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Efficacy and Tolerability of PCSK9 Inhibitors by Patients with Muscle-related Statin Intolerance – New Cleveland Clinic study published in JAMA 4/2016

Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

Medical Interpretation of Study Results and the Pharmacological Treatment Context of PCSK9 Inhibitors

Author: Larry H. Bernstein, MD, FCAP 

The Rausse-3 Clinical Trial accompanied by editorial has been published in the Apr 3, 2016 issue of JAMA comparing toleration to and efficacy of Evolocumab vs Ezetimibe in patients with Statin-related muscle intolerance.

Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance – The GAUSS-3 Randomized Clinical Trial. SE Nissen, E Stroes, RE Dent-Acosta, et al. JAMA Apr 3, 2016 http://dx.doi.org:10.1001/jama.2016.3608

PCSK9 Inhibitors for Statin Intolerance? DD Waters, PY Hsue, S Bangalore. JAMA Apr 03, 2016. http://dx.doi.org:/10.1001/jama.2016.3670

The main conclusion is as follows:

The very long-term outcomes reported for early statin primary prevention trials^17,18are impressive. The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) randomized patients with hypertension and multiple risk factors to receive atorvastatin (10 mg daily) or to placebo and was stopped after a median follow-up of 3.3 years because of benefit.¹⁷  Approximately 8 years later, 11 years after randomization, total mortality, cardiovascular mortality, and noncardiovascular mortality were all significantly reduced in patients who had been in the statin group. Among patients with statin intolerance related to muscle-related adverse effects, the use of evolocumab compared with ezetimibe resulted in a significantly greater reduction in LDL-C levels after 24 weeks. Whether PCSK9 inhibitors will have the same impressive long-term outcomes will not be known for many years.

Importance  Muscle-related statin intolerance is reported by 5% to 20% of patients.

Objective  To identify patients with muscle symptoms confirmed by statin rechallenge and compare lipid-lowering efficacy for 2 nonstatin therapies, ezetimibe and evolocumab.

Design, Setting, and Participants  Two-stage randomized clinical trial including 511 adult patients with uncontrolled low-density lipoprotein cholesterol (LDL-C) levels and history of intolerance to 2 or more statins enrolled in 2013 and 2014 globally. Phase A used a 24-week crossover procedure with atorvastatin or placebo to identify patients having symptoms only with atorvastatin but not placebo. In phase B, after a 2-week washout, patients were randomized to ezetimibe or evolocumab for 24 weeks.

Interventions  Phase A: atorvastatin (20 mg) vs placebo. Phase B: randomization 2:1 to subcutaneous evolocumab (420 mg monthly) or oral ezetimibe (10 mg daily).

Main Outcome and Measures  Coprimary end points were the mean percent change in LDL-C level from baseline to the mean of weeks 22 and 24 levels and from baseline to week 24 levels.

Results  Of the 491 patients who entered phase A (mean age, 60.7 [SD, 10.2] years; 246 women [50.1%]; 170 with coronary heart disease [34.6%]; entry mean LDL-C level, 212.3 [SD, 67.9] mg/dL), muscle symptoms occurred in 209 of 491 (42.6%) while taking atorvastatin but not while taking placebo. Of these, 199 entered phase B, along with 19 who proceeded directly to phase B for elevated creatine kinase (N = 218, with 73 randomized to ezetimibe and 145 to evolocumab; entry mean LDL-C level, 219.9 [SD, 72] mg/dL). For the mean of weeks 22 and 24, LDL-C level with ezetimibe was 183.0 mg/dL; mean percent LDL-C change, −16.7% (95% CI, −20.5% to −12.9%), absolute change, −31.0 mg/dL and with evolocumab was 103.6 mg/dL; mean percent change, −54.5% (95% CI, −57.2% to −51.8%); absolute change, −106.8 mg/dL (P < .001). LDL-C level at week 24 with ezetimibe was 181.5 mg/dL; mean percent change, −16.7% (95% CI, −20.8% to −12.5%); absolute change, −31.2 mg/dL and with evolocumab was 104.1 mg/dL; mean percent change, −52.8% (95% CI, −55.8% to −49.8%); absolute change, −102.9 mg/dL (P < .001). For the mean of weeks 22 and 24, between-group difference in LDL-C was −37.8%; absolute difference, −75.8 mg/dL. For week 24, between-group difference in LDL-C was −36.1%; absolute difference, –71.7 mg/dL. Muscle symptoms were reported in 28.8% of ezetimibe-treated patients and 20.7% of evolocumab-treated patients (log-rank P = .17). Active study drug was stopped for muscle symptoms in 5 of 73 ezetimibe-treated patients (6.8%) and 1 of 145 evolocumab-treated patients (0.7%).

