Suffolk PCT Drug & Therapeutics Committee New Medicine Report (Adopted by the CCG until review and further notice)

Transcription

1 Suffolk PCT Drug & Therapeutics Committee New Medicine Report (Adopted by the CCG until review and further notice) This drug has been reviewed because it is a product that may be prescribed in primary care. Medicine (Ranexa, Menarini Pharma) Document status Considered at NHS Suffolk Drug and Therapeutics Committee meeting September 2010 Date of last revision 20 th August 2010 Traffic light decision GREEN- hospital initiated, GP prescribed Prescribers rating Judgement reserved - The Committee postpones its judgement until better data and a more thorough evaluation of the drug are available. Mechanism of action Licensed indication Dosage Treatment alternatives Place in therapy is a novel agent. Its precise mechanism of action is uncertain, but includes selective inhibition of the late inward sodium current. Unlike other antianginal drugs it does not significantly alter heart rate or blood pressure. (1) Ranexa is indicated as add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled or intolerant to first-line antianginal therapies (such as beta-blockers and/or calcium antagonists). (2) Initial dose 375mg twice daily, increased after two to four weeks to 500mg twice daily. It can be titrated to a maximum dose of 750mg twice daily if tolerated. (2) Nitrates, betablockers, dihydropyridine calcium channel blockers, nicoranidl and ivabradine. will only be suitable for patients who do not have significant co-morbidities or concurrent medication that would preclude its use and who can tolerate it. At present it should be reserved for use when all other treatment options have failed. NICE are scheduled to publish guidance on angina in (1) was rejected by the SMC, and the AWMSG and was not recommended by MTRAC (3,4,5) Evidence for use Details of the key clinical trials are shown in appendix 1. Short-term randomized controlled trials (RCTs) have shown that ranolazine is more effective than placebo at improving exercise tolerance, reducing the frequency of episodes of angina, and reducing use of short-acting nitrates. Evidence from one further RCT suggests that ranolazine is similarly effective to the betablocker atenolol. In one large, long-term morbidity study in people with

2 recent ischaemic symptoms, ranolazine had no significant effect on a composite outcome of cardiovascular death, myocardial infarction (MI), or recurrent ischemia. There are concerns regarding the safety of ranolazine including QT prolongation, drug interactions with several other cardiovascular drugs, and safety in renal and hepatic disease. (6,7,8,9) Critical Appraisal Cautions / side effects Although, patients treated with ranolazine showed a statistically significant improvement in exercise duration and angina frequency compared with placebo, these effects were modest and there are limited data on concurrent use with maximal doses of first-line antianginal agents. Doses used in clinical trials were higher than the licensed dose. A total of 1,030 chronic angina patients were treated with ranolazine during the phase 3 clinical trials. (1) Undesirable effects in patients receiving ranolazine are generally mild to moderate in severity and often develop within the first 2 weeks of treatment. The most frequent adverse effects in clinical trials were dizziness, nausea and vomiting. There is a sharp increase in adverse effects at higher doses and some patients are at increased risk: the elderly, those with body weight 60kg, mild renal or hepatic impairment, or congestive heart failure. (2) Common adverse events, considered to be at least possibly related to treatment, are as follows, dizziness, headache constipation, vomiting, nausea and asthenia. (2) For further details refer to the Summary of Product Characteristics. The adverse event profile was generally similar in the long term study. (8) In this study, acute renal failure was also reported with an incidence less than 1% in placebo and ranolazine patients. Evaluations in patients who may be considered at higher risk of adverse events when treated with other antianginal medicinal products, e.g. patients with diabetes, Class I and II heart failure, or obstructive airway disease, confirmed that these conditions were not associated with clinically meaningful increases in the incidence of adverse events. In general, adverse events occurred more frequently among elderly patients and patients with renal impairment; however, the types of events in these subgroups were similar to those observed in the general population. The following events

