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 Table of Contents  
BOOKS AND TRIALS
Year : 2017  |  Volume : 6  |  Issue : 2  |  Page : 83-86

Recent landmark trials: From atherosclerosis imaging to lipid lowering


Department of Cardiology, Medanta-The Medicity, Gurgaon, Haryana, India

Date of Web Publication31-Mar-2017

Correspondence Address:
Manish Bansal
3rd Floor OPD, Medanta-The Medicity, Gurgaon-122 001, Haryana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JCPC.JCPC_12_17

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How to cite this article:
Wander GS, Bansal M. Recent landmark trials: From atherosclerosis imaging to lipid lowering. J Clin Prev Cardiol 2017;6:83-6

How to cite this URL:
Wander GS, Bansal M. Recent landmark trials: From atherosclerosis imaging to lipid lowering. J Clin Prev Cardiol [serial online] 2017 [cited 2020 May 25];6:83-6. Available from: http://www.jcpconline.org/text.asp?2017/6/2/83/203527



Elevated low-density lipoprotein cholesterol (LDL-C) level is a major risk factor for cardiovascular disease (CVD). Newer evidence has suggested that high-intensity statins are more efficacious than moderate-intensity statins in reducing cardiovascular (CV) events. However, despite the available evidence of efficacy, the usage of high-intensity statin therapy remains suboptimal, primarily because of concerns about the safety of high-intensity statin therapy. At the same time, even with the use of adequate dose statins, either alone or in combination with other lipid-lowering medications, many “at-risk” patients continue to have elevated levels of LDL-C. Hence, there is a need for not only improving statin usage but also for developing additional treatment options for incremental LDL-C lowering. Simultaneously, demonstrating that intense LDL-C lowering is not unsafe for health is required for ensuring effective LDL-C lowering in clinical practice.

While aggressive LDL-C lowering is essential to reduce CV risk, it is equally important to accurately identify the individuals who are most likely to benefit from such therapies. So far, the risk stratification for primary prevention of CVD has relied mainly on clinical risk algorithms such as Framingham risk score,[1],[2] American College of Cardiology/American Heart Association pooled cohort equations,[3] and QRISK.[4],[5],[6] However, the limitations of these conventional risk algorithms are also well recognized.[7] Assessment of subclinical atherosclerosis offers to overcome some of the limitations inherent in these conventional risk assessment tools.


  Coronary Artery Calcium Score Improves Coronary and Cardiovascular Risk Assessment above Statin Indication by European Society of Cardiology and American College of Cardiology/american Heart Association Primary Prevention Guidelines Top


Mahabadi AA, Möhlenkamp S, Lehmann N, Kälsch H, Dykun I, Pundt N, et al; Heinz Nixdorf Recall Study Investigators. J Am Coll Cardiol Imaging 2017;10:143-53.


  Trial Summary Top


Background:Although numerous studies have demonstrated the prognostic utility of coronary calcium score (CCS), its true place in decision-making for statin prescription for primary prevention of cardiovascular disease (CVD) remains uncertain.

Methods: CCS was measured between 2000 and 2003 in 3745 participants (59 ± 8 years of age, 47% men) from the population-based longitudinal Heinz Nixdorf Recall cohort study. The individuals were free from CVD at baseline and were not receiving any lipid-lowering therapy. Statin indication was determined per 2012 European Society of Cardiology (ESC) and 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines. The potential incremental value of CCS in predicting major adverse cardiovascular (CV) events was assessed in relation to statin indication at baseline.

Results: The ESC guideline recommended statin therapy in less number of individuals (34%) as compared to the ACC/AHA guideline (56%, P < 0.001). However, for both the guidelines, almost three-fifths of the individuals with statin indication had CCS <100 (59% for ESC and 62% for ACC/AHA). The overall incidence of hard CV events (myocardial infarction, stroke, and CV death) was 6.43% over a mean follow-up of 10.4 ± 2.0 years. CCS was able to stratify risk in individuals with and without statin indication per both the ESC and ACC/AHA guidelines. In patients without statin indication according to ESC recommendations, the CV event rates were 1.5 versus 8.7/1000 person-years for CCS 0 versus >100, respectively [Figure 1]. The event rates in patients with statin indication were 5.7 versus 17.4/1000 person-years, respectively. Similarly, when using the ACC/AHA recommendations, the event rates were 0.8 versus 6.5/1000 person-years in patients without statin indication and 5.4 versus 14.6/1000 person-years in those with statin indication. It was estimated that incorporating CCS in decision-making could significantly enhance the appropriateness of statin therapy while reducing the total number of individuals required to be treated.
Figure 1: Cardiovascular event rates stratified according to coronary calcium score in patients without and with statin indication per European Society of Cardiology and American Heart Association/American College of Cardiology guidelines

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Conclusions: CCS has the ability to match intensified risk factor modification to atherosclerotic plaque burden as well as actual risk while avoiding therapy in patients with low CV risk.


