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The 3rd Merck Serono Intercontinental Symposium on Cardiovascular Diseases [25th March 2010]

Beta-blockers:

Continue Astonishing Us.

3 Merck Serono Intercontinental Symposium on Cardiovascular Diseases [March 25, 2010, Cairo, Egypt]

rd

The 3rd Merck Serono intercontinental symposium on cardiovascular disease was held in Cairo on 25th of March 2010. The symposium was chaired by Professor M. Mohsen Ibrahim (Cairo, Egypt) and feature additional presentations by Professor Yosuf Veriava (Johannesburg, South Africa), Professor Mohamed A Taher Khalil (Cairo, Egypt), Professor Mostafa Qaid Ahmed Al-Shamiri (Abha, Saudi Arabia), Professor Andreas Schuchert (Neumnster, Germany), Professor Olaf Schouten (Rotterdam, Netherlands) and Professor Hussien Hassan Rizk (Cairo, Egypt).

Chronic sympathetic stimulation is very harmful for the cardiovascular system. It can lead to cardiac necrosis / apoptosis, increased risk of ventricular fibrillation, increased rate of atheroma formation and left ventricular hypertrophy. So beta-blockade is mandatory in the cardiovascular continuum with this basic introductory statement, Professor Mohsen Ibrahim started the symposium emphasizing the undeniable role of beta-blockade (Figure 1).
Prof. M. Ibrahim, Egypt

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The 3rd Merck Serono Intercontinental Symposium on Cardiovascular Diseases [25th March 2010] Also Professor Veriava stressed that the development of heart failure is a complex, continuous and progressive process which is usually associated with cardiovascular disease resulting from classic risk factors such as hypertension, obesity, diabetes, smoking and dyslipidaemia. In the early stages of the process of progression to heart failure, the left ventricular structure and function will typically be normal, however, with time the pathologic effects of one or more cardiovascular risk factor will result in the development of structural and functional changes with or without left ventricular hypertrophy and myocardial infarction. This may result in left ventricular remodeling and the development of systolic or diastolic dysfunction which in turn often leads to heart failure[2,3]. Whilst there have been advances in the treatment of heart failure, it is essential that our approach should be the prevention of heart failure by attending to the cardiovascular risk factors which includes the effective treatment of hypertension.

Figure 1. Beta-blockers can intervene at many points in the cardiovascular continuum[1]. The symposium focused on four key uses of beta-blockade which are hypertension, coronary artery disease, heart failure and perioperative management of non-cardiac surgery. Also the symposium discussed a new trend in management of ischemia.

Pathophysiology of heart failure: Heart failure is a relatively common problem associated with a poor prognosis. It is responsible for a significant number of hospital admissions with social and economic burdens. Professor Veriava opened his lecture.

Prof. Y. Veriava, SA

The beta blockade debate: chronology and evidence Beta blockers have been used for more than 45 years in coronary artery disease, heart failure and hypertension. Their use in hypertension has been questioned recently Professor Taher opened his lecture putting the accusation in focus.

Hypertension, ischemic heart disease, dilated cardiomyopathy and valvulopathies are the major causes of heart failure. Maladaptative mechanical, neurohumoral and other factors contribute to the progressive nature of heart failure. So an understanding of the pathophysiological mechanisms underlying heart failure has contributed to the advances in the management of this disorder. The underlying cause of both systolic and diastolic dysfunction is intracellular calcium handling.

Prof. A. Taher, Egypt

When we investigate this dilemma, we have to rely on evidence and putting all studies together after critical appraisal of each study to define its level of evidence.

