Nicotinic Acid, tablets (prolonged release), 500 mg, 750 mg and 1 g, Niaspan®, March 2007
Public summary document for Nicotinic Acid, tablets (prolonged release), 500 mg, 750 mg and 1 g, Niaspan®, March 2007
Page last updated: 29 June 2007
Public Summary Document
Product: Nicotinic Acid, tablets (prolonged
release), 500 mg, 750 mg and 1 g, Niaspan®
Sponsor: Alphapharm Pty Ltd
Date of PBAC Consideration: March 2007
1. Purpose of Application
This re-submission sought listing of a prolonged release
formulation of nicotinic acid as a restricted benefit for use in
combination with an HMG CoA reductase inhibitor (statin) in
patients with dyslipidaemia with adequately controlled Low Density
Lipoprotein (LDL-C) and whose High Density Lipoprotein Cholesterol
(HDL-C) levels are inadequately controlled despite monotherapy with
A submission seeking listing of this product was considered at the
July 2006 PBAC meeting, as a restricted benefit for use in
combination with an HMG CoA reductase inhibitor (statin) in Type II
diabetic patients with dyslipidaemia whose HDL-C levels are
inadequately controlled despite monotherapy with a statin.
The PBAC rejected the submission on the basis that the comparator was not appropriate and there was a lack of clinical evidence to support the implicit claim that an increase in HDL levels reduces cardiovascular risk.
3. Registration Status
The TGA registered Niaspan on the 27 February 2006 for “the
treatment of mixed dyslipidaemia, and primary
hypercholesterolaemia, as adjunctive therapy to diet. Prior to
initiating therapy with nicotinic acid, secondary causes of
hypercholesterolaemia (e.g. poorly controlled diabetes mellitus,
hypothyroidism, nephrotic syndrome, dysproteinaemias, obstructive
liver disease, other drug therapy, alcoholism) should be identified
4. Listing Requested and PBAC’s View
Niaspan is indicated for use in combination with a HMG CoA reductase inhibitor (statin) in patients with dyslipidaemia with adequately controlled LDL-C and whose HDL-C levels are inadequately controlled despite monotherapy with a statin.
Inadequate control is defined as HDL-C<1 mmol/L after at least 3 month’s treatment with a statin.
See Recommendation and Reasons for PBAC’s view
5. Clinical Place for the Proposed Therapy
Niaspan will provide add-on treatment for patients with
dyslipidaemia whose HDL-C levels are inadequately controlled with a
The submission nominated placebo as an add-on to statin therapy as
the comparator. This was considered appropriate by the PBAC.
7. Clinical Trials
The submission provided one randomised, placebo-controlled trial
comparing prolonged release nicotinic acid added to ongoing statin
therapy with placebo plus ongoing statin therapy.
|First Author||Publication Title||Publication Citation|
|Taylor AJ et al||Arterial Biology for the Investigation of the Treatment Effects of Reducing cholesterol (ARBITER) 2. A double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins.||Circulation 2004; 110:3512-3517.|
A meta-analysis of evidence from randomised, placebo-controlled, lipid-altering therapy trials in high-risk patients was also included. A total of 23 individual trials whose primary outcome was either predefined clinical event composites or change in coronary artery stenosis were included in this analysis, aimed at linking LDL-C and HDL-C changes to stenosis change or event reduction.
|First Author||Publication Title||Publication Citation|
|Brown B G||Stimultaneous low-density lipoprotein-C lowering and high-density lipoprotein-C elevation for optimum cardiovascular disease prevention with various drug classes, and their combinations: a meta-analysis of 23 randomised lipid trials.||Current Opinion in Lipidology 2006; 17: 631-636.|
8. Results of Trials
The primary outcome of the trial was mean change from baseline in
common carotid intima-media thickness (CIMT). Changes in serum
lipid concentrations and a composite of clinical cardiovascular
outcomes were included as secondary outcomes.
There was no statistically significant difference in mean change from baseline to endpoint CIMT for patients treated with prolonged release nicotinic acid plus a statin, however, there was a significant increase in CIMT in patients treated with placebo plus a statin. The difference between the two treatment groups did not reach statistical significance.
There was a statistically significant increase in HDL-C during the 12-month trial duration for patients treated with prolonged release nicotinic acid plus a statin. There was no evidence of a change in HDL-C for patients treated with placebo plus a statin. The results of the key trial are summarised below:
Changes from baseline in carotid intima-media thickness (CIMT) and lipid concentrations
|Outcome||PRNA+statin N=78||PBO+statin N=71||Between-group p-value|
|CIMT [mean (SD) mm] - baseline - endpoint - mean change||0.893 (0.259) 0.907 (0.234) 0.014 (0.104) [p=0.23]||0.868 (0.207) 0.912 (0.202) 0.044 (0.100) [p<0.001]||0.52 0.89 0.08|
|TC [mean (SD) mmol/L)] - baseline - endpoint - mean change||3.99 (0.70) 4.01 (0.98) p=0.92||4.17 (0.75) 4.04 (0.62) p=0.06||0.13 0.73 NR|
|LDL-C [mean (SD) mmol/L)] - baseline - endpoint - mean change||2.25 (0.44) 2.20 (0.65) p=0.42||2.36 (0.57) 2.23 (0.52) p=0.37||0.19 0.61 NR|
|HDL-C [mean (SD) mmol/L)] - baseline - endpoint - mean change||1.01 (0.18) 1.22 (0.41) p<0.001||1.04 (0.18) 1.04 (0.23) p=0.61||0.52 0.003 NR|
|TG [mean (SD) mmol/L)] - baseline - endpoint - mean change||1.74 (0.93) 1.51 (0.98) p=0.009||1.94 (1.18) 1.85 (0.94) p=0.07||0.25 0.03 NR|
CIMT: carotid intima-media thickness; TC: total cholesterol; LDL-C:
low-density lipoprotein cholesterol; HDL-C: high-density
lipoprotein cholesterol; TG: triglycerides; PRNA: prolonged release
nicotinic acid; PBO: placebo
Three patients (3.8%) treated with prolonged release nicotinic acid plus a statin had four cardiovascular events over the 12-month trial duration, compared with seven (9.6%) placebo plus statin patients, who experienced a total of 11 events. There was no evidence of a difference between treatment groups in the proportion of patients with cardiovascular events.