  Perspective Top


Primary prevention of CVD requires aggressive risk factor modification in individuals who are at high risk of developing CVD. However, accurate identification of the high-risk individuals remains a major challenge. Although the currently available risk assessment tools are able to predict CV risk at population level, their accuracy at individual level is suboptimal. Assessment of subclinical atherosclerosis has been proposed as one of the means to overcome this limitation. It is based on the premise that the evidence of ongoing atherosclerotic process identifies the individuals who are truly at risk of developing CVD regardless of the presence or absence of CV risk factors. Conversely, the lack of any evidence of atherosclerosis indicates low susceptibility to develop CVD, despite the presence of one or more CV risk factors.

CCS is currently the most robust measure of subclinical atherosclerosis with numerous studies demonstrating its excellent predictive value for future CV events. However, so far, there have been only limited data to show that a treatment strategy guided by CCS can reduce CV event rates better than the current practice of guiding management based on the risk estimates derived from clinical risk algorithms. In this context, a few pivotal studies have now been published that show potential incremental value of CCS in allowing matching of the intensity of the risk reduction strategy (especially statin therapy) with the actual CV risk.[8],[9],[10] The present study adds further weight to this growing body of evidence supporting the clinical utility of CCS. Together, these studies suggest that CCS should be assigned preeminence as an advanced risk stratification tool in participants requiring primary prevention of CVD, particularly in those perceived to be at 'intermediate risk' based on the conventional risk assessment tools.


  Association between Intensity of Statin Therapy and Mortality in Patients With Atherosclerotic Cardiovascular Disease Top


Rodriguez F, Maron DJ, Knowles JW, Virani SS, Lin S, Heidenreich PA. Association between intensity of statin therapy and mortality in patients with atherosclerotic cardiovascular disease. JAMA Cardiol 2017;2:47-54.


  Trial Summary Top


Background: All the current guidelines universally recommend high-intensity statin therapy for individuals with established atherosclerotic cardiovascular disease (ASCVD). Despite these recommendations, the usage of high-intensity therapy remains suboptimal due to lingering doubts about its incremental benefit over moderate-intensity statin therapy as well as concerns about side effects with high-dose statins.

Methods: The study involved a retrospective review of the medical records of 509,766 patients (mean age: 68.5 ± 8.8 years, 98.0% men) with ASCVD treated in the Veterans Affairs Health Care System from April 1, 2013, to April 1, 2014. The participants were eligible for inclusion in the study if (1) their records indicated a diagnosis of ASCVD on at least two separate occasions and (2) they had had a statin prescription filled during the preceding 6 months. Those who had received a higher dose of statin during the past 5 years than the dose received during the past 6 months were excluded on the assumption that intolerance might have been the reason for lowering of the statin dose. The primary outcome was all-cause mortality during a mean follow-up of 492 days.

Results: Of the total cohort, 29.6% were receiving high-intensity statin therapy, 45.6% moderate-intensity statin therapy, 6.7% low-intensity statin therapy, and 18.2% no statins. A graded association was found between the intensity of statin therapy and all-cause mortality, with 1-year mortality rates being 4.0%, 4.8%, 5.7%, and 6.6% in decreasing statin-dose categories (P < 0.001) [Figure 2]. The unadjusted hazard ratio for mortality was 0.82 (95% confidence interval [CI]: 0.80–0.84, P < 0.001) for those taking high-intensity statins versus those taking moderate-intensity statins. Propensity matching attenuated this benefit, but the difference still remained significant (hazard ratio” 0.91, 95% CI: 0.88–0.93). Even within the high-intensity statin therapy group, maximal statin dose was associated with a lower risk as compared to the submaximal doses (hazard ratio: 0.90, 95% CI: 0.87–0.94). The patients aged 76–84 years derived similar benefit (hazard ratio for comparison between high-intensity vs. moderate-intensity statin therapy was 0.91, 95% CI: 0.87–0.95) as those aged <76 years. In comparison to the moderate-intensity statin therapy, high-intensity statin therapy was not associated with any significant increase in new diagnosis of diabetes, admission for pulmonary disease, or admission for stroke.
Figure 2: One-year, unadjusted, all-cause mortality rates according to statin dose