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The 3rd Merck Serono Intercontinental Symposium on Cardiovascular Diseases [25th March 2010] The first prospective, double-blind, cross-over, single-center, placebo-controlled pharmacogenomic study in essential hypertension, which is the GENRES study; found that in both ambulatory BP and office BP measurements, 5 mg of bisoprolol had the best antihypertensive effect, followed by 50 mg of losartan, 5 mg of amlodipine, and 25 mg of hydrochlorothiazide, in that order[5]. Beta blockers and stroke in ASCOT trial: Professor Taher reported that, most recently a meta-regression analysis of data driven from 31 trials (n=190,606) of different drug treatments versus placebo for the relationship between the reduction of SBP and the risk of stroke in a blood pressure lowering treatment was done by the BPLTTC[6]. It was noted that when the data from ASCOT trial are interpolated into this regression analysis, they fall close to the predicated position[7]. Thus, the reduced protection against stroke reported in ASCOT can be concluded to be due to a difference in bloodpressure lowering effect between treatments as shown in Figure 2[6].

The recent reappraisal of ESH/ESC guidelines for management of hypertension (2009) stated that cardiovascular protection depends on blood pressure control per se regardless of the class of therapy[4]. Thiazide diuretics, beta-blockers, calcium antagonists, ACE-I and ARBs can all be considered for initiation & maintenance either alone or in combination with each other[4]. Traditional Ranking of drugs to 1st, 2nd & 3rd lines has now little scientific & practical justification & should be avoided [4]. It is mainly the blood pressure reduction that protects patients, not which drug is used to initiate treatment. For this reason, the guidelines stick to the statement that initiation and maintenance of antihypertensive treatment can make use of several drug classes[4]. ESH/ESC 2007 guideline confirmed that all 5 major antihypertensive agents (including betablockers) are suitable for the initiation of therapy even in the elderly! The Canadian Hypertension Education Program Recommendations (2009) also emphasized the non-inferior role of beta-blockers in management of hypertension. Now the BHS IV, 2004 and Update of the NICE Hypertension Guideline, 2006 which downgraded beta-blockers have little agreement. It was based upon one of the largest trials namely the ASCOT trial which is found to have some limitations. One of these limitations is using atenolol once daily as a representative of beta-blockers. Atenolol has a short half life which jeopardizes the judgement. Also amlodipine arm had lower BMI, TGs, s. creatinine, serum blood glucose and higher HDL-C. Moreover when adjustments were made for covariates no differences were found between the groups.

Figure 2. Relationship between the reduction in systolic blood pressure (SBP) and the risk of stroke in a meta-regression analysis of different trials (drugs versus placebo or other drugs).

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Heterogeneity of betaadrenergic drugs:

The 3rd Merck Serono Intercontinental Symposium on Cardiovascular Diseases [25th March 2010] blocking per se. They can thus all be considered for treatment. In diabetes, combination treatment is usually needed to effectively lower blood pressure. Have B1-selective beta-blockers a unique role in type 2 DM & obese hypertensive patients? Professor Taher explained that in type 2 DM, the hyperinsulinemia due to insulin resistance as well as the increased leptin secretion cause stimulation of the sympathetic nervous system with a subsequent release of nor-adrenaline. Increase in nor-adrenaline causes 4 effects which are ventricular arrhythmia, increasing vessel stress causing atheroma, non-dipping of blood pressure at night and increased plasma renin activity causing increased angiotensin II which consequently increases intraglomerular pressure leading to nephropathy as seen in Figure 3.

Who said that Atenolol is the standard reference beta-blocker? Professor Taher wondered. Professor Taher pointed out that atenolol may be less useful than other beta-blockers, and other antihypertensive drugs, in reducing cardiovascular disease in hypertensive patients. It should therefore no longer be considered the reference beta-blocker in hypertension. Also there is no logical reason to downgrade more modern selective beta-blockers based on results from atenolol trials. Also we know that beta-blockers differ in their pharmacological properties and in their clinical effects. Bisoprolol has the highest selectivity, therefore it has no effect on glucose metabolism, and thus there is no need for oral antidiabetic drug dose adaptation. Also there is a lower risk of masked hypoglycemia. For the pulmonary function selective beta-blockers are safe to be used with COPD. In peripheral vascular resistances there is a lower risk of cold extremities and erectile dysfunction. Beta blockers patients: in diabetic hypertensive