Conclusions and Relevance  Among patients with statin intolerance related to muscle-related adverse effects, the use of evolocumab compared with ezetimibe resulted in a significantly greater reduction in LDL-C levels after 24 weeks. Further studies are needed to assess long-term efficacy and safety.

Trial Registration  clinicaltrials.gov Identifier: NCT01984424

Background:

Administration of HMG-CoA reductase inhibitors (statins) to reduce levels of low-density lipoprotein cholesterol (LDL-C) represents an essential component of contemporary strategies to reduce morbidity and mortality from atherosclerotic vascular disease.¹ However, a significant proportion of patients with clinical indications for statin treatment report inability to tolerate evidence-based doses, most commonly because of muscle-related adverse effects.² These patients typically report muscle pain or weakness when treatment is initiated or dosage increased and relief when the drug is discontinued or the dosage reduced. Although some patients with statin-associated muscle symptoms experience marked elevation in serum creatine kinase (CK) levels, most do not. Accordingly, diagnosis of this disorder remains largely subjective, based on the presence of patient-reported symptoms.³ The incidence of similar symptoms in placebo-treated patients has resulted in skepticism about the true incidence of statin intolerance.

Patients with muscle-related intolerance often refuse to take statins despite elevated LDL-C levels and a high risk of major cardiovascular events. Current management may include very low or intermittent administration of statins or use of ezetimibe, but these strategies seldom achieve the greater than 50% reduction recommended by current guidelines.^1,4,5 Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors markedly lower LDL-C levels and have shown potential as an alternative therapy for patients who experience intolerable adverse effects during statin therapy.^6– 8 Currently available data suggest that muscle-related adverse effects are uncommon with PCSK9 inhibitors, even in patients with a history of such symptoms, but prior trials relied exclusively on medical history to document statin intolerance.

The GAUSS-3 (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects 3) trial was designed as a 2-stage randomized clinical trial to first identify patients with statin-induced muscle symptoms during a placebo-controlled statin rechallenge procedure and subsequently to compare the effectiveness and tolerability of 2 nonstatin therapies—ezetimibe or evolocumab, a recently approved PCSK9 inhibitor.

Figure 2.

Time to First Occurrence of a Muscle-Related Adverse Effect Resulting in Discontinuation of Study Drug During Period 1 and Period 2 of Phase A, GAUSS-3 Trial

Atorvastatin dose, 20 mg daily; placebo indicates matching placebo. GAUSS-3 indicates Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects 3

http://amaprod.silverchaircdn.com/data/Journals/JAMA/0/joi160031f2.png

The two curves compare phase 1 versus phase 2 with the first showing a separation at about day 60 and the second at about day 18. The hazard ratios are 1.34 vs 1.96 for cumulative event probability with p < 0.02 vs 0.001.

Lipid values at week 22 and week 24 during phase B are reported in the eTable in Supplement 3; the effect of ezetimibe and evolocumab on LDL-C levels during phase B is displayed graphically in Figure 3.
For the first coprimary end point, LDL-C level for the mean of weeks 22 and 24 was 183.0 mg/dL (95% CI, 167.4 to 198.6; least-squares mean percent change from baseline, −16.7% [95% CI, −20.5% to −12.9%]) for ezetimibe and 103.6 mg/dL (95% CI, 92.5 to 114.8; mean percent change, −54.5% [95% CI, −57.2% to −51.8%]) for evolocumab)—a mean difference of −37.8% (95% CI, −42.3% to −33.3%) (P < .001). For the other coprimary end point, LDL-C level at week 24 was 181.5 mg/dL (95% CI, 164.9 to 198.0; least-squares mean percent change from baseline, −16.7% [95% CI, −20.8% to −12.5%]) for ezetimibe and 104.1 mg/dL (95% CI, 92.4 to 115.7; mean percent change, −52.8% [95% CI, −55.8% to −49.8%]) for evolocumab—a mean difference of −36.1% (95% CI, –41.1% to –31.1%) (P < .001).

Figure 3.