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Conclusions: Compared with moderate-intensity statin therapy, high-intensity statin therapy was associated with a small but significant reduction in all-cause mortality. Even within the high-intensity statin therapy group, the maximal doses of statins were associated with a further survival benefit. The benefit was equally apparent in older adults also.


  Perspective Top


Although this was a retrospective analysis, this study provides compelling evidence that high-intensity statin therapy is associated with greater benefits in patients with ASCVD. The benefit is seen in very old individuals also. These findings suggest that there is a substantial opportunity for improvement in the secondary prevention of ASCVD through optimization of intensity of statin therapy.


  Safety of Very Low Low-density Lipoprotein Cholesterol Levels With Alirocumab: Pooled Data from Randomized Trials Top


Robinson JG, Rosenson RS, Farnier M, Chaudhari U, Sasiela WJ, Merlet L, et al. Safety of very low low-density lipoprotein cholesterol levels with alirocumab: Pooled data from randomized trials. J Am Coll Cardiol 2017;69:471-82.


  Trial Summary Top


Recent evidence suggests that reduction of low-density lipoprotein cholesterol (LDL-C) to very low values leads to further reduction in CV risk. New lipid-lowering drugs are known to decrease LDL-C levels to very low levels, but the safety of such low levels of LDL-C needs to be established.

Proprotein convertase subtilisin/kexin type 9 monoclonal antibodies can reduce LDL-C to very low levels when added to background lipid-lowering therapy. The safety of alirocumab was evaluated in patients with at least two consecutive LDL-C values <25 or <15 mg/dl in the ODYSSEY program. LDL-C values were considered as consecutive if > 21 days apart. Pooled data from 14 randomized Phase 2 and 3 studies (double-blind periods of 8–104 weeks) were evaluated, and individual-level analysis of patients with LDL-C <25 and <15 mg/dl was done.

Of the 4029 alirocumab-treated patients, 839 (25.1%) achieved 2 consecutive LDL-C values <25 mg/dl and 314 (9.4%) patients achieved 2 consecutive LDL-C values <15 mg/dl. Similar rates of adverse events occurred in patients achieving LDL-C <25 and <15 mg/dl (72.7% and 71.7%, respectively) compared with 76.6% in those who did not achieve LDL-C <25 mg/dl. Neurological and neurocognitive events were similar among the three groups. In a propensity score analysis, the rate of cataracts was higher in patients with LDL-C <25 mg/dl (2.6%) versus >25 mg/dl [0.8%; hazard ratio: 3.40, 95% confidence interval: 1.58–7.35]. However, no difference in cataract incidence was observed between pooled alirocumab and control groups.


  Perspective Top


Low levels of LDL-C (<25 mg/dl) appear to be generally well tolerated over 18 months of alirocumab therapy. LDL-C levels <25 or <15 mg/dl were not associated with an increase in overall treatment-emergent adverse event rates or neurocognitive events although cataract incidence appeared to be increased in the group achieving LDL-C levels <25 mg/dl.


  a Highly Durable Rna Interference Therapeutic Inhibitor of Proprotein Convertase Subtilisin/kexin Type 9 Top


Fitzgerald K, White S, Borodovsky A, Bettencourt BR, Strahs A, Clausen V, et al. A highly durable RNAi therapeutic inhibitor of PCSK9. N Engl J Med 2017;376:41-51.


  Trial Summary Top


Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is now well-established target for low-density lipoprotein cholesterol (LDL-C)-lowering therapy. It is a serine protease, which is expressed and secreted predominantly by the liver. It binds to LDL receptors both intracellularly and extracellularly and promotes the lysosomal degradation of these receptors in liver cells, thereby increasing the circulating LDL-C levels.

