From High-Risk Dyslipidemia to CV Disease: It’s Time to ...Walid Amara, MD Scientific Director, WebMD Global, LLC ... CV causes, major coronary event, or nonfatal stroke) being reduced

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From High-Risk Dyslipidemia to CV Disease: It’s Time toImprove Management


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From High-Risk Dyslipidemia to CV Disease: It’s Time to Improve Management

Target AudienceThis educational activity is intended for an international audience of Asia-Pacific healthcare professionals, specifically cardiologists, diabetologists, endocrinologists, and primary care physicians involved in the management of patients with high-risk dyslipidemia.

GoalThe goal of this activity is to present new data on available and upcoming treatments for high-risk dyslipidemia and to improve physicians’ education regarding the management of patients with high cardiovascular risk.

Learning ObjectivesUpon completion of this activity, participants will:

• Have increased knowledge regarding the

– Impact of dyslipidemia on cardiovascular events

– Latest clinical data on new lipid-lowering therapies, including proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors, in patients with high-risk dyslipidemia, and particularly, familial hypercholesterolemia

• Have greater competence related to

– The interpretation of statistics in clinical trials

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Posted: 11/9/2017

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Disclosures

FacultyJunya Ako, MDProfessor and Chairman, Department of Cardiovascular Medicine, Kitasato University, Sagamihara, Kanagawa, Japan

Disclosure: Junya Ako, MD, has disclosed the following relevant financial relationships:

Served as a speaker or a member of a speakers bureau for: Abbott Vascular; Actelion Pharmaceuticals, Ltd; Amgen Inc.; Astellas Pharma, Inc.; AstraZeneca; Boehringer Ingelheim Pharmaceuticals, Inc.; Bristol-Myers Squibb Company; Eisai Co., Ltd; JIMRO; Kaneka; Kyowa Hakko Kirin Co., Ltd.; Merck Sharp & Dohme Corp.; Mitsubishi Tanabe Pharma Corporation; Mochida; Ono Pharmaceutical Co., Ltd.; Pfizer Inc.; Sanofi; Shionogi & Co., Ltd.; St. Jude Medical; Sumitomo Dainippon Pharma; Takeda; Terumo Medical Corporation; Toa Eiyo; Volcano Corporation

Received grants for clinical research from: Abbott Vascular; Asahi Intec; Astellas Pharma, Inc.; AstraZeneca; Bayer HealthCare; Boehringer Ingelheim Pharmaceuticals, Inc.; Bristol-Myers Squibb Company; Daiichi Sankyo, Inc.; Eisai Co., Ltd; Japan Lifeline; Kowa Company Ltd.; Kyowa Hakko Kirin Co., Ltd.; Mediphysics; Mitsubishi Tanabe Pharma Corporation; Mochida; Ono Pharmaceutical Co., Ltd.; Otsuka Pharmaceutical Co., Ltd.; Pfizer Inc.; Sumitomo Dainippon Pharma; Takeda; Teijin

David K. L. Quek, MBBS, FRCP, FESC, FACCSenior Consultant Cardiologist, Pantai Hospital Kuala Lumpur, Kuala Lumpur, Malaysia

Disclosure: David K. L. Quek, MBBS, FRCP, FESC, FACC, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Amgen Inc.; Menarini; Merck & Co., Inc.; Sanofi; Zuellig Pharma

Served as a speaker or a member of a speakers bureau for: Menarini; Merck & Co., Inc.; Pfizer Inc.; Sanofi; SERVIER

Tan Ru San, MBBS, MRCPSenior Consultant, National Heart Centre Singapore, Singapore

Disclosure: Tan Ru San, MBBS, MRCP, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Amgen Inc.; Merck Sharp & Dohme Corp.

Served as a speaker or a member of a speakers bureau for: AstraZeneca

Khung Keong Yeo, MBBSAssociate Professor (Adjunct); Senior Consultant Cardiologist, Department of Cardiology, National Heart Centre Singapore, Singapore

Disclosure: Khung Keong Yeo, MBBS, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Boston Scientific

Served as a speaker or a member of a speakers bureau for: Abbott Vascular; Amgen Inc.

