New Medicine Eplerenone Report Document Status Post Suffolk D&TC

Traffic Light Decision GREEN Date of Last Revision 12.07.04

Approved Name Eplerenone Trade Name Inspra™ Manufacturer Pfizer Legal Status Not licensed - expected to be POM Indication To reduce the risk of death and cardiovascular hospitalisation in stable patients with left ventricular dysfunction and clinical evidence of heart failure after an acute myocardial infarction Dosage 50mg daily initiate at 25mg and increase within 4 weeks as tolerated Cost Price not yet known Possible Number of Suffolk Not calculated Patients Number Needed to Treat From the EPHESUS authors 50 to save one life in one year 33 to prevent one death from cardiovascular causes or one hospitalisation for a cardiovascular event Treatment Alternatives Spironolactone Future Alternatives None known Possible Future Indications Treatment of hypertension either alone or in combination with other antihypertensives (already an indication in the USA)

This is an NHS Suffolk document that has been adopted by the WSCCG.

Reviewer’s Comments

Eplerenone is the first selective aldosterone receptor antagonist. It is claimed to be more specific than spironolactone having less affinity for androgen and progesterone receptors. This, it is suggested should lower the incidence of adverse events such as gynaecomastia impotence and breast tenderness which are seen with spironolactone. As yet no head to head study has been conducted to see if, all other treatments being similar, this proposition is supported.

It is not yet clear for how long treatment should be continued post MI. The trial presented ended after 16 months.

The results show an improved outcome for those patients taking eplerenone.

Evidence Reviewed

Paper, Review, Abstract etc. Level of evidence Pitt B, Remme W, Zannad F et al Eplerenone, a selective I aldosterone blocker in patients with left ventricular dysfunction after myocardial infarction N Engl J Med 2003;348:1309-21 also known as the EPHESUS study Correspondence N Engl J Med 349;1 www.nejm.org III July 3 2003 National Prescribing Centre New drugs in clinical III development – Eplerenone Monograph 3/03/05 Cambridegeshire Joint Prescribing Group Submission III Eplerenone 23 Jan 2004 InfoPOEM Eplerenone reduces mortality in post-MI III patients with CHF – POEM review of study www.druginfozone.nhs.uk/record%20Viewing/viewDetail.aspx?ids+517295 Atributed to InfoPOEM, Inc www.InfoPOEMs.com Level of evidence adapted from “Quick and Clean” : authorative health technology assessment for local health care contracting Andrew Stevens, Duncan Collin-Jones & John Gabbay Health Trends Vol 27 No 2 1995

Submitted for comment to: Date Medical Information Department, Pfizer 10.06.04 Dr N Irvine, The Ipswich Hospital 10.06.04 Dr Chakrabaty, The Ipswich Hospital Dr E Lee, West Suffolk Hospital Dr D Stone, West Suffolk Hospital Dr W Grabau, James Paget Hospital Dr Jesudason, James Paget Hospital

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Review

With improving care of patients following an episode of acute myocardial infarction and also with an increasingly elderly population the prevalence of congestive heart failure is rising in this country. This reduction in the heart’s ability to pump blood through the vascular system is, in developed countries, in most cases due to systolic left ventricular dysfunction (SLVD).

The rennin-angiotensin-aldosterone and sympathetic nervous systems play an important part in the neurohormonal response in heart failure. It is recognised that neurohormonal blockade through the use of ACE inhibitors, beta-blockers and spironolactone improves outcome. Other treatments include diuretics and digoxin.

It has been recognised that spironolactone with its affinity for androgen and progesterone receptors is associated with gynaecomastia, breast pain and impotence in males and reduced libido and menstrual irregularities in females.

Eplerenone, a new drug, is a competitive antagonist of aldosterone at the mineralocorticoid receptor. However it has less affinity for androgen and progesterone receptors than spironolactone and therefore, it is suggested, will have a lower incidence of side effects.

In the EPHESUS study (supported by Pfizer) Pitt et al report on a multi-centre multi-national randomised double-blind placebo controlled trial. Patients were assigned to receive eplerenone 25mg per day or placebo for four weeks after which the dose of eplerenone was increased to 50mg per day. If at any time the serum potassium concentration was higher than 5.5mmol per litre the dose of the study drug was decreased or treatment was temporarily discontinued until the level fell below 5.5mmol per litre.

Patients were eligible for randomisation 3 to 14 days post myocardial infarction (MI) if they met the following criteria: acute MI documented, left ventricular dysfunction as documented by a left ventricular ejection fraction of 40% or lower on echocardiography, radionuclide angiography, or angiography of the left ventricle after the index MI and before randomisation; and heart failure as documented by the presence of pulmonary rales, chest radiography showing pulmonary venous congestion or the presence of a third heart sound. In diabetic patients who met the criteria for left ventricular dysfunction after an MI, symptoms of heart failure did not have to be demonstrated as they have an increased risk of cardiovascular events similar to that of non-diabetic patients with symptoms of heart failure.