3 occurred more often with ranolazine in elderly ( 75 years of age) than in younger patients: constipation, nausea, hypotension and vomiting. In patients with mild or moderate renal impairment (creatinine clearance ml/min) compared to those with normal renal function, the most commonly reported events included: constipation, dizziness and nausea. Small, clinically insignificant, reversible elevations in serum creatinine levels have been observed in healthy subjects and patients treated with ranolazine. There was no renal toxicity related to these findings. A renal function study in healthy volunteers demonstrated a reduction in creatinine clearance with no change in glomerular filtration rate consistent with inhibition of renal tubular secretion of creatinine. In post-marketing experience, there have been reports of acute renal failure, including in patients with pre-existing mild to moderate renal impairment and/or taking concomitant medications that are known to interact with ranolazine. NNT/NNH Costs Costs of alternatives for 28 days treatment (MIMS, August 2010) Potential number of patients in NHS Suffolk interacts with a wide variety of medicines. It is contraindicated with potent CYP3A4 inhibitors e.g. clarithromycin and class Ia or class III antiarrythmics (except amiodarone). The NNT to avoid a composite of cardiovascular death, myocardial infarction (MI) or recurrent ischaemia in 1 year in ACS patients = mg twice daily costs for 28 days Drug (dose) Cost (28 days) Amlodipine 10mg daily 1.53 Diltiazem MR 200mg daily 6.66 Nicorandil 20mg twice daily Ivabradine 7.5mg twice daily The cost of treatment with ranolazine (375mg, 500mg or 750mg twice daily) is 596 per patient per year. More than 1.98 million people living in the UK aged over 35 years have had angina. There are approximately 96,000 new cases per year. The manufacturers estimate that the number of patients with chronic stable angina and intolerant to current antianginal medication to be 1,605 in 2009/10, rising to 2,287 by This assumes a 100% uptake of the drug amongst eligible patients. (5) The numbers of patients for 2009/10 might therefore be 190 rising to 271 by 2013/14 Therefore within NHS Suffolk the cost of giving ranolazine as

4 Points for consideration Decisions sought from other bodies add on therapy could be 113,240 in the first year rising to 161,516 per annum by 2013/2014. is a novel agent licensed as add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled on, or intolerant to, first-line anti-anginal therapies. Unlike other antianginal drugs it does not significantly alter heart rate or blood pressure has been associated with QTc prolongation and syncope and contraindications include concomitant use of some other cardiac agents. Furthermore, other well established treatment options are available for the treatment of chronic stable angina which gives ranolazine a very low place in therapy. In clinical trials patients treated with ranolazine showed a statistically significant improvement in exercise duration and angina frequency compared with placebo. However, these effects were modest and there are limited data on concurrent use with maximal doses of first-line antianginal agents. Doses used in clinical trials were higher than the licensed dose. In an add-on trial comparing SR ranolazine (500mg twice daily for one week followed by 1,000mg twice daily for 6 weeks) with placebo in 565 patients with chronic angina on the maximum dose of amlodipine (10mg daily), patients receiving ranolazine had a statistically significant lower weekly rate of angina episodes than patients on placebo (2.88 vs. 3.31, respectively). This is a reduction of less than one angina attack per week. The most frequent adverse effects in clinical trials were dizziness, nausea and vomiting. There is a sharp increase in adverse effects at higher doses and some patients are at increased risk: the elderly, those with body weight 60kg, mild renal or hepatic impairment, or congestive heart failure. interacts with a wide variety of medicines. It is contraindicated with potent CYP3A4 inhibitors e.g. clarithromycin and class Ia or class III antiarrythmics (except amiodarone). will only be suitable for a select group of patients who do not have significant co-morbidities or concomitant medications that would preclude its use, and who can tolerate it. Evidence on combining two drugs for symptomatic relief of angina is limited. Cambridgeshire JPG Double Red Norfolk TAG Not considered IHT Not considered WSH Not considered

