Guidelines on the Management of Stable Angina Pectoris ... - Cardio

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36 ESC <strong>Guidelines</strong>factors which are not modified by traditional anti-ischaemicagents.The TIBBS study 514 showed anti-ischaemic and anti-anginaleffects of both bisoprolol and nifedipine, but bisoprolol wasclearly more effective. The TIBET study compared theeffects of atenolol, nifedipine, or their combination onexercise-induced ischaemia and the total ischaemic burdenin a double-blind, parallel group design. Both medications,alone and in combination, caused significant improvementsin exercise parameters and significant reductions in ischaemicactivity during daily activities when compared with placebobut there were no significant differences between groupsfor any of the measured ischaemic parameters. There weresignificantly more withdrawals because of side-effects inthe nifedipine group compared with the atenolol and thecombination groups. 48,515 Meta-analyses comparing effectsof beta-blockers and CCBs in stable angina pectoris indicatethat beta-blockers are more effective than CCBs in reducinganginal episodes, 494 but that effects on exercise toleranceand ischaemia of the two drug classes are similar. 157,494Thus, in the absence of prior MI, the available datasuggest that the choice between a beta-blocker and a CCBfor anti-anginal treatment may be guided by individualtolerance and the presence of other disease andco-treatment. If these factors are equally weighted, abeta-blocker is recommended as the first choice.Comparison of nitrates with beta-blockers or CCBs. Thereare relatively few studies comparing anti-anginal and antiischaemiceffects of long-acting nitrates with beta-blockersor CCBs, and there is no documentation concerning possibleeffects of nitrates on morbidity in stable angina pectoris. 494There were non-significant trend towards less nitroglycerinuse with beta-blockers, and fewer angina episodes perweek with CCBs compared with long-acting nitrates in themeta-analysis by Heidenreich et al. 494 Thus long-actingnitrates have no overall therapeutic advantages over betablockersor CCBs.Potassium channel openers. The principal agent in this class,nicorandil, has a dual mechanism of action, and is a potassiumchannel activator with a nitrate moiety and nitrate likeeffects. 516 Nicorandil is administered at a usual dose of20 mg bid for the prevention of angina. Tolerance to theanti-anginal effect may develop with chronic dosing, 517but cross-tolerance with nitrates does not seem to be aproblem. 516 In addition to its anti-anginal properties,nicorandil is thought to have cardioprotective properties.516,518 The Impact Of Nicorandil in Angina (IONA) trialshowed a significant reduction of major coronary events instable angina patients treated with nicorandil comparedwith placebo as add-on to conventional therapy. 254However, the result was driven by effects of nicorandil on‘hospital admission for cardiac chest pain’, and the riskreduction regarding cardiac death or non-fatal MI during1.6 years of treatment was non-significant; 254 thus thevalue of the treatment effect has been argued. 518Nicorandil is not available in all countries.Other agents. Sinus node inhibitors, such as ivabradine, actby selectivity inhibiting the cardiac pacemaker current I f,and have negative chronotropic effects both at rest andduring exercise. I f inhibition has proven anti-anginal efficacy461,519,520 and ivabradine may be used as an alternativeagent in patients who do not tolerate beta-blockade. It hasbeen licenced by the EMEA for this purpose.Metabolically acting agents protect from ischaemia byincreasing glucose metabolism relative to that of fattyacids. Trimetazidine and ranolazine are both considered asmetabolic anti-anginal drugs. However, ranolazine has alsomore recently been shown to be an inhibitor of the latesodium current, 521 which is activated in case of ischaemia,leading to calcium overload of the ischaemic myocardium,decreased compliance, increased LV stiffness, and compressionof the capillaries. The inhibition of the latesodium current by ranolazine reverses these effects, andprevents calcium overload, and the subsequent consequencesthereof. 522,523Both trimetazidine 524–526 and ranolazine 527,528 have beenshown to have anti-anginal efficacy. They may be used incombination therapy with haemodynamically actingagents, as their primary effect is not through reduction inheart rate or blood pressure. Trimetazidine has been availablefor several years, but not in all countries. Ranolazine,although under intensive investigation is not yet licencedfor use by the EMEA. Whether these drugs influence theprognosis of patients with stable angina has not beendetermined.Molsidomine is a vasodilator with an action similar to thatof organic nitrates and in the appropriate dosage is aneffective anti-ischaemic and anti-anginal agent. 529 It is notavailable in all countries.Recommendations for pharmacological therapy. Antianginaldrug treatment should be tailored to the needs ofthe individual patient, and should be monitored individually.Short-acting nitrate therapy should be prescribed for allpatients for immediate relief of acute symptoms as tolerated.Although different types of drugs have been shownto have additive anti-anginal effects in clinical trials, thismay not necessarily be so in the individual patient. Moreintense anti-anginal treatment may also cause problems,as it has been shown that three anti-anginal drugs mayprovide less symptomatic protection than two drugs. 530,531Thus, the dosing of one drug should be optimized beforeadding another one, and it is advisable to switch drug combinationsbefore attempting a three drug regimen. Pooradherence is always a factor to consider when drugtherapy is unsuccessful.An algorithm depicting the strategy for medical managementof stable angina, if revascularization is not considerednecessary after initial evaluation and risk stratification,includes treatments aimed at improving prognosis and symptomsand is shown in Figure 7. The following recommendationspertain to anti-anginal therapy and the level ofevidence refers to anti-anginal or anti-ischaemic efficacyunless stated otherwise.Recommendations for pharmacological therapy toimprove symptoms and/or reduce ischaemia in patientswith stable anginaClass I(1) Provide short-acting nitroglycerin for acute symptomrelief and situational prophylaxis, with appropriateinstructions on how to use the treatment (level ofevidence B)