Patients were able to receive optimal drug therapy including ACE inhibitors, angiotensin-receptor blockers, diuretics and beta-blockers as well as coronary reperfusion therapy.

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Important exclusion criteria were the use of potassium-sparing diuretics, a serum creatinine concentration of more than 2.5 mg per decilitre (220μmol per litre) and a serum potassium concentration of more than 5.0mmol per litre before randomisation.

Two primary end points were identified, time to death from any cause and time to death from cardiovascular causes or first hospitalisation for a cardiovascular event including heart failure, recurrent acute myocardial infarction, stroke or ventricular arrhythmia.

The major secondary end points were death from cardiovascular causes and death from any cause or any hospitalisation.

Analysis was by intention to treat principle.

A total of 6642 patients were recruited and randomised. Ten patients from one centre were excluded pre analysis but before unblinding because of data quality concerns. The results are shown in Table 1

Table 1 To show the summary of primary and secondary end points

Eplerenone Placebo RRR NNT Variable (n=3319) (n=3313) No of % of No of % of patients patients patients patients Primary end point Death any cause 478 14 554 17 15% 44 (4-25) (25-174) Death or hospitalisation for 885 27 993 30 13% 31 CV event (5-21) (19-88) Secondary end point Death from any cause or 1730 52 1829 55 8% 33 hospitalisation (2-14) (19-147) Death from CV causes 407 12 483 15 17% 44 (6-18) (26-148)

The results show that eplerenone has a beneficial outcome on both the primary and secondary end points of the trial.

Adverse Effects etc.

For full information please see the SPC when available.

A number of adverse events are recorded in the trial and are shown in Table 2

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Table 2 To show the adverse events

Adverse event Eplerenone Placebo P value % % N 3307 3301 ≥1 event 78.9 79.5 0.57 Cardiovascular disorder 48.6 50.3 0.16 Respiratory disorder 22.0 24.3 0.03 Cough 5.0 6.3 0.03 Dyspnea 7.3 9.3 0.004 Pneumonia 2.8 3.7 0.03 Metabolic or nutritional disorder 17.2 19.2 0.03 Hyperkalemia 3.4 2.0 <0.001 Hypoglycemia 0.6 1.1 0.04 Hypokalemia 0.5 1.5 <0.001 Hyperuricemia 2.6 3.4 0.08 Neoplasm 1.7 1.8 0.93 Urinary tract disorder 14.3 12.7 0.06 Disorder of skin or appendages 6.7 6.8 0.88 Musculoskeletal disorder 6.3 6.5 0.84 Nervous system disorder 14.9 13.6 0.14 Psychiatric disorder 7.2 8.2 0.12 Gastrointestinal disorder 19.9 17.7 0.02 Endocrine disorder 1.0 0.7 0.18 Disorders in men (n=2370e/2326p) 2.5 2.8 0.53 Gynecomastia 0.5 0.6 0.70 Impotence 0.9 0.9 1.00 Disorders in women (n=937e/975p) 1.8 1.7 1.00 Breast pain 0.1 0.3 0.63 Serious hyperkalemia (serum potassium 5.5 3.9 0.002 ≥6mmol/litre) Serious hypokalemia (serum potassium 8.4 13.1 <0.001 <3.5mmol/litre)

It should be noted that serious hyperkalaemia occurred in 5.5% of the treatment group and 3.9% of the placebo group giving a NNH of 63.

Fifteen patients with serious hyperkalaemia were hospitalised (12 in the active treatment arm and 3 in the placebo arm).

Serious hypokalaemia was less frequent in the treatment arm than in the placebo arm.

Coca and Buller, in a letter to the NEJM, postulate that the difference in the incidence of hypokalaemia may be the reason for the reduction in sudden death since hypokaalemia frequently leads to ventricular arrhythmias. Pitt in response states that preliminary analysis of the data reveals a reduction in the risk of sudden death from cardiac causes which is independent of the effects of eplerenone in preventing hypokalaemia and thus does not support the hypothesis

Printed 14/11/12 ©David Evans Suffolk Public Health Network Not to be used for promotional purposes Page 5 of 10 May be freely copied by NHS agencies The number of patients reporting gynaecomastia, impotence and breast pain were almost identical in the treatment and placebo groups. This would support the claim of specificity. It would have been interesting to see what the rates were in this group of patients. We know from the RALES trial that the rate of gynaecomastia was 9%. However this is dose dependent and more likely if digoxin, which was used much more widely in the RALES trial, is taken.

Economic Information

The Cambridge JPG estimate that a GP with a list of 2,000 would expect to have an average of 12 hospitalisations and to have 50 patients making 130 visits per year to the GP for ischaemic heart disease.

