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

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)