Increased Risk of Adverse Neurocognitive Outcomes With Proprotein Convertase Subtilisin-Kexin Type 9 Inhibitors
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The researchers found the overall incidence of serious adverse events to be similar among studies.
But, when they only looked at the two large studies (ODYSSEY LONG TERM and OSLER), which accounted for about 65% of all patients, they found a more than twofold increase in incidence of neurocognitive events (odds ratio 2.81, 95% CI 1.32–5.99; P=0.007). These events included delirium (including confusion), cognitive and attention disorders and disturbances, dementia and amnestic conditions, disturbances in thinking and perception, and mental-impairment disorders.
The researchers pointed out that in all studies analyzed, neurocognitive events were self-reported and no study had information on baseline cognition in patients.
Among the research questions now, they write, are what the lower limit for LDL cholesterol should be and what subgroups of patients might be at greater risk for neurocognitive events.
Increased Risk of Adverse Neurocognitive Outcomes With Proprotein Convertase Subtilisin-Kexin Type 9 Inhibitors
Circ Cardiovasc QualOutcomes. 2017
Abdur Rahman Khan, Chirag Bavishi, Haris Riaz, Talha A. Farid, Sobia Khan, Michel Atlas, Glenn Hirsch, Sohail Ikram, Roberto Bolli
Background-There is encouraging evidence of the efficacy of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors; however, their long-term safety remains unclear. We performed a meta-analysis of studies to evaluate the long-term safety of PCSK9 inhibitors.
Methods and Results-Our search strategy yielded 11 studies (9 smaller early-phase and 2 larger outcome trials). The outcomes assessed were cumulative serious adverse events, musculoskeletal adverse events, neurocognitive adverse events, and stroke. Odds ratio (OR) was calculated using the Mantel–Haenszel method. Subgroup analysis was done to assess the difference in safety between the smaller early-phase studies and the larger outcome studies. Our meta-analysis suggested no difference in the incidence of serious adverse events (OR, 1.00; 95% confidence interval [CI], 0.88-1.15), musculoskeletal adverse events (OR, 1.01; 95% CI, 0.87-1.13), neurocognitive adverse events (OR, 1.29; 95% CI, 0.64-2.59), or stroke (OR, 1.44; 95% CI, 0.57-3.65) with the use of PCSK9 inhibitors. Subgroup analysis of the 2 large outcome studies did suggest an increased incidence of neurocognitive adverse events (OR, 2.85; 95% CI, 1.34-6.06) with the use of PCSK9 inhibitors. However, the overall incidence of neurocognitive adverse events and stroke was <1%, whereas the cumulative incidence of serious adverse events and musculoskeletal events was >10% in both the groups.
Conclusions-Our analysis suggests that PCSK9 inhibitors are not associated with an increased risk of cumulative severe adverse effects, musculoskeletal effects, or stroke. There is a signal toward adverse neurocognitive effects, seen in the outcome studies with a larger sample size and longer follow-up. There should be close monitoring, for the increased risk of neurocognitive events in the ongoing outcome studies and post-marketing surveillance.
WHAT IS KNOWN
⋅PCSK9 inhibitors have demonstrated marked reduction in LDL cholesterol levels.
⋅Initial evidence of impact on cardiovascular outcomes is encouraging with a signal toward improved outcomes
WHAT THE STUDY ADDS
⋅The initial studies with PCSK9 inhibitors were of small sample size and designed to establish lipid-lowering ability, and only 2 trials were designed to assess clinical outcomes and long-term safety.
⋅The cumulative incidence of adverse events (musculoskeletal, stroke) was low with PCSK9 inhibitors supporting their safety; however, there was a 2-fold increase in neurocognitive events shown in studies with a larger sample size.