WHO Report 1997 stated that 65% of deaths in diabetes are due to CV causes[8]. According to the American guideline JNC 7th Report 2003; diabetes is one of the compelling Indications for beta- blockers followed by heart failure, post MI and high coronary disease risk. Beta-blockers, especially B1 selective agents such as bisoprolol are beneficial to diabetics[9]. The ESH/ESC Guidelines 2009 reported also that a meta-analysis of available trials show that in diabetes all major antihypertensive classes protect against cardiovascular complications, probably because of the protective effects of blood pressure lowering Figure 3: Selective B1-blockade in type 2 DM & obese hypertensive patients ACE inhibitors block only the last pathway, while beta blockers close the 4 problematic pathways. That is why selective beta-blockers are the mainstay in the combination therapy. UKPDS provides strong evidence on hard endpoints proving the essential need for beta blockers. In UKPDS 10 Years post trial follow up beta-blockers are superior to ACE inhibitors

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The 3rd Merck Serono Intercontinental Symposium on Cardiovascular Diseases [25th March 2010] the management of hypertension, CHF, and CAD (i.e. in angina pectoris), post-myocardial infarction (MI), and in preventing cardiac complications of non-cardiac surgery. In 2009, Law et al, published a huge metaanalysis of 147 Randomized Trials (n = 464 000) about the usage of BP lowering drugs in the prevention of cardiovascular disease. In the BP difference trials, beta-blockers had a special effect exceeding that of BP reduction in preventing recurrent CAD events in people with a history of CAD: 29% risk reduction compared to 15% in trials of other drugs.

with 23% reduction in long term mortality in diabetes as shown in Figure 4[10].

Figure 4: KaplanMeier Cumulative-Incidence Plots and Log-Rank P Values for Prespecified UKPDS End Points during the 20-Year Period of the Trial and the Post-Trial Monitoring Period, According to Treatment Assignments. Increased insulin resistance and a higher incidence of new-onset diabetes mellitus were reported in early trials with beta-blockers. However, more modern agents such as bisoprolol and carvedilol have no effect on glucose metabolism[11]. Beta blockers and cardiovascular diseases: Globally, cardiovascular diseases are the number one cause of death. World Health Organization statistics show that about 17.5 million people die each year from cardiovascular causes about 30% of all deaths worldwide[12]. In Western industrialized countries, the percentage is higher (60% in the US). Moreover Professor Taher stressed that it is well-known that the Egyptians have a high risk of CAD. For that reason prevention and treatment with effective pharmacological therapies is essential. As this symposium demonstrated, beta-blockers bring benefits across the whole cardiovascular continuum (Figure 1). They have a key role in

The assessment of beta-blockers as inferior drugs for lowering BP was based on fewer trials than were considered here; they had a similar protective effect to other drugs and a greater protective effect after MI, supporting Guidelines that do not discourage their use.[13] Beta blockers in peripheral arterial diseases (PAD) and chronic obstructive pulmonary disease (COPD): In 2007, TASC II Consensus reported that betablockers are not contraindicated in PAD patients[14]. This is in agreement with a metaanalysis of 11 studies showing that betablockers do not adversely affect walking capacity or symptoms of intermittent claudication in patients with mild-to-moderate peripheral arterial disease[15]. Although clinicians are reluctant to prescribe beta-blockers to COPD patients for fear of provoking bronchospasm and exacerbating lung dysfunction, there is compelling evidence to indicate that the benefits (related to cardiovascular morbidity and mortality) are likely to outweigh the potential risk of adverse events in patients with COPD, especially when B1 selective beta-blockers are used. We all know that asthma is an absolute contraindication to beta-blockade. But asthma must be separated clearly from COPD, which