ESC <strong>Guidelines</strong> 37(2) Test the effects of a beta-1 blocker, and titrate to fulldose; consider the need for 24 h protection againstischaemia (level of evidence A)(3) In case of beta-blocker intolerance or poor efficacyattempt monotherapy with a CCB (level of evidence A),long-acting nitrate (level of evidence C), or nicorandil(level of evidence C)(4) If the effects of beta-blocker monotherapy are insufficient,add a dihydropyridine CCB (level of evidence B)Class IIa(1) In case of beta-blocker intolerance try sinus nodeinhibitor (level of evidence B)(2) If CCB monotherapy or combination therapy (CCB withbeta-blocker) is unsuccessful, substitute the CCB with along-acting nitrate or nicorandil. Be careful to avoidnitrate tolerance (level of evidence C)Class IIb(1) Metabolic agents may be used, where available, asadd-on therapy, or as substitution therapy when conventionaldrugs are not tolerated (level of evidence B)Consider triple therapy only if optimal two drug regimensare insufficient, and evaluate the effects of additional drugscarefully. Patients whose symptoms are poorly controlled ondouble therapy should be assessed for suitability for revascularization,as should those who express a strong preferencefor revascularization rather than pharmacologicaltherapy. The ongoing need for medication to improve prognosisirrespective of revascularization status, and thebalance of risk and benefit on an individual basis, shouldbe explained in detail. Despite the array of therapeuticoptions outlined, the management of refractory angina continuesto pose a challenge, and management options in suchcases are outlined in a separate section below.Special therapeutic considerations: cardiac Syndrome Xand vasospastic anginaTreatment of Syndrome X. Treatment should focus on symptomaticrelief. 532 As nitrates are effective in about half of thepatients, 303,532 it is reasonable to start treatment withlong-acting nitrates. If symptoms persist, calcium antagonists533 and b-blockers, 534 which are beneficial in Syndrome Xpatients, may be added. Although a-adrenergic blockadeincreases vasodilator reserve in patients with Syndrome X, 535a-adrenergic blocking agents are clinically inefficient. 536,537There are reports that other drugs such as nicorandil 538 andtrimetazidine 539 might be helpful in some patients.ACE-inhibitors 540 and statins 541 are helpful to reverseunderlying endothelial dysfunction. Thus, these drugsshould be actively considered for patients with Syndrome Xas part of their risk factor management, 542 and there aresome data to suggest that ACE-inhibitors and statins mayalso be beneficial in reducing exercise-induced ischaemia inthis population. 541,543,544The challenge of achieving long-lasting therapeutic effectsin patients with Syndrome X requires a multidisciplinaryapproach. 545 This might include analgesic interventionusing imipramine 546 or aminophylline, 547 psychological intervention,545 electrostimulation techniques, 548 and physicaltraining. 549 Some studies of transdermal hormone replacementtherapy 550,551 in post-menopausal patients haveshown an improvement in endothelial function and symptoms,but in the light of recent trials documenting adversecardiovascular outcomes with the use of HRT, caution isadvised in prescription of HRT for this purpose.Recommendations for pharmacological therapy toimprove symptoms in patients with Syndrome XClass I(1) Therapy with nitrates, b-blockers, and calcium antagonistsalone or in combination (level of evidence B)(2) Statin therapy in patients with hyperlipidaemia (levelof evidence B)(3) ACE inhibition in patients with hypertension (level ofevidence C)Class IIa(1) Trial of therapy with other anti-anginals includingnicorandil and metabolic agents (level of evidence C)Class IIb(1) Aminophylline for continued pain, despite Class Imeasures (level of evidence C)(2) Imipramine for continued pain, despite Class Imeasures (level of evidence C)Treatment of vasospastic angina. Removal of precipitatingfactors such as cessation of smoking is essential. 552 Themain elements of drug therapy are nitrates and calciumantagonists. Although nitrates are highly effective in abolishingacute vasospasm, they are not as successful in preventingattacks of resting angina. 340 CCBs are moreeffective in alleviating the signs and symptoms of coronaryspasm and treatment should be aimed at using high doses(up to 480 mg/d verapamil, up to 260 mg/d diltiazem, upto 120 mg/d nifedipine). However, calcium antagonistsachieve a complete resolution of symptoms in only 38% ofpatients. 340 In most patients, a combination therapy withlong-acting nitrates and high doses of calcium antagonistswill result in an improvement of symptoms. In patientswith resistant symptoms, addition of a second calciumantagonist of another class may be successful. Medical treatmentseems to be more effective in women and in patientswith ST-elevation during provocation testing. 340The role of a-blockers is controversial but occasionaltherapeutic benefit has been reported. 553 Nicorandil, a potassiumchannel activator, may also be useful in occasionalpatients with refractory vasospastic angina. 554 Reports ofsuccess in treating drug-resistant focal vasospasm by coronaryartery stenting exist, 555,556 but this approach is notadvocated for widespread application. CABG is not indicatedbecause spasm distal to the anastomosis may occur.Spontaneous remission of spasmodicity occurs in abouthalf of western people following medical treatment for atleast 1 year. 557 Thus, it is acceptable to taper and discontinuetreatment 6–12 months after angina has disappearedon drug treatment. If vasospasm occurs in association withsignificant coronary disease, guideline recommendationsfor treatments to improve prognosis and secondary preventionshould also be adhered to.Recommendations for pharmacological therapy ofvasospastic anginaClass I
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Guidelines on the Management of Stable Angina Pectoris ... - Cardio

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