⋅The current ongoing larger outcome studies will provide more definitive results on the incidence and severity of neurocognitive events and may shed some light on subgroups particularly predisposed to these events
Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors have generated considerable interest because of their potential for cardiovascular risk reduction based on substantial lowering of low-density-lipoprotein (LDL) cholesterol. PCSK9 inhibitors have been recently approved by the United States Food and Drug administration for use in adult patients with heterozygous familial hypercholesterolemia, homozygous familial hypercholesterolemia, or clinical atherosclerotic cardiovascular disease that requires additional lowering of LDL.
The evidence of LDL lowering has been used as a surrogate end point for cardiovascular outcomes in the studies with PCSK9 inhibitors. Several studies1–24 and their meta-analysis26 have demonstrated not only a marked decrease in LDL levels but also improvement in cardiovascular outcomes with PCSK9 inhibitors. There has been some suggestion of an increased risk of neurocognitive events with the use of PCSK9 inhibitors.27 Statins had also been postulated to be associated with neurocognitive effects because of their lipid-lowering ability. There is a biological plausibility in support of the argument that lipid lowering may have an impact on cognitive function regardless of the capability of the drug to cross the blood–brain barrier.28,29 However, high-quality evidence has not shown that lipid lowering achieved with statins leads to impaired cognitive function.30–34 However, the mean reduction of LDL cholesterol was ≈22% as reported in a Cochrane review, which was achieved by a moderate intensity statin.32 The effect on cognitive function of a much greater magnitude of lipid lowering achieved with PCSK9 inhibitors is still unclear. Given the clinical importance of these adverse events and their public health consequences, we performed a meta-analysis of randomized controlled trials to assess the safety of PCSK9 inhibitors.
Our meta-analysis suggests that the administration of PCSK9 inhibitors is not associated with an increased risk of cumulative SAEs, musculoskeletal adverse events, or stroke when compared with the current standard of care. However, we did find >2-fold increase in the incidence of neurocognitive events with PCSK9 inhibitors in a subgroup analysis of the larger outcome studies; ODYSSEY LONG TERM21 and OSLER.14 However, these were the only studies designed to assess clinical outcomes and long-term safety with a large sample size and longer duration of follow-up. If the outcome studies are reflective of improved cardiovascular outcomes with PCSK9 inhibitors,25 then their signal toward an increased risk of NCE is a cause for concern. Even though there is an overall low incidence of NCE (<1% in both the groups), these adverse events may have important public health implications with the expected increase in use of PCSK9 inhibitors and possible expansion of their indication. In a recent systematic review,25 Navarese et al25 found PCSK9 inhibitors to be effective with a reduction in all-cause mortality and cardiovascular outcomes; however, they did not evaluate safety parameters such as neurocognitive or stroke events. Our analysis expands on the previous review, by inclusion of relevant safety parameters such as neurocognitive or stroke events to help assess the safety of PCSK9 inhibitors.
Although our analysis shows a possibility of neurocognitive impairment with the use of PCSK9 inhibitors, there are some limitations to our analysis that negatively affect the evidence. First, the NCE were self-reported with no objective assessment of cognitive ability performed. Second, there was no information of the baseline cognition of the patients in the individual studies. In addition, there were differences in the population studied with regards to the magnitude of LDL lowering, which may have an effect on neurocognition. The evaluation of all these factors will only be possible in an individual patient data meta-analysis or by the ongoing large outcome studies. The United States Food and Drug administration is aware of the neurocognitive adverse events of these inhibitors and have advised the drug developers to gather data on these events.26
There are some other questions that also need to be answered before the widespread use of these monoclonal antibodies. With the extent of LDL lowering demonstrated by PCSK9 inhibitors, it needs to be established the lower limit to which LDL can be decreased without any impact on cognition. With the LDL levels reaching lower than 25 mg/dL, which is far lower than found in healthy neonates and native hunter-gatherers;39 the long-term effect on NCE is not known. However, one of the studies included in the analysis did not find an association of NCE with LDL levels even as low as 25 mg/dL.14 There is a possibility that not all patients develop NCE with PCSK9 inhibitors and high-risks subgroups need to be identified. Also the type of NCE occurring would be important, whether the events are relatively minor and reversible (such as confusion or temporary delirium) or relatively severe and persistent (such as dementia). With the current evidence, because of the relatively low incidence of NCE, we were unable to assess either the different types of NCE that occurred or subgroups that are at a higher risk for these events.