Mean Percent Change in Low-Density Lipoprotein Cholesterol Level During Randomized Treatment With Ezetimibe or Evolocumab, GAUSS-3 Trial

Ezetimibe dose, 10 mg daily; evolocumab dose, 140 mg 3 times monthly (420 mg total dosage). GAUSS-3 indicates Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects 3. Error bars indicate 95% CIs.

http://amaprod.silverchaircdn.com/data/Journals/JAMA/0/joi160031f3.png

The first cosecondary end point, absolute change in LDL-C level for the mean of weeks 22 and 24, showed a least-squares mean change of −31.0 mg/dL (95% CI, −38.4 to −23.5) for ezetimibe and −106.8 mg/dL (95% CI, −112.2 to −101.4) for evolocumab—a mean difference of −75.8 mg/dL (95% CI, −84.7 to −67.0) (P < .001). The other cosecondary end point, absolute change in LDL-C level at week 24, showed a least-squares mean change of −31.2 mg/dL (95% CI, −39.2 to −23.3) for ezetimibe and −102.9 mg/dL (95% CI, −108.7 to −97.2) for evolocumab—a mean difference of −71.7 mg/dL (95% CI, −81.3 to −62.2) (P < .001).

Statin intolerance related to muscle symptoms represents a major unresolved challenge to the delivery of optimal cardiovascular care. The reported incidence of statin-associated muscle symptoms in observational studies ranges from 5% to 29% of treated patients, varying by statin and dose.² Often, despite multiple attempts to find a statin regimen acceptable to the patient, practitioners resort to less effective therapies. Alternative approaches typically include use of ezetimibe or administration of statins intermittently or at dosages below the approved starting dose.^4,5,12 These alternative therapeutic strategies provide less LDL-C reduction than recommended by current practice guidelines and result in higher LDL-C levels than most practitioners consider acceptable for optimal reduction of cardiovascular risk.

Both coprimary end points showed a 16.7% reduction with ezetimibe and a more than 50% reduction with evolocumab. These reductions in LDL-C levels are consistent with current labeling for both products. Despite very high baseline values, the LDL-C goal of less than 70 mg/dL was achieved in nearly 30% of evolocumab-treated patients and 1.4% of ezetimibe-treated patients (Table 3). The LDL-C reduction for both drugs was stable by 4 weeks and sustained during the course of the 24 weeks of treatment (Figure 3).

Because some patients cannot tolerate statins, the need for alternative LDL-C–lowering strategies in such patients is self-evident. Previous trials have suggested that PCSK9 inhibitors are effective at lowering LDL-C levels and well tolerated by patients with a history of statin-associated muscle symptoms.^6– 8  The studies did not use a placebo-controlled statin rechallenge procedure to identify the presence of statin intolerance.

To our knowledge, the GAUSS-3 trial represents the largest and most comprehensive study using a blinded rechallenge procedure to assess the ability of patients with a history of muscle-related adverse effects to tolerate statins. The trial provides insights into the time course of statin-associated muscle-related adverse effects. As shown in Figure 2A, initial randomization to either atorvastatin or placebo in phase A resulted in similar rates of muscle symptoms during the first 50 days, with a modest increase in occurrence with atorvastatin near the end of the 10-week exposure (HR, 1.34 [95% CI, 1.05 to 1.71]; P = .02). After crossover to period 2, larger numbers of patients experienced symptoms in the atorvastatin treatment group, with differences in event rates occurring relatively early (HR, 1.96 [95% CI, 1.44 to 2.66]; P < .001) (Figure 2B).

1

Stone  NJ, Robinson  JG, Lichtenstein  AH,  et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines.  2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(25, pt B):2889-2934.
PubMed   |  Link to Article

2

Stroes  ES, Thompson  PD, Corsini  A,  et al; European Atherosclerosis Society Consensus Panel.  Statin-associated muscle symptoms: impact on statin therapy—European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J. 2015;36(17):1012-1022.
PubMed   |  Link to Article

3

Zhang  H, Plutzky  J, Skentzos  S,  et al.  Discontinuation of statins in routine care settings: a cohort study. Ann Intern Med. 2013;158(7):526-534.
PubMed   |  Link to Article

4

Baigent  C, Blackwell  L, Emberson  J,  et al; Cholesterol Treatment Trialists’ (CTT) Collaboration.  Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670-1681.
PubMed   |  Link to Article

SOURCE

http://jama.jamanetwork.com/article.aspx?articleID=2511043

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