Received grants for clinical research from: Medtronic, Inc.

Other: Abbott Vascular (Proctor)


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Editor

Walid Amara, MDScientific Director, WebMD Global, LLC

Disclosure: Walid Amara, MD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: BIOTRONIK; Servier

Served as a speaker or a member of a speakers bureau for: Bayer HealthCare Pharmaceuticals; Boehringer Ingelheim Pharmaceuticals, Inc.; Boston Scientific; Bristol-Myers Squibb Company; Daiichi Sankyo, Inc.; Livanova; MEDA; Medtronic, Inc.; MSD; Novartis; Pfizer Inc.; Physiomed; St. Jude, Servier

Content Reviewer

Robert Morris, PharmDAssociate CME Clinical Director

Disclosure: Robert Morris, PharmD, has disclosed no relevant financial relationships.

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Khung Keong Yeo, MBBS: Hello, I am Khung Keong Yeo. I am a Senior Consultant Cardiologist at the National Heart Center, Singapore. Welcome to this presentation titled “New Available Therapeutic Data in High-Risk Dyslipidemia”.

New Available Therapeutic Data in High-Risk Dyslipidemia

The goal of lipid-lowering therapies for patients with coronary artery disease (CAD) is to prevent cardiovascular (CV) events, including myocardial infarction (MI), CV death and total death. Statins reduce CV events and mortality in these patients. Many of our patients whom we treat with statin therapy continue to have LDL levels that are still not optimally controlled. We know that the older guidelines recommended achieving a low-density lipoprotein cholesterol (LDL-C) level of <100 mg/dL and in high-risk patients, such as those with diabetes, <70 mg/dL.

Of course, these guidelines have changes somewhat with time and now the target is based on the initial baseline LDL-C level. Despite that, many of our patients remain sub-optimally controlled. We know that the lower the LDL-C levels are, the better our patients do, and we can reduce outcomes if we can get their LDL-C levels even lower. There is a need to reduce LDL-C levels.


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We know from literature that if we use high-dose statins, particularly the current generation of statins, whether it is atorvastatin at a high dose or rosuvastatin, we can potentially reduce LDL-C significantly and this does translate to CV outcomes including MI, repeat procedures, as well as other CV events including stroke.

We also know that the addition of other agents, such as ezetimibe, can also further reduce LDL-C levels.

In the IMPROVE-IT study, LDL-C was reduced from 70 mg/dL in the placebo arm to 54 mg/dL in the treatment group. This significant reduction of LDL-C translates to some degree of clinical improvement with the primary efficacy endpoint (death from CV causes, major coronary event, or nonfatal stroke) being reduced by about 2% in absolute terms.

We have now these two major agents in our armamentarium, largely the statins and in patients who need it, ezetimibe. Other agents, such as fenofibrate, have also been shown to help from a lipid-lowering perspective. Despite these agents, there is still a need. Some patients, despite being on optimal doses of statins, even if you include ezetimibe, remain non-optimally controlled.

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We are delighted that, most recently, at the American College of Cardiology meeting, the FOURIER trial showed results that demonstrated the value of a new class of agents, the PCSK9 inhibitors. The FOURIER trial studied evolocumab, which is a recombinant agent, which target the PCSK9 target. This study included almost 27,000 patients, with a follow-up period of 2.2 years. Evolocumab, in the FOURIER trial, was associated with a relative reduction of 59% of LDL-C. This was associated with an improvement of clinical outcomes.

The main primary efficacy outcome is a composite of cumulative incidence of CV death, MI, stroke, hospitalization for unstable angina and/or coronary revascularization. This reduction in LDL-C was associated with a significant reduction in the primary efficacy criteria. This demonstrates that a reduction in LDL beyond the usual target is associated with a further reduction in CV events


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The breakdown of the specific components of the primary endpoint shows that there was a reduction in MI, stroke, and coronary revascularization in the treatment arm. There was no statistical significant difference in the rates of CV death or all-cause mortality. We note that in other trials such as the PROVE IT trial, this was also not shown. I suspect that this is largely due to the duration of follow-up and, the fact that with very aggressive statin therapy, it is very hard to demonstrate any further reduction in mortality in the number of patients that we have in this particular study.

