Optimum doses of secondary preven-tion cardiac medicines need to be

achieved post-myocardial infarction (MI)to derive evidence-based benefits,including reduction in mortality, less hos-pital readmission and better symptomcontrol.1–3 While intensive statin therapycan be started at high-target doses, ACEinhibitors and beta-blockers require up-titration to reach target or maximum tol-erated doses.1–3

Ideally dose titration should occurbefore discharge from hospital, but thisdoes not always happen because of a lack of knowledge of the hospital prescriber, contraindications to dosetitration or short duration hospitaladmissions.4

In the event of partial dose titrationon discharge, then communication toGPs should ensure that a plan is in placeto continue titration post-discharge.

Evidence for lack of dose titrationStudies on prescribing post-MI show thatbetween 60 and 90 per cent of patientsare receiving each discharge medicationas recommended by NICE.5–8 Recent

audits indicate that this does appear tobe increasing.9

According to the 2013 MyocardialIschaemia National Audit Project(MINAP)9 the use of ACE inhibitors andbeta-blockers for secondary preventionon discharge remains high, 95 and 97per cent respectively. However, variousstudies and audits continue to show thatACE inhibitors and beta-blockers are pre-scribed at suboptimal doses on dis-charge, and not appropriately up-titratedto target doses or maximum tolerateddoses thereafter.4,10 In its updated guid-ance, NICE (2013) highlights that sincethe publication of the 2007 guidance,there have been apparent inconsisten-cies in the speed of ACE inhibitor titra-tion and often clinically effective dosesare not reached at the time of hospitaldischarge and in the community.11

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Dose optimisation following myocardial infarction Duncan Petty PhD, DipClinPharm, MRPharmS, IP and Rani Khatib DPharm, PgDipClinPharm, MRPharmS, IP

Dose optimisation of medicines for secondary prevention of MI providesevidence-based benefits, but studies show that ACEinhibitors and beta-blockersare prescribed at subopti-mal doses on discharge andare not appropriately up-titrated thereafter. Here welook at the reasons why andthe possible solutions.

ECG showing myocardial infarction

SPL

One of the recommendations of NICEto overcome the problem of lack of dosetitration is to fast titrate the ACEinhibitors in hospital. This recommenda-tion was based on studies that examinedfast versus slow up-titration regimens ofACE inhibitors.12,13 In the Pfeffer et alstudy, ramipril was up-titrated to 10mg/day over a three-day period.13

A recent small audit (n=37) on thecardiology wards at Leeds TeachingHospitals NHS Trust, which will be pub-lished in full at a later stage, showed that40 per cent of patients who were startedon ACE inhibitors and 43 per cent ofpatients on beta-blockers could havebeen up-titrated to higher doses beforedischarge. Six months’ follow-up of thosepatients post-discharge revealed thatalmost 50 per cent did not have any up-titration of their ACE inhibitor doses, nordid 85 per cent of beta-blocker doses getup-titrated in the absence of any obviousclinical reason (eg low BP or heart rate).

Benefits of dose optimisationIn heart failure, a lack of dose titrationcan lead to treatment failures with likelyconsequences of increased mortalityand hospital admissions.14

The prognostic benefits for the useof ACE inhibitors and beta-blockers post-MI are based on various studies such asAcute Infarction Ramipril Efficacy(AIRE)1, Carvedilol Post-Infarct SurvivalControl in Left-Ventricular Dysfunction(CAPRICORN)2 and other secondary pre-vention studies. These trials used higherdoses of these drugs and doses were up-titrated to specific target doses. It is forthat reason that NICE and other guide-lines recommend up-titration of ACEinhibitors and beta-blocker doses, aslower doses may not confer the samebenefit seen in these trials.

NICE guidanceNICE guidance on secondary preventionof MI recommends offering all peoplewho have had an acute MI an ACEinhibitor, dual antiplatelets (aspirin plusanother antiplatelet), a beta-blocker anda statin.11

NICE states that the ACE inhibitordose should be up-titrated at shortintervals (eg every 12 to 24 hours)

before the person leaves the hospitaluntil the maximum tolerated or targetdose is achieved. If not achieved duringthe hospital stay then dose titrationshould be completed within four to sixweeks of hospital discharge. Plans forup-titrating the beta-blocker until themaximum tolerated or target dose isachieved should be communicated inthe discharge summary.11

The discharge summary shouldinclude: confirmation of the diagnosisof an MI, results of investigations,incomplete drug titrations, future man-agement plans and advice on second-ary prevention.