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The 3rd Merck Serono Intercontinental Symposium on Cardiovascular Diseases [25th March 2010] high sympathetic activity, but also elderly patients due to co-morbidities. ESH/ESC Guidelines 2009 recommend all classes including beta-blockers as 1st line option in elderly hypertensives. Salutary role of beta blockers beyond BP control: Beta-blockers are well established as cardiovascular protective class beyond BP control as they reduce heart rate, so decrease oxygen demand & prolong the filling period thus aid the hearts perfusion & recuperation. It also prevents the thrombus formation by preventing platelet aggregation and preventing plaque rupture due to reduction of wall stress. Moreover it increases ventricular fibrillation threshold thus reducing the incidence of sudden death. It has a dual action on RAAS & sympathetic nervous system and protects against the direct action of catecholamines on cardiac myocytes (programmed apoptosis)

certainly is not a contraindication for betablockers. In fact, many patients with COPD and concomitant CAD or CHF stand to benefit greatly from beta-blockers as about one third of patients with COPD die from cardiovascular causes. However, lung function in patients with COPD receiving beta-blockers should be carefully monitored, as asthma and COPD may coexist. Patients with COPD and CAD show a clear reduction in mortality with beta-blockade (1543% in randomized controlled trials)[16]. A Cochrane systematic review found that cardioselective beta-blockers in COPD patients were not related to respiratory adverse effects. The meta-analysis of studies in COPD patients demonstrated no significant change in FEV1 versus placebo when B1 selective beta-blockers were used[17]. Among 3,371 patients undergoing vascular surgery; selective beta-blockers had no material impact on quality of life of patients with PAD & COPD co-existing. Also intensified doses of beta-blockers were superior to low-dose therapy in reducing mortality in patients with COPD, which suggests that although it is reasonable to initiate beta-blockers at a low dose, the dose should be titrated upwards slowly to reach therapeutic doses in these patients[18]. Beta blockers and sexual dysfunction: Both physicians & patients are worried about impact of various drugs on sexual function. Erectile dysfunction is common with cardiovascular diseases regardless of the used drugs. After myocardial infarction sexual activity is reduced by 22 75%. Analysis of self reported erectile dysfunction in 6 double blind trials with drug exposure for 6 14 weeks found a lower percentage of ED with either bisoprolol or HCTZ compared to placebo[11]. Beta blockers and age: Professor Taher mentioned that beta-blockers are targeting not only young patients for their

Beta blockers in coronary artery disease: Despite the tremendous improvements in treatments, CAD has an increasing burden with the ageing of the population in many countries. And as we know CAD is the major cause of morbidity and mortality all over Prof. M. Al-Shamiri, KSA the world. Professor Al-Shamiri emphasized on how critical is CAD management. The stated goals of CAD treatment are delay of the disease progression to improve long-term outcomes and to control symptoms and ischemia. Beta-blockers have a key role to play in achieving both goals. Regarding to disease progression, lifestyle management (diet, exercise, and smoking cessation) is undoubtedly important, but most patients will also require medications.

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The 3rd Merck Serono Intercontinental Symposium on Cardiovascular Diseases [25th March 2010] prevent HF, sudden death and re-infarction. The rationale for their use: is to reduce myocardial ischemia, anti-arrhythmic properties and their effects on remodeling. There are numerous trials that have confirmed the benefits of beta-blocker therapy in the postMI patient. In a meta-analysis of 15 betablockers trials, there were risk reduction in overall mortality by 22%, sudden cardiac death by 33%, non-sudden death by 20% and nonfatal MI by 20%[22]. According to ACC/AHA Guidelines, beta blockers are indicated in all patients with a recent or remote history of MI regardless of LVEF or Also the HFSA guideline presence of HF[23]. stated that ACE inhibitors and beta blockers are recommended for all patients with prior MI, with strength of evidence = A.[24] Beta blockers reduce the risk of death in individuals with known cardiovascular disease. A meta-analysis that included 24,298 patients with stable coronary heart disease, treatment with a beta-blocker resulted in a reduction in the risk of death by 23% as shown in Figure 6.