9. Clinical Claim
The submission claimed that prolonged release nicotinic acid in
combination with a statin has significant advantages in
effectiveness over placebo plus ongoing statin therapy and has
similar or less toxicity.
See Recommendation and Reasons for PBAC’s view.
10. Economic Analysis
The submission presented a preliminary economic evaluation. The
choice of the cost-effectiveness approach was considered by the
PBAC to be valid if the superior efficacy and similar toxicity of
prolonged release nicotinic acid were considered to have been
The resources included were drug costs, the percentage reduction in HDL-C and the relationship between increase in HDL-C and reduction in cardiovascular risk. The submission assumed that a 1% increase in HDL-C is associated with a 1% reduction in cardiovascular risk, based on a recently published meta-analysis (Brown et al, 2006).
The PBAC noted that the meta-analysis combined 23 trials and plotted the HDL-C response in the intervention arm of the trial against the reduction in one year cardiovascular event rates. The submission argued that this constituted sufficient trial evidence to support the claim that a HDL-C increase translated into a reduction in cardiovascular events. However, there was only one data point for nicotinic acid and the confidence intervals crossed zero. In addition, the publication did not explain the rationale for the zero placebo event rate shown by the graph, nor did it discuss the individual variation across the trials. Overall, the meta-regression as presented in this submission was subject to possible ecological confounding and therefore the results could not be relied upon to provide evidence of the relationship between reduction in HDL and clinical events.
The submission estimated the trial-based incremental cost/additional patient avoiding a cardiovascular event (based on clinical data from the trial) to be less than $15,000.
A modelled economic evaluation was not presented. A modelled economic evaluation using long term mortality and morbidity data would have provided more information to the PBAC on which to base its decision.
11. Estimated PBS Usage and Financial Implications
The submission estimated the likely number of patients/year would
be more than 200,000 in Year 4. The submission estimated the
financial cost/year to the PBS would be less than $10 million in
12. Recommendation and Reasons
With respect to the trial data submitted, the PBAC noted there was
no statistically significant difference in mean change from
baseline to endpoint CIMT (carotid intima-media thickness) for
patients treated with prolonged release nicotinic acid plus a
statin, however, there was a significant difference for patients
treated with placebo plus a statin. The difference between the two
treatment groups did not reach statistical significance.
There was a statistically significant increase in HDL-C during the 12-month trial duration for patients treated with prolonged release nicotinic acid plus a statin, and there was no evidence of a change in HDL-C for patients treated with placebo plus a statin. However, no comparative statistics were provided for the outcome which was of primary interest in the economic evaluation, mean change from baseline in HDL-C.
The PBAC also noted that although only limited toxicity data were presented, prolonged release nicotinic acid appeared to be associated with more toxicity, compared with placebo, with more than two-thirds of patients treated with prolonged release nicotinic acid experiencing flushing. The product information contains a precaution that diabetic patients should be observed closely since there may be a dose-related increase in glucose intolerance and adjustment of diet and/or antidiabetics and/or insulin therapy may become necessary.
The use of changes in CIMT as a surrogate outcome for change in HDL-C was not considered by the PBAC to be adequately validated at this time. The PBAC noted this matter would be discussed at the March 2007 meeting of American College of Cardiology. Further, the PBAC noted the epidemiological data suggest that raising HDL-C may provide independent and additive cardiovascular benefit and that the clinical trial evidence is weakly supportive. However the PBAC did not consider a conclusion on this issue could be reached, in general, nor for Niaspan, in particular, by the evidence provided in the submission.
The PBAC therefore rejected the application on clinical grounds because in the key trial submitted there was no statistically significant benefit demonstrated for prolonged release nicotinic acid over placebo plus statin, uncertainty that the key trial outcome (change in CIMT) was a validate surrogate for improved cardiovascular outcomes, and uncertainty associated with the impact of raising HDL-C on cardiovascular outcomes.
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be
subsidised in Australia. It considers submissions in this context.
A PBAC decision not to recommend listing or not to recommend
changing a listing does not represent a final PBAC view about the
merits of the medicine. A company can resubmit to the PBAC or seek
independent review of the PBAC decision.
14. Sponsor’s Comment
The sponsor is currently reviewing its position regarding this