HPS2-THRIVE: niacin NOT the answer for residual cardiovascular risk

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4 January 2013

HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events). Final results reported at:
HPS2-THRIVE Collaborative Group. HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J 2013; online ahead of print 27 February 2013.
HPS2-THRIVE Trial website: http://www.thrivestudy.org/

HPS2-THRIVE Collaborative Group.

STUDY SUMMARY

Objective

To evaluate whether adding niacin (nicotinic acid) to current best lipid-modifying treatment (including simvastatin ± ezetimibe) would reduce the risk of major cardiovascular events in high-risk patients with well-controlled low-density lipoprotein cholesterol (LDL-C) levels

Study design

Randomised, double-blind, placebo-controlled, parallel-group, multicentre, international trial.

Study population

Patients aged 50-80 years with previous myocardial infarction (MI), cerebrovascular disease (ischemic stroke or transient ischemic attack), peripheral arterial disease; or diabetes with other coronary heart disease (CHD).
Of 51,698 patients screened by 245 sites in six countries, 25,673 were randomised to treatment with ER niacin/laropiprant (2 g/40 mg, n= 12,838) or matching placebo (n= 12,835). Baseline characteristics are given in Table 1.
Table 1. Baseline characteristics of HPS2-THRIVE population

Variable	ER niacin/ laropiprant	Placebo
Total N	12,838	12,835
Mean age, yr	64.9	64.9
Male, %	83	83
Prior CVD, %
Coronary	78	78
Cerebrovascular	32	32
Peripheral	13	12
Diabetes	32	32
Mean ± SD baseline lipids*, mmol/L (mg/dL)
LDL-C	1.64 ±0.44 (63 ±17)
HDL-C	1.14 ± 0.29 (44±11)
Triglycerides	1.43 ±0.84 (125 ±74)
* Before randomisation; CVD cardiovascular disease; HDL-C high-density lipoprotein cholesterol; SD standard deviation

Primary variable

Major vascular events, a composite of major coronary events (nonfatal myocardial infarction [MI] or coronary heart disease [CHD] death), stroke or revascularisation (coronary and non-coronary)

Secondary variables

Individual components of the primary endpoint
Major vascular events in patients with or without CHD, cerebrovascular disease, peripheral artery disease and diabetes
Mortality, overall and by specific causes of death
Safety (adverse events and clinical investigations)

Methods

Screened patients entered the LDL-C lowering phase and received simvastatin 40 mg/day (±ezetimibe). Patients who achieved a total cholesterol target of 3.5 mmol/L (135 mg/dL) then received active ER niacin plus laropiprant for one month. Patients who were compliant with this regimen were subsequently randomised to treatment with ER niacin/laropiprant (2 g/40 mg) or matching placebo.

Main results

Lipids

Average lipid changes in the ER niacin/laropiprant group over the 4 years of the study were:

LDL-C: 0.25 mmol/L or 10 mg/dL reduction
Triglycerides: 0.37 mmol/L or 33 mg/dL reduction
HDL-C: 0.16 mmol/L or 6 mg/dL increase

Based on previous studies, these lipid differences would be expected to translate to a 10-15% reduction in vascular events.

Efficacy

There was no significant difference in the primary endpoint after 4 years of follow-up. This occurred in 14.5% on ER niacin/laropiprant versus 15.0% of patients on placebo (risk ratio [RR] 0.96, 95% CI 0.90 – 1.03, p=0.29). Most of the benefit was observed in European patients (absolute change in risk: -1.1% versus +0.3% in Chinese patients). Secondary endpoints are summarised in Table 2.

Table 2. Secondary endpoints in HPS2-THRIVE; no. (%) of patients

Endpoint	ER niacin/ laropiprant	Placebo	RR (95% CI)	p-value*
Major coronary events	668 (5.2)	694 (5.4)	0.96 (0.87-1.07)	0.51
Non-fatal MI	402 (3.1)	431 (3.4)	0.93 (0.82-1.07)	0.33
CHD death	302 (2.4)	291 (2.3)	1.04 (0.89-1.22)	0.63
Stroke	498 (3.9)	499 (3.9)	1.00 (0.88-1.13)	0.56
Ischemic	389 (3.0)	415 (3.2)	0.94 (0.82-1.08)	0.37
Hemorrhagic	114 (0.9)	89 (0.7)	1.28 (0.97-1.69)	0.08
Revascularisation	807 (6.3)	897 (7.0)	0.90 (0.82-0.99)	0.03
Coronary	591 (4.6)	664 (5.2)	0.89 (0.80-0.99)	0.04
Other	236 (1.8)	258 (2.0)	0.92 (0.77-1.09)	0.33
*Uncorrected p-value

Safety

More patients were withdrawn due to adverse events with ER niacin/laropiprant than placebo (25.4% versus 16.6%, p<0.0001). There were significant excesses in serious adverse events relating to diabetes complications, gastrointestinal and musculoskeletal symptoms, skin, bleeding and infection (Table 3). Notably there was more than 4-fold increase in myopathy with ER niacin/laropiprant compared with statin alone. This was especially problematic in Chinese patients (absolute excess risk of any myopathy 0.53% per year with ER niacin/laropiprant versus 0.03% per year with statin alone).