5 SMC is not recommended for use within NHS Scotland as add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled or intolerant to first-line antianginal therapies (such as beta-blockers and/or calcium antagonists). When added to standard doses of antianginal drugs, ranolazine increased exercise duration at trough drug levels after 12 weeks compared with placebo. However, the effect size was small. The manufacturer did not present a sufficiently robust economic analysis to gain acceptance by SMC. The licence holder has indicated their intention to resubmit. MTRAC - The Committee concluded that ranolazine cannot be recommended for prescribing because the current evidence for its efficacy and safety is inadequate to support its use. Only one randomised controlled trial demonstrated efficacy within the licensed indication and dose range and sizes of the effects were considered to be very small. has been associated with QTc prolongation and syncope and contraindications include some other cardiac agents. Furthermore, other well established treatment options are available for the treatment of chronic stable angina which gives ranolazine a very low place in therapy. AWMSG is not recommended for use within NHS Wales for the treatment of stable angina pectoris. The case for the cost effectiveness of ranolazine has not been proven. NICE TA anticipated July 2011 Decision review date Dec 2011 References 1. New Medicines Profile.. March Accessed on 2/8/10 via 2. Summary of Product Characteristics: Ranexa, Menarini Pharma UK SRL. Accessed on 2/8/10 via 3. All Wales Medicines Strategy Group. Final Appraisal Report. (Ranexa) December Accessed on 2/8/10 via 4. Midlands Therapeutic Review and Advisory Committee.. Verdict and Summary. May Accessed on 18/8/10 via 5. Scottish Medicines Consortium.. Published September Accessed on 2/8/10 via gust% doc 6. Chaitman B et al. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: A randomized controlled trial. JAMA 2004; 291: Stone P et al. Antianginal efficacy of ranolazine when added to treatment with

6 amlodipine. J Am Coll Cardiol 2006; 48: Morrow D et al. Effects of ranolazine on recurrent cardiovascular events in patients with non-st-elevation acute coronary syndromes. JAMA 2007; 297: Chaitman et al. Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol 2004; 43:

7 Appendix 1; Key Clinical Trials Trial Trial Design Trial Population Treatment Primary Outcome 6 Multi-centre, randomised, double-blind, placebocontrolled parallel group N=823 vs. placebo as add on therapy. (T) trial over 12 Baseline weeks. (6.3) 7 Multi-centre, randomised, double-blind, placebocontrolled trial over 6 weeks. 9 Multi-centre, randomised, double-blind, placebocontrolled, cross-over study over one week Inclusion criteria - 21 years of age (MARISA) - 18 years of age (ERICA) - Coronary artery disease - 3 month history of effort angina. Exclusion criteria - Digoxin treatment - 1mm ST-segment depression at rest - Left bundle branch block - Pacemaker rhythm - Class III/IV congestive heart failure - Unstable angina - Myocardial infarction or any coronary revascularisation procedure within preceding 2 months - Corrected QTc interval >500ms - Mediation known to prolong QTc interval N=565 vs. placebo as add on therapy. N=191 vs. placebo as monotherapy Change from baseline at 12 weeks Difference from placebo Weekly angina frequency Trimmed mean (SE) Exercise duration (seconds) Mean (SE) Results Placebo 750mg BD 1000mg BD Trough Peak T P T P (P) Exercise duration (seconds) Mean (SE) (8.2) (6.2) (8.1) (6.3) (7.9) (8.3) (8.1) (8.0) (7.8) (8.2) (8.1) 23.7 (10.9) p= (10.7) p= (11.0) p=0.03 Placebo 1,000mg BD 3.31 (+/- 0.22) 2.88 (+/-0.19) p= (10.8) p=0.02 Placebo 500mg BD 100mg BD 1,500mg BD T P T P T P T P (5.7) (5.2) (7.3) (7.9) p= (7.2) p= (8.0) p= (7.2) p= (8.0) p=0. 001

8 8 Multi-centre, randomised, double-blind, placebocontrolled trial over approximately 12 months Inclusion and exclusion criteria see end column * N=6, mg twice daily vs. placebo Results 753 (23.5% of placebo patients vs. 696 (21.8% of ranolazine patients achieved the primary outcome of composite of cardiovascular death. MI, or current ischaemia HR (95% CI) 0.93 ( ) p=0.11 *Inclusion criteria 18 years of age Hospitalised with NSTE-ACS defined as chest discomfort or anginal equivalent at rest, lasting 10 mins consistent with myocardial ischaemia Presence of ischaemic symptoms ( 10 mins) at rest within 48 hours prior to enrolment At least one indicator of moderate to high risk of death or recurrent ischaemic events Exclusion criteria Cardigenic shock, acute pulmonary oedema, sustained systolic BP<90mm Hg Persistent ST-segment elevation Successful revascularisation of the culprit stenosis before randomisation Hepatic disease, end-stage renal disease requiring dialysis Treatment with drugs known to prolong the QTc interval, digoxin or strong inhibitors of cytochrome P450 3A4 Abnormalities of ECG which would interfere with Holter monitoring Life expectance of less than 12 months