Treatments aimed at improving prognosis include aspirin (or clopidogrel where aspirin is contraindicated), statins, and beta-blockers in post-MI patients, and ACE inhibitors in proven cardiovascular disease (CVD). Unless contraindicated, beta-blockers are the recommended first-line treatment for symptom relief from angina. Calcium antagonists and a number of other agents are used as second-line treatments. ESC guidelines stated that revascularization may be considered in high-risk patients or those in whom ischemia is not controlled by pharmacological treatment after dose optimization[19]. This ESC recommendation is based not only on the overall experience with beta-blockers in the full spectrum of CVD, but also on the direct evidence of its superior benefit as compared to other anti-ischemic agents[19]. ESC recommendations for pharmacological therapy in patients with stable angina was to test the effect of B1 blocker, and titrate to full dose and to consider the need for 24 hours protection against ischemia[19]. Beta blockers appear to be the most efficacious agents for not only stable angina but also unstable angina. This is because they lower heart rate, reduce myocardial oxygen demand and increase the duration of diastole, resulting in an increase of coronary artery flow. They are the only anti-anginal agents shown to improve clinical outcomes in myocardial ischemia[20,21]. Also According to ACC/AHA 2006 recommendations for pharmacotherapy to prevent MI and death in asymptomatic patients; beta-blockers are mentioned as initial therapy in patients without prior MI, unless contraindicated. Beta-blockers in Post-MI Professor Al-Shamiri reminded the audience that the role of beta-blockers in post MI is to

Figure 6: Summary of Secondary Prevention Trials of beta-blocker Therapy[25] Also Professor Al-Shamiri advised the audience to start beta-blockers treatment in-hospital as an excellent strategy for increasing compliance.

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Beta blockers in heart failure: There are no concerns for using beta-blockers in heart failure. They can be used at any stage in the maximal tolerated dose. They can be used in the elderly. Professor Schuchert said.

The 3rd Merck Serono Intercontinental Symposium on Cardiovascular Diseases [25th March 2010] bisoprolol group lead to overall savings despite additional cost for bisoprolol and office visits for dose titration[28]. Regarding the starting dose of beta-blockers in CHF, Professor Schuchert said that it can be bisoprolol 1.25 mg o.d.under supervision in outpatient setting. Also it may be initiated prior to discharge in recently decompensated patients with caution. Up-titration visits every 24 weeks to adjust the dose. Double the dose at each visit until the evidence-based target dose is reached e.g. Bisoprolol 10 mg o.d. or maximum tolerated dose.

Prof. A. Schuchert, Ger

So beta-blockers can be used in all patients with mild, moderate and severe heart failure from ischaemic and non ischaemic cardiomyopathies and reduced LVEF[26]. ACC/AHA Guidelines of management of chronic heart failure 2009 updates, recommends only three beta-blockers which are bisoprolol, carvedilol and metoprolol because they are the only beta-blockers having mortality results. Beta-blockers should be given early and never be withheld from any patient with CHF unless they are absolutely contraindicated. The results of CIBIS III support a free choice between bisoprolol and enalapril as initial therapy for patients with stable, mild-to-moderate, systolic CHF. Starting early may help to protect against sudden death in early CHF[26]. In CIBIS III trial Bisoprolol-first reduces sudden death in first year by 46%, compared with an enalapril-first strategy as seen in Figure 5[27].

Beta blockers in non-cardiac surgery: Ischemic cardiac complications are common and are a major cause of perioperative morbidity and mortality in noncardiac surgery. As 10-40% of the perioperative deaths are due to MI. A major Prof. O. Schouten, NLD contribution to this field was done by the DECREASE series of studies[29]. Professor Schouten highlighted that the pathophysiology of perioperative MI is a complex issue, but it may include myocardial oxygen demand/supply mismatch associated with tachycardia, hypertension, and pain. Other factor may be coronary plaque instability and its subsequent rupture. This is where beta-blockers act to improve myocardial oxygenation by decreasing heart rate and myocardial contractility; and may also have plaque-stabilizing effect[30].