SPIRE-1 and SPIRE-2: Confirmation of Attenuation in LDL-C Reduction Over Time[4]

Another monoclonal antibody that has been created to target the PCSK9 molecular target is bococizumab.

The studies, related to this agent, were also released at the American College of Cardiology Meeting in 2017. These were the SPIRE-I and SPIRE-II studies.

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Unfortunately, although there was some benefit, as you can see from the slides, in terms of LDL reduction in both SPIRE-I and SPIRE-II, the results of LDL-C reduction were not able to persist with time. This was largely due to the fact that there was a murine component of the antibody and this is likely to provoke an immune response that weakens the efficacy of this drug. As I understand, Pfizer has withdrawn further development of this drug, which highlights the difficulty in developing new molecular agents to treat this particular target.

SPIRE-1 did not achieve its primary prespecified outcome; SPIRE-2 did. The combined data only showed a trend toward meeting the primary outcome

In addition, SPIRE-I and SPIRE-II did show some concerns regarding the adverse event rates. There was an increase in injection site reactions on bococizumab (10.4%), as well as more drug discontinuations because of serious adverse events (AEs).


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Now, the other drug that is being evaluated is alirocumab. Alirocumab has been studied in the ODYSSEY long-term trial and we were glad to see that this particular drug also showed a significant reduction in LDL-C levels of approximately 60%.

Although the trial was not powered to evaluate an effect on CV outcomes, in the subgroup analysis a reduction in CV events has been noticed, in this cohort of 2300 patients.

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We are awaiting the long-term results of the ODYSSEY outcome study, which, hopefully, will be presented soon and this will tell us whether or not alirocumab is also associated with improvements in clinical outcomes.

Now, we know that these new agents, evolocumab, alirocumab, are or will be available, hopefully, in the near future for treatment of patients with high LDL-C despite adequate statin therapy. What is our perspective on how we can treat these patients? I think, from a clinician standpoint, as these are new drugs and because of the cost associated with these drugs, we should be very mindful of the appropriate patients we should treat.

The American Association of Clinical Endocrinologists have put up a statement saying that in extreme risk patients, we should target LDL-C <55 mg/dL. I think that is a good starting point. I am not sure whether 55 or 60 or 45 would be ideal, but I think the point is to be as aggressive as we can. In that particular statement, they have targeted patients who continue to have myocardial events, whether it is infarction or unstable angina, despite adequate statin therapy, despite an LDL less than 70 mg/dL. I think that we should consider the use of these new agents in those patients who are already maximally treated and who continue to have events.


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In patients with familial hypercholesterolemia who do not tolerate statins, I would certainly consider this entire class of drugs as a therapy in order to prevent events. There is a group of patients that I think are at a very high risk and these are the patients who have diabetes, who continue to have events, and who also have a renal disease, particularly Stage 3 or 4 or higher stage renal failure.

Of course, to be sure, it will be ideal to have more data. I will be looking out for the studies coming out to show additional benefits in these patients.

I would like to summarize with the following points.

First of all, I think we have seen from numerous sets of data that LDL reduction is critical. It helps prevent coronary events and that, in practice, I still use the original guidelines in which we target an LDL of less than 70 mg/dL for high-risk patients such as those with diabetes and less than 100 for other less high-risk patients. This is despite the fact that I know there are guidelines that now advocate a different strategy for targeting LDL.

We know that despite adequate statin therapy, LDL-C may not be adequately controlled and, therefore, there is a place for a new class of agents that have since entered the market, the PCSK9 inhibitors. These agents do demonstrate a strong reduction in LDL-C levels. The FOURIER trial demonstrated a significant reduction of CV events with evolocumab, and we are waiting to see whether the ongoing ODYSSEY outcome study will show us similar findings.