Although no price has yet been set for the product it is expected to be priced around the same value as a branded ACE inhibitor at about £15 per packet as opposed to just over £2.10 for 28 days of spironolactone. If all patients receive eplerenone post MI it can be estimated that the cost could be just over £89,000 per 100,000 population. The following Table 3 can be constructed to give costs for PCTs in Suffolk.

Table 3 To show estimated costs as described above

PCT Estimated possible cost (£) Central Suffolk PCT 87,632 Ipswich PCT 126,319 Suffolk Coastal PCT 87,924 Suffolk West PCT 190,941 Waveney PCT 108,308 Total Suffolk system 601,123 Eastern system 301,874

Using the NNT of 50 to save one life in one year the cost of the life saved by using eplerenone would be £9,750 and to save one life or one hospitalisation for a cardiovascular event (NNT=33) with eplerenone the cost would be £6,435.

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Following discussion with Pfizer further information has been presented which enables Table 3 to be updated.

Given that the published evidence is for the treatment to begin 3 to 14 days post MI Pfizer suggest that no patients who have had an MI prior to launch will be eligible for treatment.

Using figures supplied by them it is suggested that in a year 58 patients in a population of 100,000 will have an MI progressing to heart failure. Of the treated population there will be 40% mortality.

The cost of the product is estimated at £43 per 28 days or £559 per year.

Table 4 shows the expected costs for each PCT. There is no attempt to phase the use through the year and thus true costs in year one will be lower than shown and that they will rise over the coming years. However it should be noted htat there has been no attempt to model the 40% mortality across the year but it has been applied as a 40% reduction of full costs.

Table 3 To show estimated costs as described above

PCT Number of Cost if all receive Cost assuming 40% patients treatment through year mortality applied across (58/100,000) the full year Central Suffolk 57 31,863 19,118 PCT Ipswich PCT 82 45,838 27,503 Suffolk Coastal 57 31,863 19,118 PCT Suffolk West 124 69,316 41,590 PCT Waveney PCT 71 39,689 23,813 Total Suffolk 392 219,128 131,477 system Eastern system 197 110,123 66,074

Given the new information on likely cost the cost of life saved data can be recalculated.

Using the NNT of 50 to save one life in one year the cost of the life saved by using eplerenone would be £27,950 and to save one life or one hospitalisation for a cardiovascular event (NNT=33) with eplerenone the cost would be £18,447.

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Charts to be used in the decision making process in Suffolk

Quality of Evidence categories Cost utility categories Per life year gained I Strong evidence from at least 1 RCT A Less than £3,000 II-1 Evidence from a well designed CT without randomisation B £3,000 to £20,000 II-2 Evidence from well designed cohort or case controlled study C > £20,000 II-3 Evidence from multiple time series or dramatic results D Negative life years III Opinions of respected clinicians or expert committees IV Evidence inadequate

Recommendations informed by cost utility and quality of evidence Key to Table at Right Quality of A B C D evidence ++ Strongly recommended I ++ (high) ++ - X + Recommended II ++ + - X - Beneficial but high cost III + - - X X Not recommended IV 0 0 0 0 (low) 0 Not proven

Adapted from

“Quick and Clean” : authorative health technology assessment for local health care contracting Andrew Stevens, Duncan Collin-Jones & John Gabbay Health Trends Vol 27 No 2 1995

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To Decide If A Medication Is To Be Used In Suffolk

Criterion Tends to 2 Medium 4 Tends to poor good Quality of evidence in the papers reviewed IV III II-2 II-1 I Magnitude of effect inferred from the trials reviewed Low Medium High Known Side Effect Profile High Medium Low Known Interactions High Medium Low Concern re Possible Side Effects Not Yet Uncovered High Medium Low Balance of Benefit To Harm (side effects toxicity interactions etc) Poor Medium Good NNT High Medium Low Comparison Of Effectiveness With Other Medicines In Use For Poor Medium Good The Same Condition Severity of Condition to be Treated Trivial Medium Severe Cost Utility Score D C B ?A A Recommendations informed by cost utility and quality of 0 X - + ++ evidence

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To Decide Where A Medication Is To Be Used In Suffolk

Criterion Red Amber Green D Green Skills of the Experience Of The Condition Specific Specific Specific General prescriber Diagnosis Specific Specific Specific General Monitoring Progress Of Treatment Difficult Specific General General

Therapy Patient Selection Difficult Specific Specific Easy Initiation Of Treatment Difficult Difficult Easy Easy Dose Titration Difficult Specific Easy Easy Monitoring Of Side Effects Complex Easy Easy Easy Method Of Administration Complex Normal Normal Normal Discontinuation Of Treatment Complex Complex Easy Easy

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