Figure 5: In CIBIS III, a bisoprolol-first reduced the incidence of sudden death by 46% (p=0.049). The addition of bisoprolol to standard therapy in CHF significantly increased survival and reduced hospital admissions in the CIBIS II trial. Fewer and shorter hospitalisations in the For these reasons beta-blockers have protective role as they markedly reduce perioperative cardiac events in high-risk and intermediate risk

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The 3rd Merck Serono Intercontinental Symposium on Cardiovascular Diseases [25th March 2010] NICORANDIL: Advances in anti-ischemia The need to treat refractory angina seems to be ever increasing nowadays. So new options are always needed, Professor Hussien Rizk started his talk.
Prof. H. Rizk, Egypt

patients, as evidenced by randomized trials such as the DECREASE series of studies (with bisoprolol) as in Figure 7[29,31,32].

Events %

Current anti-anginal therapies have some limitations; one is that isosorbide dinitrate is a symptomatic treatment and the second is the development of tolerance[34]. For these reasons, there is a great need for new treatments. One of the newly developed drugs is nicorandil which is a nicotinamide ester with a dual mechanism of action; one is to open KATP channels (dilating resistance arterioles) and the other is its nitrate moiety dilates systemic veins and epicardial coronary arteries. Thus it increases coronary blood flow, reduces preload and after-load. Nicorandil has an anti-anginal efficacy and safety profile similar to that of nitrates, betablockers, and calcium channel blockers. Also nicorandil has preconditioning mimetic effect that offers myocardial protection. It enhances the prognosis in patients with stable & unstable angina and MI. It also increases the success of PCI. The hemodynamic effect of nicorandil on CHF is also good and there is less tolerance than NTG. The beneficial effect of nicorandil on patients with acute MI come from preserved coronary capillary network, reduced QT dispersion, reduced free radicals & inhibited apoptosis. In the IONA study which addressed the effect of nicorandil on coronary events in patients with stable angina; when nicorandil was used as antianginal therapy in patients with stable angina it showed a significant improvement in outcome due to a reduction in major coronary events as shown in Figure 8[35].

Figure 7: DECREASE showed that in high-risk patients undergoing non-cardiac surgery, perioperative beta-blockade with bisoprolol significantly reduced the combined primary endpoint of cardiac death and MI A recent meta-analysis of 15 studies (n =1,077) enrolling high-risk patients; pointed to betablockers ability to reduce the risk of perioperative cardiac death or nonfatal MI by 67%. It also emphasized the importance of using B1 selective agents and titrating the dose to achieve a preoperative heart rate of 6070 beats per minute[33]. Professor Schouten recommends continuing chronic beta-blockers during surgery and to avoid the initiation of high dose beta-blockers shortly before surgery. Also Beta-blockers should be dosed sensibly to avoid hypotension and / or bradycardia. He recommend to start with low dose of bisoprolol (2.5 mg daily) or metoprolol succinate (25-50 mg daily) as early as possible and up-titrate if necessary.

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The 3rd Merck Serono Intercontinental Symposium on Cardiovascular Diseases [25th March 2010] [2] When are beta-blockers contraindicated? There is absolute contraindication for betablockers in case of shock, severe hypotension with peripheral hypoperfusion, chronic heart failure with severe pulmonary congestion plus chest crepitation up to two thirds of the chest, more than grade I heart block, symptomatic bradycardia and bronchial asthma where inhalation therapy is needed.

Figure 8: Kaplan-Meier estimates of primary endpoint: coronary heart disease death, nonfatal MI, or unplanned hospital admission for cardiac chest pain.

[3] Can ACEIs be used in combination with ARBs to start treatment in cases of hypertension? No, for two reasons; one is that there is no additional effect and the other is the risk on renal functions.

Some practical advices from the panel discussion Here are just a few of the interesting practical questions addressed for and answered by the panel. [1] In young hypertensive patient, what class of anti-hypertensive agents should we start with? According to recent guidelines; all classes of anti-hypertensive agents can be used. But first we should evaluate the case properly and search for other factors and comorbidities like obesity, hyperlipidemia,.. etc. Also before start treatment, life style modification should be done, diet control and physical exercise then if blood pressure is not controlled, we move to drug treatment. However, any class can be used in such cases, beta-blockers are recommended if young patient is obese or has a hyperdynamic circulation.