NICE also advises that a clear man-agement plan should be available to theperson who has had an MI and the GPincluding: details and timing of any fur-ther drug titrations, and monitoring ofboth BP and renal function.

Post-MI patients are supported for-limited period through outpatientappointments and cardiac rehabilitation.However, most patients receive little sup-port and mechanisms are not normallyput in place to dose-optimise medicinesand support adherence. Even if second-ary care support is available, after aperiod of time patients are ‘discharged’back to GP care and more intensive sup-port can stop. If dose optimisation hasnot occurred by this point then there isa danger it will not happen.

Why doesn’t dose optimisationoccur?There are a number of theoretical rea-sons that can be postulated as to whydose titration does not occur, but littleempirical evidence.

Adverse effectsLegitimate reasons as to why doses can-not be increased include low BP onhigher doses or other adverse effects,such as bradycardia from higher dosesof beta-blockers, or clinically significantdecreases in renal function with higherdoses of ACE inhibitors.

Lack of knowledgeA simple explanation might be that GPslack knowledge about the benefits ofdose titration. However, in other condi-

tions lack of knowledge has been shownnot to be a barrier.15

Collusion of anonymityDuring the period after an MI when thepatient is still being seen as an outpa-tient, there may be confusion betweenthe specialist and the generalist teamas to whose responsibility it is to makedose changes.

Lack of communication between secondary and primary careWhile the discharge summaries fromthe hospital may include the correctsecondary prevention medicines, asshown in MINAP data, they do not nec-essarily include clear instructions forthe GP to up-titrate the ACE inhibitorsand beta-blocker doses to target ormaximum tolerated doses. Similarly,required follow-up monitoring should behighlighted on the discharge summary.This is a clearly emphasised NICE rec-ommendation.

Follow-up planA more likely explanation as to why dosetitration does not occur is the lack of afollow-up plan. To enable dose titrationto occur, a number of steps are required.Firstly the BP, heart rate, and urea andelectrolytes (U&Es) need checking. Whenresults are obtained a higher dose canbe prescribed accordingly. The patientthen needs to know that a higher dosehas been prescribed. This cycle needsrepeating until an evidence base or max-imum tolerated dose is achieved.

A failure in any stage will result indose titration stopping; the more stagespresent the less likely it is that dose titra-tion will occur. For instance, if a practicenurse takes a blood sample, the GP willsee the results but may be unaware thata dose titration is required. Alternativelythe cycle might be broken by a patientfailing to turn up for a test or a follow-upGP appointment.

SolutionsFewer dose titrationsThe simpler the process, the more likelythat evidence-based doses will beachieved. Ideally the patient’s doseswould be optimised before discharge

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from the acute admission as close dailymonitoring is possible during their hos-pital stay. Evidence from clinical trialsthat used ACE inhibitors showed thatdoses were usually up-titrated to targetdoses or maximum tolerated doses in avery short period in secondary care.

For example, the AIRE study1

showed an observed risk reduction ofall-cause mortality of 27 per cent (95%Cl, 11 to 40; p=0.002) using the follow-ing protocol: • Patients initially received 2.5mg oframipril (or placebo) twice daily. If toler-ated for two days the dose was increasedto 5mg twice daily thereafter. If the higherdose was not tolerated, patients were dis-charged on 2.5mg twice daily.• Ramipril 1.25mg was provided forpatients who could not tolerate the initial2.5mg dose. After two days, the dosewas increased to 2.5mg twice daily andthen 5mg twice daily.

Based on the aforementioned, it isapparent that trials had usually usedonly two to three up-titrations beforereaching target dose or maximum toler-ated doses. A similar protocol can beimplemented in practice and made avail-able to all prescribers in hospitals. TheAIRE trial excluded patients who couldnot tolerate doses less than 2.5mg twicedaily. The protocol stated that patientswho were unable to tolerate at least2.5mg twice daily of ramipril should bewithdrawn from the study. The protocoldid not allow discharge of a patient onthe low dose of 1.25mg twice daily.

