Clinical Research Article
 
Beta blockers in Coronary artery disease
with and without hypertension

Dr. Santanu Guha, Dr.S aumitra Ray
Professor and Head, Department of Cardiology, Medical College, Kolkata, West Bengal.
Associate Professor, Vivakananda Institute of Medical science, Kolkata, West Bengal

Abstract:
Beta-adrenergic blockers (BB) were developed to treat angina. Trials of BB with myocardial infarction (MI) setting were highly successful in the pre-thrombolytic era. Subsequently BB proved to be beneficial in post-thrombolytic MI in long-term use. In stable angina BB gives good symptomatic relief primarily by reducing myocardial oxygen demand. In the set-up of unstable angina/non-ST elevation MI they prevent arrhythmia and progression to ST elevation MI. BB have also been shown to retard the progression of atherosclerosis. In congestive cardiac failure (CHF) they are now the first-line drugs with ACE inhibitors to impart prognostic benefit. Their role in improving outcome of cardiac and non-cardiac surgeries has found good evidence and recommendation. But in the field where BB have scored maximally,ie,in hypertension, their role is recently debated. But the unchallenged fact remains that in presence of any form of coronary artery disease (CAD), BB are the most preferred class of drugs to treat hypertension.

Key-words:
Beta-blockers, coronary artery disease, hypertension, controversies, the truth.

Introduction:

The saga of betablockers (BB) is like that of a Greek mythological hero. He was born with a silver spoon in his mouth and quickly grew to become the apple of everybody’s eye. Then suddenly the coin flipped and he became a villain overnight. Now with the new daybreak, we see him in a new light as what he is ; neither a fairytale prince , nor a black knight, but our next-door neighbour ready to help us out whenever we need him.

BB were originally conceived and developed by Sir James Black to treat angina by reducing myocardial oxygen demand by dint of their anti-adrenergic action. Actually because of this pioneering work Sir James received the Nobel prize. Propranolol was developed and found widespread utility in cardiac and extracardiac maladies.
Metoprolol and atenolol were discovered soon thereafter and early trials established them as a remarkable class of therapy in acute myocardial infarction. They became popular in the entire spectrum of coronary artery disease (CAD) from silent ischemia, stable angina, unstable angina , myocardial infarction upto secondary prevention after an acute coronary event. The pathophysiological basis of their beneficial effects in each of these conditions were adequately explained and they passed the real life clinical trials with flying colours.
At the same time BB pushed their way into the therapeutic domain of hypertension. They became widely accepted in the treatment of all forms of hypertension, irrespective of patients’ age, ethnicity, type of hypertension, associated co-morbid conditions or presence of secondary causes of hypertension. However, how they work in hypertension has never been fully elucidated and clinical trials from the very beginning generated conflicting results. Ultimately the situation exploded in a negative manner and BB were adjudged to be inadequate treatment for hypertension.
At the moment the whole scenario is getting reappraised and BB are being given their proper position, ie, extremely helpful in certain hypertensive populations and not so useful in certain other situations.
However, CAD in general with and without hypertension remain the bread and butter indication of BB.

Pathophysiology of antiischemic effects of BB:

The basic pathology of myocardial ischemia is a mismatch of myocardial oxygen demand and oxygen supply.(1) BB primarily affect the oxygen demand side and in turn this is achieved primarily by their negative chronotropic effect on the sinus node acting through beta 1 receptors. Additionally they reduce myocardial contractility ( negative inotropic effect) , afterload and oxygen wastage ( by switching myocardial metabolism from fatty acid to glucose ) to reduce myocardial oxygen demand. On the other hand they also help to increase the myocardial oxygen supply to some extent by increasing diastolic perfusion (primarily by increasing diastolic filling time) and by attenuating exercise-induced vasoconstriction. However, in vasospastic angina they may induce angina by coronary vasospasm as mediated via beta 2 receptors.