[4] Have beta-blockers a bad impact on sexual functions in females? First there is a difference between erectile dysfunctions and decreased libido. In females, there is no effect on sexual functions. In males, with b1-selective agents like bisoprolol erectile dysfunction is less than placebo so there is no impact on sexual functions.

[5] Can the new agent nicorandil be used with viagra? No, absolutely not; that is because severe hypotension was reported when nicorandil used with viagra.

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SUMMARY

The 3rd Merck Serono Intercontinental Symposium on Cardiovascular Diseases [25th March 2010]

1. Chronic sympathetic stimulation is very harmful for the cardiovascular system so beta-blockade is mandatory in CV diseases. 2. Recent (2009) reappraisal of ESH/ESC guidelines for management of hypertension stated that cardioprotection depends on blood pressure control per se regardless of the class of therapy. st nd rd 3. Now, traditional ranking of drugs to 1 , 2 & 3 line should be avoided. 4. All 5 major antihypertensive agents (including beta-blockers) are suitable for the initiation of therapy even in the elderly! 5. Selective beta-blockers are mainstay in the combination therapy in type 2 DM & obese hypertensive patients. 6. Beta-blockers are superior to ACE inhibitors in reducing long term mortality in diabetes. 7. A huge meta-analysis of 147 randomized trials stated that, beta-blockers had a special effect over and above that due to BP reduction in preventing recurrent CAD events in people with a history of CAD. 8. Beta-blockers are not contraindicated in PAD patients. Cardioselective beta-blockers in COPD were not related to respiratory adverse effects. 9. Analysis of self reported ED in 6 double blind trials with drug exposure for 6 14 weeks showed that the percent of ED was less than placebo with either the Bisoprolol or HCTZ.

10. There are no concerns for using beta-blockers in heart failure. They can be used at any stage in the maximal tolerated dose. They can be use in the elderly. 11. ACC / AHA Guidelines of management of chronic heart failure 2009 updates, recommends only three beta-blockers which are bisoprolol, carvedilol and metoprolol because they are the only beta-blockers having mortality results. 12. According to ACC/AHA-2006 recommendations for pharmacotherapy to prevent MI and death in asymptomatic patients, unless contraindicated; beta-blockers mentioned as initial therapy in patients without prior MI. 13. In ACC/AHA Guidelines, beta blockers are indicated in all patients with a recent or remote history of MI regardless of LVEF or presence of HF. 14. Beta-blockers have protective role in non-cardiac surgery as they markedly reduce perioperative cardiac events in high-risk patients and intermediate risk patients, as shown by randomized trials such as the DECREASE series of studies (with bisoprolol). 15. Nicorandil; a new anti-anginal agent with a dual mechanism of action; has preconditioning mimetic effect that offers myocardial protection.

Acronym list
ACC American College of Cardiology ESH European Society of Hypertension ADA American Diabetes Association HFSA Heart Failure Society of America AHA American Heart Association IDF International Diabetes Federation BHS British Hypertension Society NICE The National Institute Of Clinical Excellence ESC European Society of Cardiology TASC The Trans-Atlantic inter-Society Consensus Glossary of Study Abbreviations ASCOT Anglo-Scandinavian Cardiac Outcomes Trial BPLTTC Blood Pressure Lowering Treatment Trialists Collaboration CIBIS Cardiac Insufficiency Bisoprolol Study DECREASE Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study GENRES GENetics of drug RESponsiveness in essential hypertension IONA Effect of Nicorandil on Coronary Events in Patients with Stable Angina: the Impact Of Nicorandil in Angina UKPDS United Kingdom Prospective Diabetes Study
"Disclaimer: Merck Serono is a financial sponsor of the presentations contained herein. This sponsorship is subject to the requirement that the presentations' content is of a scientific nature. Merck Serono has not contributed to or interfered with the contents of these presentations in any way whatsoever. The views expressed by the presenters do not necessarily reflect the views, ideas or policy of Merck Serono. Merck Serono makes no representations of any kind about the completeness, accuracy, or reliability with respect to the information provided. Merck Serono does not accept any liability for reliance placed on such information." 11