I think in our Asian experience, in patients at high CV risk, we should also consider the use of these agents if they remain inadequately controlled despite optimal and high-dose statin therapy.

Thank you very much for participating in this Medscape activity. Please continue to follow the other video presentations.

Thank you.

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Atherosclerosis and High-Risk Dyslipidemia: Disease Burden in Asia Pacific and Unmet Needs

Junya Ako, MD: Hello, I am Junya Ako. I am Professor and Chairman of the Department of Cardiovascular Medicine in Kitasato University, Kanagawa, Japan. Welcome to this presentation titled “Atherosclerosis and High-Risk Dyslipidemia: Disease Burden in Asia-Pacific and Unmet Needs”.

Atherosclerosis is now an Asian disease. CV disease, including coronary heart disease (CHD), is now increasing in number of Asian countries. Especially, the Incidence rate of stroke is much higher in Asian countries compared with European or American countries.


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Higher cholesterol level is associated with higher incidence of CHD in Asian people.

There is no clear trend in hemorrhagic stroke related to serum cholesterol level. There is a clear association between increased rate of stroke and increased serum cholesterol level.

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This is an old study from Japan. This compared CHD incidence in Japanese patients and Japanese people immigrated into America. There is a higher incidence of CHD in people in San Francisco as compared with Japan, and there is an increase in serum cholesterol level in those Japanese-American people living in San Francisco as compared with Japanese people. In Japanese-American people living in Hawaii, the CHD incidence was somewhere in between as serum cholesterol level was between the level of the two other groups.

There is a trend toward decreased level of cholesterol in American patients; however, in the Japanese population, there is a steady increase in serum cholesterol level starting in the 1970s when Western diets were introduced in Japanese society. Now, the serum level of cholesterol is 213 mg/dL in Japanese men and 212 mg/dL in Japanese women and that exceeded the level of United States population.


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As for the treatment of serum cholesterol levels, there is a sub-optimal LDL-C goal attainment in Asian population.

In secondary prevention settings, there is a significant underuse of secondary prevention drugs in Asian people.

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We are conducting the EXPLORE-J registry. This registry includes 2000 patients with acute coronary syndrome (ACS). PCSK9 level and genetic testing for familial hypercholesterolemia (FH) are performed. In every patient, Achilles tendon thickness (ATT) is measured using x-ray. The objectives are to clarify the lipid management in these patients with ACS and the main secondary objective of this study is to identify familial hypercholesterolemia (FH) patients, among ACS patients.

In the EXPLORE-J registry, LDL-Cs levels were measured. In these patients in secondary prevention settings, LDL-C was >100 mg/dL in about half of the patients, which means that about half of the patients admitted for ACS in secondary prevention settings, has the cholesterol level which is not optimally treated.


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In Japanese guidelines, LDL levels, familial history of FH or familial history of early CV disease or xanthomas are considered to be the major components of FH. According to Japanese guidelines, about 3% of all patients fall into the category of FH. In younger patients, aged <55 years, about 6% are in this FH category.

There is a key message to primary care physicians. I think very high-risk patients of CV disease should be referred to specialists. In my opinion, patients with high LDL-C levels, with an early CV disease or with a family history of early CV disease or FH, or presenting signs of FH including xanthomas and Achilles tendon thickness, should be referred to a CV or lipid specialist.

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These are take-home messages. Dyslipidemia is an important modifiable risk factor for atherosclerosis diseases in Asia. Dyslipidemia is undertreated in Asians, and particularly FH is an underrecognized disorder. There is potentially a high prevalence of FH among ACS patients, the importance of family history taking and physical examination should be stressed.

Thank you for participating in this Medscape activity. Please continue to follow the other video presentations.


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Why Is It Important to Screen Asian Patients and to Reduce LDL Cholesterol?

David KL Quek, MBBS, FRCP, FESC, FACC: Hello. I am Dr David Quek. I am a Cardiologist at the Pantai Hospital in Kuala Lumpur, Malaysia and welcome to this presentation titled “Why Is It Important to Screen Asian Patients and To Reduce LDL Cholesterol?”.