Role of BB in myocardial infarction:
The use of BB in acute MI setting is best analysed if seen separately in prethrombolytic and postthrombolytic eras. ISIS-1 trial (2)was published in 1986 where intravenous atenolol was used and this was shortly preceded by MIAMI trial (3)with metoprolol. Both revealed a significant 13-15% reduction of in-hospital cardiovascular mortality. This was primarily due to BB’s antiarrhythmic effects and also they reduced cardiac rupture. However, in the thrombolytic realm their utility was doubted and small trials produced conflicting results. In 2005 COMMIT trial (4) was published and acute use of BB , particularly their early intravenous use , earned a bad repute. The COMMIT trial involved 45,852 patients of acute MI and randomized them to either placebo or intravenous metoprolol followed by oral metoprolol for 1 month. There was no difference in mortality. Metoprolol did show a significant 18% reduction of reinfarction and 17% reduction of ventricular fibrillation; but the entire good job was eaten away by a whooping 30% increase of cardiogenic shock, mainly within the first 24 hours of admission.
In the prethrombolytic days, 2 large studies were conducted with long term use of BB in post MI setting. The Norwegian Multicenter Study Group (5)followed 1884 post MI patients for 12-33 months and showed 39% less death and 28% less re-infarction with timolol. BHAT study (6) followed 3837 post MI patients for 27 months and showed a 26% reduction in mortality with propranolol.

Correspondence: Prof. Santanu Guha, Professar and Head, Department of Cardiology, Medical College, Kolkata-700 019, West Bengal, India.
E-mail: [email protected]

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In 1999 a large meta-analysis reviewed all available data from 51 short-term and 31 long-term use of BB in post MI period involving 54,234 patients.(7) Long-term use of BB resulted in 23% reduction in the odds ratio of death, whereas comparative value of short-term trials was only 4%. But even in the latter group there was benefit in terms of re-infarction. Yusuf et al (8) examined this aspect and concluded that BB without intrinsic sympathomimetic activity (ISA) reduced long-term mortality by 30% compared to about 10% with BB with ISA. This can be comprehended because the benefit is directly related to the fall of resting heart rate which is much more pronounced with the former agents. Additionally, BB with ISA may also act through beta 3 receptors on endothelium causing nitric oxide mediated negative inotropism not easily tolerated by an acutely injured heart on verge of failure.(9)

As of now, BB are recommended to be started orally in those in hemodynamic stability and may be 2-3 days after the MI if not indicated otherwise for earlier initiation. American College of Cardiology/ American Heart Association (ACC/AHA) guidelines (10) recommend initiation with half-dose beta blockade on day 2 in hemodynamically stable patient followed by gradual build-up upto the maximum tolerated or recommended dose and to continue that for long term. Timolol, metoprolol, propranolol and atenolol are the BB licensed for this use.

Carvedilol is unique in being evaluated in reperfused patients and in addition to ACEI. CAPRICORN trial (11) proved excellent efficacy and tolerability of carvedilol in this set-up. When the issue of blood pressure is superimposed on this picture, it can be interpreted that initial hypertension during an MI is an additional incentive to initiate BB whereas hypotension on presentation precludes their use for several days. The benefit of post MI beta blockade is incremental over 2 years in patients with low ejection fraction or in the elderly population. presence of heart failure when BB is added to ACEI after the correction of fluid overload status, the mortality benefit accrued is 23-40% as per SAVE (12) and CAPRICORN trials. Long term use of BB in post infarct patients saves one life of 42 treated for 2 years.

To put this in perspective it will be sufficient to mention that to save one life, 2 years treatment is required in 153 patients with antiplatelet agents, 94 patients with statins, and 24 patients with thrombolytics plus aspirin (in 4 weeks in this case).(7).

Role of BB in preventing ischemic cardiac arrhythmia:
Reduction of ventricular tachyarrhythmia is one of the contributing factors for BB benefit in MI patients. In the CAST trial BB was found to be independently associated with a significant reduction of arrhythmic death or cardiac arrest. Another important observation was that class IC agents, encainide or flecainide when combined with BB gave survival benefit rather than when used without BB. Of course, the best result was when class IC was not used at all; and these patients were mostly on BB. (13). On analysis of the EMIAT and CAMIAT trials (14) there was a clear synergistic benefit of BB and amiodarone than each drug alone in terms of cardiac death (p=0.05) and arrhythmic death/ resuscitated cardiac arrest (p=0.03). However, in the AVID trial (15) BB was independently beneficial in VF or symptomatic VT , but there was no incremental benefit when the patient was already on amiodarone or automatic implantable cardioverter defibrillator.