Table 3. Summary of serious adverse events in HPS2-THRIVE

Serious adverse event (SAE)	ER niacin/ laropiprant	Placebo	Risk ratio (95% CI)	p-value
Any diabetes complication	11.1%	7.5%	1.55 (1.34-1.78)	<0.0001
New-onset diabetes	9.1%	7.3%	1.27 (1.14-1.41)	<0.0001
Gastrointestinal SAE	4.8%	3.8%	1.28 (1.13-1.44)	<0.0001
Musculoskeletal SAE	3.7%	3.0%	1.26 (1.10-1.44)	0.0008
Skin SAE	0.7%	0.4%	1.67 (1.20-2.34)	0.0026
Infection SAE	8.0%	6.6%	1.22 (1.12-1.34)	<0.0001
Bleeding SAE	2.5%	1.9%	1.38 (1.17-1.62)	0.0002

Author's conclusion

The results of the study were very clear in showing no worthwhile benefit on top of significant harms with ER niacin/laropiprant in high-risk statin-treated patients.
These findings, consistent with other trials, highlight the need to re-consider the role of ER niacin for the treatment and prevention of cardiovascular disease.

COMMENT

The Residual Risk Reduction Initiative (R3i) has already highlighted the need to manage the residual risk of cardiovascular events persisting in high-risk patients despite best evidence-based treatment.1 Niacin has been proposed as a possibility for combination with a statin, based on its broad spectrum of lipid-modifying activity, including lowering of elevated triglycerides and raising low plasma levels of high-density lipoprotein cholesterol (HDL-C). Indeed, imaging trials have shown that niacin stabilises or even regresses atherosclerosis in high-risk statin-treated patients.2-4

However, the results of HPS2-THRIVE are consistent with AIM-HIGH in failing to show benefit on clinical outcomes with the combination of niacin plus statin in high-risk patients with well-controlled LDL-C levels (median of 74 mg/dL or 1.91 mmol/L in AIM-HIGH and mean of 63 mg/dL or 1.64 mmol/L in HPS2-THRIVE). Some have argued that AIM-HIGH had methodological issues which may have compromised the study, including the incorporation of a low dose of niacin in the placebo (equating to 200 mg day in patients on 2 g of placebo) to maintain the study blind. This had the effect of raising HDL-C levels in both placebo and niacin-treated groups, thereby reducing the statistical power of the study to detect any potential benefit and/or harm.5 In contrast, HPS2-THRIVE was adequately powered; the average lipid changes over the course of the study (decreases of 10 mg/dL in LDL-C and 33 mg/dL in triglycerides and an increase of 6 mg/dL in HDL-C) were anticipated to translate to a 10-15% reduction in major vascular events.

HPS2-THRIVE population was a well-treated group for LDL-C, HDL-C (> 40 mg/dL or 1.0 mmol/L) and triglycerides (<150 mg/dL or 1.7 mmol/L) at baseline. It is worth emphasising that these patients did not have atherogenic dyslipidemia, an important driver of cardiovascular risk at all LDL-C levels.6 Indeed, in routine clinical practice, it is highly unlikely that such patients would have been prescribed niacin.

Where data are available for AIM-HIGH, the signals for adverse events in both AIM-HIGH and HPS2-THRIVE were consistent. Both studies showed an increase in stroke (ischemic stroke in AIM-HIGH, hemorrhagic stroke in HPS2-THRIVE), gastrointestinal side effects, and elevated blood glucose (consistent with an increase in new-onset diabetes) with niacin (±laropiprant). While it has been suggested that the safety issues in HPS2-THRIVE may be in part due to laropiprant, which attenuates niacin-associated flushing, this cannot be addressed in the absence of comparator arms for niacin or laropiprant monotherapy. Taken together, risk/benefit analysis based on data from both studies suggest that niacin is not an option for combination with a statin in high-risk patients, including those with insulin resistance and/or (pre)diabetes.

In conclusion, data from clinical trials with niacin imply that it is not suitable for combination with a statin in patients at high-risk of cardiovascular disease. The studies clearly reinforce the view of the R3i that other options are urgently needed to manage the high residual cardiovascular risk that persists in such patients.

References

1. Fruchart JC, Sacks FM, Hermans MP et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidaemic patient. Diab Vasc Dis Res 2008;5:319-35.
2. Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA. 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;110:3512-7.
3. Taylor AJ, Villines TC, Stanek EJ et al. Extended-release niacin or ezetimibe and carotid intima-media thickness. N Engl J Med 2009;361:2113−22.
4. Lee JM, Robson MD, Yu LM et al. Effects of high-dose modified-release nicotinic acid on atherosclerosis and vascular function: a randomized, placebo-controlled, magnetic resonance imaging study. J Am Coll Cardiol 2009;54:1787−94.
5. AIM HIGH Investigators. Boden WE, Probstfield JL, Anderson T et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011;365:2255-67.
6. Chapman MJ, Ginsberg HN, Amarenco P et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 2011;32:1345-61.