These unresolved questions and safety concerns will be addressed by the ongoing large outcome studies, ODYSSEY OUTCOMES40,41 and FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk),42 which are looking at long-term safety and efficacy of PCSK9 inhibitors. Moreover, an ongoing substudy of 4000 patients from the FOURIER42 would shed more light with objective assessment of NCE in patients without baseline dementia or mild cognitive impairment. These studies may be able to conclusively resolve the concerns on the safety of PCSK9 inhibitors.
PCSK9 inhibitors have considerable therapeutic potential, as shown by the marked LDL lowering and initial encouraging clinical outcomes. Our analysis suggests that PCSK9 inhibitors are not associated with an increased risk of cumulative severe adverse effects, musculoskeletal effects, or stroke. There is a signal toward adverse neurocognitive effects, seen in studies with a larger sample size and longer follow-up. There should be close monitoring, for the increased risk of neurocognitive events in the ongoing outcome studies and post-marketing surveillance.
Identification of Studies
After removal of duplicates, the literature search identified 2174 publications, of which 11 studies were eligible for our analysis10,14–21,23,24 (Figure 1). As we investigated long-term safety, studies with <6-month follow-up were excluded.1–13,22 However, these early studies were included in an open-label extension study to assess long-term outcomes of PCSK9 inhibitors (OSLER [Open-Label Study of 12 Early Phase 2–3 Trials]), which was included in our analysis.14 All included studies were published articles except one, which was presented at a scientific meeting as an abstract.20
A total of 11 studies14–24 comprising 10 656 (ranging from 103 to 2341 in individual trials) were included in the analysis. The studies were divided into 2 subgroups: early phase 2 to 3 studies with a small sample size15–20,22–24 mainly designed to assess safety and efficacy of LDL lowering and outcome trials (ODYSSEY [Long-Term Safety and Tolerability of Alirocumab in High Cardiovascular Risk Patients With Hypercholesterolemia Not Adequately Controlled With Their Lipid Modifying Therapy]21 and OSLER14) with a larger sample size designed to assess long-term cardiovascular events. ODYSSEY LONG TERM21 assessed the effect of alirocumab on long-term cardiovascular events, and OSLER14 was an extension study in which patients from the previous 12 phase 2/3 studies1–4,6,8,9,12,13 of evolocumab were randomized into 2 open-label trials. The 2 larger outcome studies constituted almost two thirds of the patients in the analysis. Seven trials included patients with unspecified hypercholesterolemia,15–18,22–24 2 trials had patients with heterozygous familial hypercholesterolemia,19,20 and 1 trial included patients with both hypercholesterolemia and heterozygous familial hypercholesterolemia.21 All patients had either coronary artery disease or coronary artery disease risk equivalent or were at high risk for coronary artery disease along with hypercholesterolemia. All trials except 216,22 studied patients on a background of lipid-lowering therapy. Tables 1 and 2 highlight the characteristics of the included studies and the patient populations in these studies.
The risk of bias in all included studies was determined to be low. All studies were of sound methodological quality, with adequate randomization reported in all trials. There was no allocation bias in any trial except 2; in one20 in which the risk was unclear and another one14 in which the risk was high because of the open-label nature of the trial. All assessments of outcomes measured were blinded, with a low risk of documented bias both for selection and for reported outcomes in all trials except one,14 in which the allocation and outcome were not blinded. The randomized controlled trials included in the analysis had a low risk of bias because of attrition during follow-up (Figure 2).