The Leeds Teaching Hospitals NHSTrust’s cardiology department hasrecently adopted a similar protocol,which helped prescribers to prescribemore optimal doses of ACE inhibitorspost-MI.

Improve practice protocolPatients currently see different staffmembers for different parts of the path-way for dose titration, eg nurse forbloods, GP for prescribing. If a currentbarrier is an understanding of each teammember’s responsibility a protocol mighthelp. The protocol would detail the teammembers’ responsibilities includingcommunication with each other and thepatient. To simplify this process, nurses

might for example take the tests andalso make the dose adjustments (underprotocol) once the results are available,and communicate the change to thepatient.

Improve quality of discharge summariesMore hospitals are now using electronicdischarge systems, which can be pro-grammed to automatically insert arequest to up-titrate doses of ACEinhibitors and beta-blockers as appropri-ate. A similar automatic statement canbe included about monitoring.

Local protocols can clearly state theneed to detail dose titration and moni-toring plans for secondary preventionmedicines. All discharge prescriptionsare validated by clinical pharmacistswho can police the quality of the instruc-tions given about secondary preventionmedicines post-acute coronary syn-drome (ACS) and amend them accord-ingly to ensure that they meet agreedlocal protocols.

In Leeds Teaching Hospitals NHSTrust’s cardiology department, cardiol-ogy pharmacists have adopted this prac-tice, which led to better quality electronicdischarge advice notes. The impact ofthis practice on dose titration is currentlybeing evaluated.

Patient ownership of the processThe patient is the ‘common denomina-tor’ in the dose titration pathway. Apatient hand-held or electronic recordwould help the patient to manage thepathway by giving them responsibility toensure tests (eg U&Es) are taken and aprescriber is then communicated with(face to face or over the phone) toincrease the dose.

Patients should be informed of theintended therapeutic care plan. Manypatients are discharged without beinginformed that their ACE inhibitors or beta-blocker doses should be up-titrated.Empowering patients with more detail oftheir care plan should increase the likeli-hood of optimising therapy.

ConclusionACE inhibitors and beta-blockers areroutinely initiated after MI; however,

lack of dose titration to achieve evidence-based doses is a commonproblem. A number of interventionscould be made to increase dose titra-tion such as fewer dose titrations, bet-ter communication of care plans andpatient involvement.

References1. The AIRE Study Investigators. Lancet 1993;342:821–8.2. McMurray J. Carvedilol reduces supraven-tricular and ventricular arrhythmias aftermyocardial infarction: evidence from theCAPRICORN study. Presented at AmericanHeart Association Scientific Sessions, inAnaheim, CA, USA, 11–14 November 2001.Abstract 3303.3. Cannon C, et al. N Engl J Med 2004;350:1495–504.4. Stewart KJ, et al. Br J Cardiol2010;17:142–3.5. Birkhead JS, et al. Heart 2004;90:1004–9.6. Cox J, et al. Healthc Q 2008;11:28–41.7. Underwood P, Beck P. Qual Saf Health Care2002;11:230–2.8. Scott IA, et al. Intern Med J 2002;32:502–11.9. NICOR. Myocardial Ischaemia NationalAudit Project. How the NHS cares for patientswith heart attacks: annual public report April20120–March 2013. http://bit.ly/1zLI8f3.10. Goldberger JJ, et al. Am Heart J 2010;160:435–442.e1.11. NICE. MI secondary prevention: second-ary prevention in primary and secondary carefor patients following a myocardial infarction.CG172. November 2013.12. Flather MD, et al. J Cardiovasc Risk1995;2:423–8.13. Pfeffer MA, et al. Circulation1997;95:2643–51.14. Adams B, et al. Heart 2013;99:A12.15. Petty DR, et al. Int J Pharmacy Practice.2007;Supp2:B29–B30.

Declaration of interestsNone to declare.

Duncan Petty is a research practitionerin primary care pharmacy, University ofBradford and director of PrescribingSupport Services Ltd, Rani Khatib isconsultant pharmacist in cardiologyand cardiovascular clinical research atLeeds Teaching Hospitals NHS Trustand honorary senior clinical lecturer,University of Leeds

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