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References:

The 3rd Merck Serono Intercontinental Symposium on Cardiovascular Diseases [25th March 2010]

1. Willenheimer, R. et al. Eur Heart J Suppl 2009 11: A1-A2. 2. Vasan RS, Levy D. Arch Intern Med, 1996;156: 1789-96. 3. Himmelman A. Blood Press 1999; 8 :253-60. 4. Mancia G, et al. Journal of Hypertension 2009; 27: 11: 2121-2158. 5. Timo P. Hiltunen, Timo Suonsyrj, Tuula HannilaHandelberg, et al. AJH 2007; 20: 311318. 6. Turnbull F. Lancet 2003; 362: 152735. 7. Mancia G, Zanchetti A. J Hypertens 2008; 26: 1648. 8. WHO Report 1997. World Health Organisation - Geneva 1997. 9. Mancia G. Eur Heart J Supplement 2009; 11 (supplement A): A3-A8. 10. Rury R, Sanjoy K, et al. N Engl J Med 2008; 359: 156576. 11. Erland E. Eur Heart J Supplement 2009; 11 (supplement A): A21-A25. 12. World Health Organization. Cardiovascular diseases. 2009. http://www.who.int/cardiovascular_diseases /en/index.html. 13. MR Law, JK MORRIS & NJ Wald. BMJ 2009; 338: 1665. 14. Norgren L., Hiatt WR, Dormandy JA et al. Eur J Vasc Endovasc Surg 2007, 33, Supplement 1. 15. Radack K, Deck C. Arch Intern Med 1991; 151: 176976. 16. Andrus MR, Holloway KP, Clark DB. Ann Pharmacother 2004; 38: 1425. 17. Salpeter SR, Ormiston TM, Salpeter EE. Ann Intern Med 2002; 137: 71525. 18. Yvette RB, Sanne EH, Don DS, et al, International Journal of COPD 2009: 4: 177183. 19. Fox K, Garcia MA, Ardissino D, et al. Eur Heart J 2006; 27: 134181.

20.Deedwania P and Cardajal E. Am J Cardiol. 1997; 80 (96): 23J-28J. 21.Camm AJ, Lsher TF, Serruys PW, eds. The ESC textbook of cardiovascular medicine. Oxford: Blackwell Publishing, 2006. 22. Hanes DS, Weir MR. J Clin Hypertens. 2001; 3: 236 243. 23. Hunt SA, William TA, et al. Circulation. 2005; 112: e154-e235. 24. Kirkwod F., Adams Jr., et al, Journal of Cardiac Failure 2006; 12: 1: e12-e14 25. Antman E, Braunwald E. Acute Myocardial Infarction. In: Braunwald E, Zipes DP, Libby P, eds. Heart Disease: A textbook of Cardiovascular Medicine, 6th ed., Philadelphia, PA: W.B. Sanders, 2001, 1168. 26. Remme WJ, Swedberg K. et al. Eur Heart J. 2001: 22: 17; 1527-1560 27. Willenheimer R, van Veldhuisen DJ, Silke B, et al. Circulation 2005; 12: 242635. 28. Simon T et al. Eur Heart J 2003; 24: 552-559. 29. Poldermans D, Olaf Sch, Jereon B & Tamara A. Eur Heart J Supplement 2009; 11 (supplement A): A9-A14. 30. Fleisher LA, Beckman JA, Brown 27. KA, et al. J Am Coll Cardiol 2007; 50: 170732. 31. Poldermans D, Boersma E, Bax JJ, 28. et al. Eur Heart J 2001; 22: 13538. 32. Poldermans D, Boersma E, Bax JJ, 29. et al. N Engl J Med 1999; 341: 178994. 33. Schouten O, Shaw LJ, Boersma E, 30. et al. Coron Artery Dis 2006; 17: 1739. 34. Thadani et al. Am J cardiol 1982; 49: 411. 35. Dargie HJ, Ford I, Fox KM et al. The Lancet 2002; 359: 1269-1275.

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