Serious Adverse Events
The incidence of SAE was 741 of 6760 (11.0%) among patients on PCSK9 inhibitors and 403 of 3896 (10.3%) among patients without PCSK9 inhibitors. The meta-analysis suggested no difference in the incidence of SAE with the use of PCSK9 inhibitors (OR, 1.00; 95% confidence interval [CI], 0.88-1.15; P=0.96). There was no between-study heterogeneity (P=0.94; I2=0%; P=0.2; Figure 3). There was no funnel plot asymmetry, and the Egger test also did not show any presence of publication bias (P=0.2; Figure I in the Data Supplement).
Subgroup analysis showed no difference in the risk of SAE between the early-phase studies (OR, 1.08; 95% CI, 0.85-1.36; P=0.53; I2=0%) and the outcome studies (OR, 0.97; 95% CI, 0.83-1.14; P=0.71; I2=0%; P=0.2; Figure 3).
The incidence of musculoskeletal adverse events was reported in 8 studies. There were 957 of 6760 (14.2%) events among patients on PCSK9 inhibitors and 494 of 3896 (12.7%) events among patients without PCSK9 inhibitors. The meta-analysis suggested no difference in the incidence of musculoskeletal adverse events with the use of PCSK9 inhibitors (OR, 1.01; 95% CI, 0.87-1.13; P=0.90). There was mild between-study heterogeneity (P=0.33; I2=13%; P=0.2; Figure 4). There was some suggestion of funnel plot asymmetry, but the Egger test also did not show any presence of publication bias (P=0.6; Figure II in the Data Supplement).
Subgroup analysis showed no difference in the risk of musculoskeletal adverse events between the early-phase studies (OR, 0.90; 95% CI, 0.71-1.14; P=0.37; I2=0%) and the outcome studies (OR, 1.07; 95% CI, 0.87-1.34; P=0.51; I2=56%; Figure 4).
Neurocognitive events were reported in 8 studies. These events included delirium (including confusion), cognitive and attention disorders and disturbances, dementia and amnestic conditions, disturbances in thinking and perception, and mental impairment disorders. The incidence of all reported neurocognitive events was 56 of 6760 (0.8%) among patients on PCSK9 inhibitors and 20 of 3896 (0.5%) among patients not on PCSK9 inhibitors. The meta-analysis suggested no difference in the incidence of neurocognitive events with the use of PCSK9 inhibitors (OR, 1.29; 95% CI, 0.64-2.59; P=0.47; I2=27%). There was a slight between-study heterogeneity (P=0.22; I2=27%; Figure 5). There was some funnel plot asymmetry and Egger test demonstrated the presence of publication bias (P=0.02; Figure III in the Data Supplement). There was no change in the adjusted odds ratio by the Trim and Fill method.
Subgroup analysis done to assess the effect of individual studies demonstrated that although there was no difference in the incidence of neurocognitive events with the early studies (OR, 0.69; 95% CI, 0.30-1.58; P=0.38; I2=0%), the outcome studies showed >2-fold increased incidence of neurocognitive adverse events (OR, 2.81; 95% CI, 1.32-5.99; P=0.007; I2=0%; Figure 5).
The incidence of stroke was 16 of 6760 (0.2%) among patients on PCSK9 inhibitors and 05 of 3896 (0.1%) among patients not on PCSK9 inhibitors. The meta-analysis suggested no difference in stoke risk between the 2 groups (OR, 1.44; 95% CI, 0.57-3.65; P=0.45; I2=0%). There was no between-study heterogeneity (P=0.82; I2=0%; Figure 6). There was no funnel plot asymmetry, and the Egger test also did not show any presence of publication bias (P=0.38; Figure IV in the Data Supplement).
Subgroup analysis revealed a numerically higher stroke events (13/3784 [0.3%]) among patients with PCSK9 inhibitors than among patients without PCSK9 inhibitors (03/2407 [0.1%]) in the outcome studies; however, it did not reach statistical significance (OR, 1.52; 95% CI, 0.49-4.71; P=0.47; I2=0%; Figure 6).