9 Grids used to assist the NHS Suffolk PCT Drug & Therapeutics Committee in reaching a decision about new medications For many years scientists have recognised two types of research: Primary: original studies, based on observation or experimentation on subjects. Secondary: reviews of published research, drawing together the findings of two or more primary studies. In biomedical science there is general agreement over a hierarchy: the higher up a methodology is ranked, the more robust and closer to objective truth it is assumed to be. The orthodox hierarchy looks something like this- Rank: Methodology Description 1 Systematic reviews and meta-analyses Systematic review: review of a body of data that uses explicit methods to locate primary studies, and explicit criteria to assess their quality. Meta-analysis: A statistical analysis that combines or integrates the results of several independent clinical trials considered by the analyst to be "combinable" usually to the level of re-analysing the original data, also sometimes called: pooling, quantitative synthesis. Both are sometimes called "overviews." 2 Randomised controlled trials (finer distinctions may be drawn within this group based on statistical parameters like the confidence intervals) Individuals are randomly allocated to a control group and a group who receive a specific intervention. Otherwise the two groups are identical for any significant variables. They are followed up for specific end points. 3 Cohort studies Groups of people are selected on the basis of their exposure to a particular agent and followed up for specific outcomes. 4 Case-control studies "Cases" with the condition are matched with "controls" without, and a retrospective analysis used to look for differences between the two groups. 5 Cross sectional surveys Survey or interview of a sample of the population of interest at one point in time 6 Case reports. A report based on a single patient or subject; sometimes collected together into a short series 7 Expert opinion A consensus of experience from the good and the great. 8 Anecdotal Something a bloke told you after a meeting or in the bar. Adapted from Systematic reviews, What are they and why are they useful? ScHARR 2008

10 To Decide if a Medication Is To Be Used In Suffolk Criterion to be measured Tends to poor 2 Medium 4 Tends to good Quality of evidence in the papers reviewed Magnitude of effect inferred from trials reviewed Low Medium High Are trial end-points surrogate markers or clinical outcomes? Clinical usefulness of trial end-points x Known Side Effect Profile High x Medium Low Known Interactions High Medium Low Concern re Possible Side Effects Not Yet Uncovered High x Medium Low Balance of Benefit To Harm (side effects toxicity interactions etc) Poor x Medium Good NNT High x Medium Low Comparison Of Effectiveness With Other Medicines In Use For The Poor Medium Good Same Condition Severity of Condition to be Treated Trivial Medium x Severe Novel drug or member of existing class Novel Uptake (estimated proportion of people with this condition likely to be prescribed the medication under consideration maximum and minimum uptake) Is the drug to be used in Suffolk? Prescriber s Rating Definitions Bravo! -The drug is a major therapeutic advance in an area where previously no treatment was available. A real advance - The product is an important therapeutic innovation but has certain limitations. Offers an advantage - The product has some value but does not fundamentally change present therapeutic practice. Possibly Helpful - The product has minimal additional value, and should not change prescribing habits except in rare circumstances. Judgement reserved - The Committee postpones its judgement until better data and a more thorough evaluation of the drug are available. Nothing New - The product may be a new substance but is superfluous because it does not add to the clinical possibilities offered by previous products available. In most cases these are me-too products. Not acceptable - Product without evident benefit over others but with potential or real disadvantages. (With acknowledgement to Prescrire) To Decide Where A Medication Is To Be Used In Suffolk

11 Skills of the prescriber Criterion Red Amber Green Blue Experience Of The Condition Specific Specific Specific General 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 References Jonsen A. Bentham in a box: Technology assessment and health care allocation. Law Med. Health Care. 1986;14: Suffolk Drug & Therapeutics Committee Responsibility for prescribing, Hospital Trust or GP Attached as Appendix 1 & Appendix 2