics 1.13 0.99-1.13 Placebo 0.80 0.66-0.96 ACE inhibitors/ARBs 1.00 0.72-1.38 Diuretics 1.17 0.65-2.09 Calcium blockers 1.18 1.08-1.29 ACE inhibitors/ 1.30 1.11-1.53 ARBs Calcium 1.24 1.11-1.40 blockers
ASCOT-BPLA TRIAL (Prototype: Atenolol)End point Amlodipin Atenolol- Unadjusted p e-based based hazard ratio regimen regimen (95% CI)Primary end 429 474 0.90 0.1052 point (n) (0.79-1.02) OL Fatal and 327 422 0.77 0.0003 OL nonfatal (0.66-0.89) ENstroke (n) AT Total CV 1362 1602 0.84 <0.0001events and (0.78-0.90)procedures (n) All-cause 738 820 0.89 0.025 mortality (0.81-0.99) (n)
CAFE & CACHET TRIALS (Prototype: Atenolol) OL OL AT EN
ATENOLOL• Developed in 1976, USFDA approved in 1981.• Short acting beta blocker.• Good ↓ BP but doesn’t improve outcome.• Bad safety profile in stroke1• ↓CBF2, less reduction in central aortic pressure3• Metabolically unsafe - ↑ incidince of new onset DM4• Bad safety profile in elderly5• Must NOT be used in uncomplicated HTN. Source: 1 – ASCOT-BPLA trial 2 – CACHET trial 3 – CAFE trial 4 – LIFE trial, ASCOT-BPLA trial 5 – MRC study
BETA BLOCKERS IN HTN – WHERE DO THEY STAND??• Atenolol is BAD as a first line drug in uncomplicated HTN.• NOT ALL BETA BLOCKERS ARE.• The outcomes seen in the recent clinical trials seem to be more of a DRUG EFFECT than a CLASS EFFECT!!• Newer BB, esp. vasodilatory BB like nebivolol hold a promising future for these drugs.• Lack of clinical data on these drugs has limited their recommendation by international guidelines.
THE EVIDENCE IN FAVOUR OF BB• ESC-ESH 2007 Guidelines state: – Both the LIFE and the ASCOT studies were characterized by a design implicating early use of combination therapy, so that the vast majority of patients randomized to a BB actually received a BB-thiazide combination. – A similar combination was often used in the chlorthalidone treatment group of the ALLHAT trial, which failed to find inferiority of this combination even concerning stroke prevention.
THE EVIDENCE IN FAVOUR OF BB• ESC-ESH 2007 Guidelines state: – Also, in the INVEST trial, a treatment strategy based on the initial administration of a b-blocker followed by the addition, in most patients, of a thiazide diuretic was accompanied by an incidence of all cardiovascular and cause-specific events similar to that of a treatment initiated with the calcium antagonist verapamil followed by the addition of the ACE inhibitor trandolapril.
THE EVIDENCE IN FAVOUR OF BB• ESC-ESH 2007 Guidelines state: – Finally, a recent meta-analysis shows that, when compared with placebo, BB based therapy did indeed reduce stroke significantly. – This suggests that at least part of the inferiority of the b-blocker- thiazide combination reported in ASCOT may be due to a lesser blood pressure reduction, particularly of central blood pressure, that occurred in this trial with this therapeutic regimen.
THE LAST WORD• Newer BBs especially the vasodilatory BB like Nebivolol and Carvedilol are metabolically neutral – they DO NOT increase the incidence of newer diabetics.• Newer BBs in fact ↓ the central aortic pressure thus ↓ the risk of stroke by > 25%.• Newer BBs (nebivolol) can be used in elderly even with a reduced EF (SENIORS trial, J. Am. Coll. Cardiol. 2009;53;2150-2158).
THE LAST WORD• Newer BBs can be used in young HTNs/preHTNs to ↓CO and thus prevent worsening of HTN or development of HTN.• BB though conventionally placed as Category C drugs in pregnancy, hold promise as newer BBs are being developed with better safety profiles (Labetolol – BB OC in Pregnancy).• Newer BBs like Nebivolol, Carvedilol and Metoprolol can be safely used in Diabetes as they do not exacerbate hypoglycaemia unlike conventional BB (Ppnl, Atenolol).
THE LAST WORD• The sins of one (Atenolol) must not be made an excuse for the execution of many (BB as a class).• The bad profiles seen in recent trials seems to be more of a DRUG EFFECT than a CLASS EFFECT.• BB can remain a first line drug in HTN as HTN remains a leading cause of HF and BB are a DOC in HF as well (? dual benefit).
THE LAST WORD• In anyone with any type of cardiac condition BB remain THE first line drug of choice (JNC7, ESC-ESH 2007 guidelines).• In uncomplicated HTN (if such a term exists!), there are many other drugs that have carved a niche for themselves, namely ACEIs, ARBs, CCBs and Diuretics.• Diuretics remain the first line drugs in uncomplicated HTN, a result largely of their low cost rather than improved outcome.