Role of BB in unstable angina :
Surprisingly the role of BB in unstable angina is not well-documentsd. An old study called HINT in 1986 (16) examined metoprolol in unstable angina and got only borderline short-term benefit. A meta-analysis suggested that BB reduces the progression of non ST elevation acute coronary syndrome ( NSTE-ACS) to ST elevation MI (STEMI) by 13%. Although no significant mortality benefit of BB could be shown in NSTE-ACS by these relatively small trials, the results may be extrapolated from larger randomized trials of BB in patients with unqualified MI. At the moment BB are class I-B indication in NSTE-ACS in absence of contra-indications, and particularly in patients with hypertension or tachycardia.( European Society of Cardiology guidelines, 2007). BB is a part of the conventional in-hospital quadruple therapy along with statin, anti-platelet agent and ACEI, a combination shown to reduce 6-month mortality by 90% compared with use of none of these 4 agents.(17).

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Role of BB in chronic stable angina (CSA) :
The situation is similar in CSA as in unstable angina, ie, the use of BB is more pragmatic than evidence-based. In the ASIST trial (18) of 1994, atenolol was found to be superior to placebo in reducing the combined end-point of death, hospitalization due to unstable angina and revascularization in patients with mostly silent ischemia. In CSA mortality benefit of BB is not established. In absence of past history of MI and heart failure, their use in CSA is arbitrary as far as prognosis is concerned. However, as for symptom relief and exercise- tolerance, BB are very useful. BB with ISA may be more beneficial in presence of peripheral vascular disease but they are less effective antianginal agents. By the ACC/AHA 2002 guidelines BB are class I indication for CSA if there is a past history of MI, otherwise the use is on the basis of expert consensus.

Role of BB in atheromatous progression:
In the BCAPS trial 793 patients with asymptomatic carotid artery plaques were randomized to fluvastatin, long-acting metoprolol, their combination or placebo (19). In 36 months, there was significant slowing of the progression of carotid intima-media thickness by fluvastatin (p=0.002) and metoprolol CR/XL (p=0.014). Those on metoprolol had significant lower cardiovascular event and total mortality compared to those not on metoprolol (p=0.031).

Role of BB in hypertension :
Hypertension is the one condition which had made BB a common house-hold name and which again of late made it an object of ridicule.
To approach the issue with an open mind is the call of the day.
To begin with, this must be understood in an unambiguous term that in CAD with hypertension, BB are the first-choice. The controversy lies in cases of hypertension where CAD is not suspected. The exact mechanisms of the anti-hypertensive effect of BB remain elusive. The proposed mechanisms include a sustained fall in cardiac output, a late decrease in the peripheral vascular resistance (after an initial rise) and inhibition of rennin release (20).
All BB enjoy the license as antihypertensive agents. But though undoubtedly they reduce blood pressure, the long-term outcome studies are few and far between. The recent concerns about them are mainly based on three premises-(1) very infrequently their efficacy has been tested as sole anti-hypertensive agents; in most cases they were tagged to a diuretic, (2) their side effect profile is rather long compared to most newer antihypertensive

agents ;and in particular, the metabolic derangement that they may ensue could prove unfriendly in high risk hypertensive patients; and (3) though they reduce the adverse cardiovascular events in the hypertensive population they do not do that to the same extent as the newer agents have now shown to be capable of doing. The damage was so profound that in the US the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC) delegated BB as the second choice in hypertension treatment and even worse, in the United Kingdom they have been demoted as the fourth line treatment.