Inclisiran (ALN-PCSsc) is a long-acting RNA interference therapeutic agent that inhibits the synthesis of PCSK9. It binds intracellularly to the RNA-induced silencing complex enabling it to cleave messenger RNA molecules encoding PCSK9 specifically. The cleaved mRNA is degraded and thus unavailable for protein translation, which results in decreased levels of the PCSK9 protein.

In this Phase 1 trial, healthy volunteers with an LDL-C level of at least 100 mg/dl were randomly assigned in a 3:1 ratio to receive a subcutaneous injection of inclisiran or placebo in either a single ascending dose phase (at a dose of 25, 100, 300, 500, or 800 mg) or a multiple dose phase (125 mg weekly for four doses, 250 mg every other week for two doses, or 300 or 500 mg monthly for two doses), with or without concurrent statin therapy. Each dose cohort included four to eight participants. Safety, side effect profile, and pharmacodynamic measures were evaluated.

The most common adverse events were cough, musculoskeletal pain, nasopharyngitis, headache, back pain, and diarrhea. All the adverse events were mild or moderate in severity. There were no serious adverse events or discontinuations due to adverse events. In the single dose phase, inclisiran doses of 300 mg or more reduced the PCSK9 level up to 74.5% from baseline to day 84 and doses of 100 mg or more reduced the LDL-C level up to 50.6% from baseline. Reductions in the levels of PCSK9 and LDL-C were maintained at day 180 for doses of 300 mg or more. All multiple-dose regimens reduced the levels of PCSK9 by up to 83.8% from baseline to day 84 and LDL-C up to 59.7% from baseline to day 84.


  Perspective Top


A new LDL-C-lowering drug inclisiran has been found to have no serious adverse events in Phase 1 trial. Doses of 300 mg or more (in single or multiple doses) significantly reduced levels of PCSK9 and LDL-C for at least 6 months.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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2.
D'Agostino RB Sr., Vasan RS, Pencina MJ, Wolf PA, Cobain M, Massaro JM, et al. General cardiovascular risk profile for use in primary care: The Framingham Heart Study. Circulation 2008;117:743-53.  Back to cited text no. 2
    
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Goff DC Jr., Lloyd-Jones DM, Bennett G, Coady S, D'Agostino RB, Gibbons R, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: A report of the American College of Cardiology/American Heart Association task force on practice guidelines. Circulation 2014;129 25 Suppl 2:S49-73.  Back to cited text no. 3
    
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Hippisley-Cox J, Coupland C, Vinogradova Y, Robson J, Minhas R, Sheikh A, et al. Predicting cardiovascular risk in England and Wales: Prospective derivation and validation of QRISK2. BMJ 2008;336:1475-82.  Back to cited text no. 4
    
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Hippisley-Cox J, Coupland C, Vinogradova Y, Robson J, May M, Brindle P. Derivation and validation of QRISK, a new cardiovascular disease risk score for the United Kingdom: Prospective open cohort study. BMJ 2007;335:136.  Back to cited text no. 5
    
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Hippisley-Cox J, Coupland C, Vinogradova Y, Robson J, Brindle P. Performance of the QRISK cardiovascular risk prediction algorithm in an independent UK sample of patients from general practice: A validation study. Heart 2008;94:34-9.  Back to cited text no. 6
    
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Bansal M, Mehrotra R, Kasliwal RR. Cardiovascular risk stratification in Indians. J Clin Prev Cardiol 2015;4:7-17.  Back to cited text no. 7
    
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Nasir K, Bittencourt MS, Blaha MJ, Blankstein R, Agatson AS, Rivera JJ, et al. Implications of coronary artery calcium testing among statin candidates according to American College of Cardiology/American Heart Association cholesterol management guidelines: MESA (multi-ethnic study of atherosclerosis). J Am Coll Cardiol 2015;66:1657-68.  Back to cited text no. 8
    
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Mortensen MB, Fuster V, Muntendam P, Mehran R, Baber U, Sartori S, et al. A Simple disease-guided approach to personalize ACC/AHA-recommended statin allocation in elderly people: The BioImage Study. J Am Coll Cardiol 2016;68:881-91.  Back to cited text no. 9
    
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Pursnani A, Massaro JM, D'Agostino RB Sr., O'Donnell CJ, Hoffmann U. Guideline-based statin eligibility, coronary artery calcification, and cardiovascular events. JAMA 2015;314:134-41.  Back to cited text no. 10
    


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