We can approach this issue from two angles. Firstly to scrutinize how far these allegations are true; and secondly whether all BB should be equally blamed.
The main driving force behind the demotion of BB came from the ASCOT BPLA trial (21). Here 19257 high risk hypertensive patients were randomized to get either amlodipine (adding perindopril) or atenolol (adding bendroflumethiazide). Former group showed significant benefit in terms of coronary end point (p=0.007), stroke (p=0.0003), and mortality (p=0.02) at the end of 5.5 years. However, the primary end-point of nonfatal MI and cardiovascular death was not different between the two arms; p=0.11. A closer analysis found that in the amlodipine arm there was significant lower blood pressure, higher HDL cholesterol, lower body mass index, and lower serum levels of triglyceride, glucose and creatinine . When subjected to multivariate analysis the difference between the two arms in cardiovascular event rates was abolished (22). Thus, if anything, ASCOT BPLA proved the importance of tight blood pressure control and reminded us of the importance of co-morbid metabolic derangements to determine the ultimate outcome in hypertensive population. The parameters which improved significantly were translated to NNT (number needed to treat) for 1 year to prevent one cardiovascular event of 220 and that to prevent one death of 650 (23). This much can be said that atenolol is not very metabolic friendly and while on atenolol the patients should be regularly monitored for the metabolic parameters. By the same token, thiazide diuretics are even worse and their remaining as the first-line treatment appears to promote double-standard. Also to note that newer BB with more beta 1 selectivity than atenolol and with proven better metabolic profile have not been tested against the newer classes of antihypertensives. The results of ASCOT BPLA may not be extrapolated to these agents.

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This last point was clearly evident in the very meta-analysis of Lindholm et al (24) which precipitated the BB downgradation. In this comprehensive review they examined 13 trials comparing BB with other agents (n=105 951), and 7 trials comparing BB with placebo (n=27 433). Overall, BB were found to be inferior to other antihypertensives to prevent stroke ( relative risk, RR=1.16) but not total mortality and MI. Atenolol was found to be inferior compared to other antihypertensives not only for strokes (RR=1.26) but also for total mortality (RR=1.08). However, non atenolol BB were not found to be inferior to other antihypertensive agents in terms of stroke (RR=1.20), MI (RR=0.86) and total mortality (RR=0.89).
But again, in the very large UKPDS study (25) , type 2 diabetics with hypertension treated with atenolol or captopril did not show any trend , let alone any significant difference, between the two arms in terms of any microvascular or macrovascular complications, despite a higher weight gain and need for more antidiabetic agents in the BB group.
As far as the blood pressure lowering efficacy of the BB are concerned, it is clear that there is a wide variation among the group. BB with ISA like xamoterol actually increases resting blood pressure. Beta 2 blockade does not help either; this demolishes beta 2 mediated peripheral vasodilatory effect. Highly selective beta 2 blocker (ICI 118,551) increases blood pressure and non selective beta1 beta 2 blockers like propranolol and nadolol are less effective than beta 1 selective agents like atenolol and even more selective bisoprolol. Thus propranolol may cause a marked elevation of blood pressure in chronic heavy smokers whose plasma adrenaline levels are elevated by nicotine and when the beta 1 and 2 receptors are blocked, alpha receptor stimulation causes marked vasoconstriction (26).
In the LIFE trial (27) atenolol was found to be much inferior to losartan in terms of reduction of left ventricular hypertrophy(LVH) as assessed by voltage criteria in ECG. In the Framingham study ECG LVH was found to be the most potent of all coronary risk factors. In a study with a population of younger and middle aged hypertensives, atenolol was highly effective in reversing this over a 5 year follow-up period (28). When LVH was assessed by echocardiography, BB as a class was found to be less effective in its regression when compared to ACEI. But selective beta 1 blockers were found to be as effective as ACEI in this respect (26).
If the antihypertensive studies of younger and middle-aged people with usually narrow pulse pressure ( due to lack of arteriosclerosis) are considered, eg, IPPSH (29), MRC mild hypertension (30), MAPHY (31) and UKPDS (25), then it is clearly seen that BB are far better than diuretics in reducing cardiac events even with a lesser degree of blood pressure lowering in some trials. This becomes all the more relevant if we consider that in this age-group cardiac events far outnumber strokes. All the beta blocker mediated anti ischemic effects, like increased coronary diastolic filling time, reduced arrhythmia, slowing of atheromatous progression and reversal of LVH , play their respective roles for this added benefit of BB in preventing MI in young hypertensives apart from blood pressure lowering.
With increasing age, vascular compliance decreases both due to endothelial dysfunction and collagen deposition. Thus the augmented reflected wave from periphery to central aorta arrives early, ie in systole instead of diastole
and thus compromise diastolic coronary artery filling. Also with advancing age, plasma rennin activity and beta receptor densities decline making them less likely to contribute to elderly hypertension. Beta blockers are also not efficient to alter arterial compliance problem. In the CAFÉ substudy of ASCOT (32) atenolol was much less effective than amlodipine in lowering central aortic pressure and pulse pressure. Other betablockers like beta 1 selective bisoprolol, additional alpha blocker labetalol, and beta 2/3 ISA activity of nebivolol –they all improve compliance and can lower central aortic pressure more efficiently than atenolol or propranolol.
Thus the usefulness of BB is greatly affected by the age of the population. Khan and McAlister published an elegant meta-analysis in 2006 (33). In their review of 21 hypertension trials involving 145 811 patients, combined end-points of stroke, MI and death was analysed with respect to age. 49 826 patients were under the age of 60. In this group, in 19 414 patients were given BB or placebo. Here the combined end-points was better with BB( relative risk 0.86). In 30 412 patients BB was found to be equivalent to other anti-hypertensives; relative risk being 0.97. In patients aged 60 years and above BB was no superior to placebo ( 8019 patients with relative risk of 0.89) and inferior to other anti-hypertensives (79 775 patients; relative risk reduction of 1.06). This is explained by the fact that BB are more effective in hypertension associated with high sympathetic tone rather than with high vascular resistance. Thus it can be concluded that BB are quite efficacious in cardiovascular protection of younger people with hypertension. Beevers cautioned that there was a danger of "throwing out the baby with the bath water" in recommending against the use of ß-blockers for the treatment of hypertension (34). Betablockers earned bad repute for their adverse metabolic profile. But against expectation, in the large UKPDS trial of middle aged overweight hypertensives with T2DM atenolol and captopril were equopotent to reduce all cardiovascular endpoints despite the fact that atenolol treated patients gained weight and required more drugs for blood sugar control. If trend says anything, all the 7 primary endpoints tended to be improved more with atenolol than captopril. This proved that ultimately the control of blood pressure matters most (25).
Another issue to ponder over is whether natural T2DM and drug-induced DM (ie by atenolol or hydrochlorothiazide) pose equal cardiovascular risk. When the SHEP study was followed up for 14.3 years (35), some very novel facts came out. 4732 elderly people with isolated systolic hypertension were randomized to placebo vs diuretic+/- atenolol. In the placebo group those with initial diabetes had 63% excess cardiovascular mortality with respect to nondiabetics. When baseline diabetics were compared between placebo and treatment groups, there was a significant 31% reduction of CV mortality in the treatment group. When new onset diabetics were taken, those on placebo ( implying their diabetes developed naturally) had significant 56% increase in CV mortality then those who did not develop diabetes. But surprisingly diabetes developed on and probably due to diuretic/atenolol had no increase in CV mortality compared to persistent euglycemic patients. Thus drug-induced diabetes may not be as detrimental as natural diabetes. It may be argued that natural diabetic process had started long ago along with CV damage before blood sugar went high. But again, 14 years follow-up should have exposed any latent disease.
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A recent meta-analysis of randomized trials of blood pressure lowering medications looked specifically for CHD events and strokes (36). The analysis included 108 trials comparing study drug with placebo, 46 trials comparing different antihypertensive medications, and seven trials which fell into both categories with a total of 464,000 subjects. The authors observed that beta-blockers had an effect beyond the blood pressure reduction in preventing recurrent coronary heart disease (CHD) events in people with known CHD (22-34% versus 15%) when compared to other medications. This benefit of beta blockers was seen only in the first few years after MI ( risk reduction of 31% in recent MI versus 13% with no recent MI (p = 0.04). Otherwise, the reduction in CHD events (22%) and stroke (41%) were similar for a blood pressure reduction of 10 mm mercury systolic or 5 mm mercury diastolic by whatever agent, except for a slightly greater stroke and CHF reduction with calcium channel blockers. These reductions in events were similar regardless of presence of cardiovascular disease or baseline blood pressure. (For example, in this meta-analysis, subjects with a pretreatment systolic blood pressure between 110 and 119 mm Hg experienced a statistically significant 22% reduction in CHD events). The authors concluded that, with the above-mentioned few exceptions, all types of blood pressure medication have a similar, striking benefit in reducing CHD events and stroke, suggesting a lack of important pleiotropic effect of some agents, eg, ACEI.
It may not be out of place here to remind ourselves that the currently valid JNC guidelines, ie, JNC 7, in their own characteristic vocabulary, defined the use of BB in hypertension as “compelling indications” in co-existence of heart failure, post myocardial infarction status, high coronary artery disease risk and diabetes. In 2007, ESC guideline gently mentioned the “conditions favouring” the use of some anti-hypertensive drugs in certain situations which included the use of BB in any previous stroke, previous MI, angina pectoris, heart failure, permanent atrial fibrillation, tachyarrhythmias, pregnancy and glaucoma.

Role of beta blockers in CHF:
Few such events are there in clinical medicine which are as dramatic as beta blockers use in CHF. From being an absolute contraindication a few decades ago they now are a class I indication. Having said that, only a few beta blockers are licensed for that and their use are still to be carefully initiated and closely monitored, because they can potentially exacerbate CHF.
Plasma noradreniline is myotoxic and can precipitate programmed cell death called “apoptosis”. Excess beta 1 stimulation also can flog the failing heart by increasing the heart rate and myocardial contractility.
A detailed discussion is beyond the scope of this review. In both MERIT-HF trial (37) with metoprolol extended release and CIBIS-II trial (38) with bisoprolol, HF patients with low ejection fraction and in NYHA class II-IV showed 34% mortality benefit over and above their usual HF medicines including ACEI. In COPERNICUS trial (39) with severe CHF, patients had 35% mortality benefit with carvedilol. Recently CIBIS III (40) answered the

question of which drug to start first and which one to follow between enalapril and bisoprolol. And the answer is both approaches are equally effective. Another study with post MI patients with low ejection fraction given carvedilol showed a 25% all-cause mortality reduction. In the SENIORS study (41) with nebivolol mortality benefit was not significant probably because nebivolol is not very beta 1 selective in human heart, has ISA activity and does not reduce heart rate impressively. Only bisoprolol, extended release metoprolol and carvedilol are indicated to treat chronic stable CHF.

 

Role of beta blockers in the peri-operative period :
BB have been shown to improve post operative outcome if used perioperatively. This is true for both cardiac and non-cardiac surgery (42). In a large randomized trial post MI coronary artery bypass surgery (CABG) mortality at 1 year could be reduced from 12% to 4% by use of BB (43). But in another study where CABG was preceded by MI in only 50% of cases, there was no mortality benefit with BB use (5). So the ACC/AHA guideline recommends use of BB in post MI CABG surgery.
Use of BB is also endorsed for non-cardiac surgery on the basis of multiple randomized trials (44). The fact that must be re-emphasised is that the presence of coronary artery disease and even just multiple risk factors for CAD can draw a huge benefit from peroperative  use of BB. However, the use of BB in the perioperative setting is grossly underutilized. As many as 60% of general surgery patients have been found to be eligible for BB therapy but were not given the drug. In one study it was discovered that more than 30% of patients who were on BB preoperatively were discontinued of the drug in the post-operative period (42).

Closing remarks : 
We are at the end of the beta-blocker story. This story perfectly exemplifies how, sometimes, our vision becomes blurred about the primary focus if some stronger light comes from a secondary source. Never there was a doubt about the benefit of BB in the spectrum of coronary artery disease, and neither it is now. But the whole issue of BB and hypertension glared us so much so that in a knee-jerk reaction there was a rush to stop BB in hypertensive patients, forgetting completely whether coronary artery disease was co-existing or whether the patients qualified to be high coronary artery disease risk, in which situations, the withdrawal of BB would be the harbinger of disaster. Even in the case of unqualified hypertension, BB was never shown to be harmful in any population group; what was shown in the famous trials was only that in certain situations BB did not benefit as much as some newer anti-hypertensive agents. If we consider the track records of BB regarding their utility and safety records over five decades, the enthusiasm of using the newer agents may actually dampen slightly. And in the younger hypertensives, who are more liable to die of  ischemic heart disease rather than stroke or renal

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failure, BB remain the magic drug. In the field of heart failure their come back is a real-life rags to riches story. In the domain of arrhythmia, they occupy a full class ( class II) among the only four categorized classes and also spilled over to one more class ( sotalol in class III). Peroperative use of BB is gaining popularity every day.

Thus, the train has traveled across the picturesque valleys, and currently is passing through a dark tunnel, but gleaming light of a new dawn is already shining at the end of the tunnel; this is a time not to alight from this train, but to stay put where we are to share the new glory.

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