Hypercholesterolemia is the critical risk factor associated with rising burden of vascular disease globally. Now, in the perspective studies collaboration, we know that ischemic heart disease mortality is related to the level of cholesterol.

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The higher cholesterol level you have, at whatever age group, you are more prone to have more ischemic heart disease mortality. When you are younger, the risk is very steep. At the same time, if you are able to reduce the level of cholesterol by even 1 mmol, at the youngest age group, you are going to achieve the best results, sometimes by as much as 56% of the risk.

The Asian-Pacific Cohort Studies showed essentially the same phenomenon. We are not different from Western cohorts. When you have hypertension, when you have associated high cholesterol levels, you will have higher risk for CHD as well as stroke. This is seen across the board. It is especially important in the younger age group where, if you are less than 70 years old, the curves for CHD, for ischemic stroke, for hemorrhagic stroke, are very steep compared to those who are above 70. There is no difference between being a man or a woman. Asians are not spared from atherosclerotic CV disease and elevated plasma cholesterol level is an important risk factor.

The World Health Organization (WHO) has actually this global database, which suggests that for Asians in particular, the disability-adjusted life years (DALY) lost due to CV disease in the Asia-Pacific region, as of 2005, may be more than 50% of the global numbers. This is an important phenomenon for us to address, as 50% of the world’s cardiovascular disease (CVD) disability is in the Asia Pacific region.


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The INTERHEART study has really looked at the levels of LDL as well as the apolipoprotein (Apo) B and ApoA1. This study demon-strated a very close linear relationship across the board from various areas from Northern, Eastern regions, South Indians, South Asians, and even from Hong Kong, China, as well as in Southeast Asia, and Japan.

The INTERHEART study showed that elevated LDL-C or a high ratio of apolipoprotein (Apo) B to ApoA1, which are the atherogenic particles involved, are associated with an increase in the risk of first acute MI.

If we look at the various strategies that have been proposed, we need to be able to risk stratify and evaluate our patients better, and see what are the best levels of LDL-C to target to, for the most optimal clinical outcomes.

Now, we have got the very good robust European guidelines, the European Association for Diabetes, and the American guidelines.

It is important to note that based on the starting LDL-C level, we need to set some goals for the reduction, if not in absolute numbers, at least by some set percentage. In here, we are most agreed that we need to reduce by at least 50% of the LDL-C from the baseline.

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Now, the American Expert Consensus Guidelines in 2016 has used these patient risk groups based on their assessment of atherosclerotic CV disease risk assessment above 7.5%, and above 10%.

One of the criticisms about these guidelines is that although they use a baseline LDL level, they have not proposed a target or goal-driven type of therapy; this has caused a little bit of confusion among Asians.


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2016 ESC/EAS Guidelines for the Management of Dyslipidemias[8]

Most Asians actually prefer the use of the 2016 ESC/EAS guidelines where various risk categories are very well defined. In patients with the highest CV risk, an LDL-C goal of <1.8 mmol/L is used. This gives a lot of confidence for the patients and the physicians to target to. At the same time for those with lesser risk, just with high CV risk, then the target can be a bit less at 2.6 mmol/L or below.

Now, we also know that, using statins alone, we may be able to achieve some control of the LDL-C, but it is not always that we can do so. We know from our experience that the various statins have various potencies. The Cochrane review, which is the largest meta-analysis that we have, included 25 major studies. The benefits of statins are very clear across the board on all-cause mortality, CV disease events, fatal/nonfatal coronary events, and stroke.

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In 2017, the American Association for Clinical Endocrinologists has gone a step further. The proposed reduction in LDL-C is <55 mg/dL or <1.4 mmol/L in patients with an extreme risk, particularly, patients with established clinical CV disease, with diabetes, chronic kidney disease and failure, heterozygous FH and also in those with a history of premature atherosclerotic cardiovascular disease.

The association of achieved LDL-C and major coronary events has been very well described. This is particularly important in the secondary prevention trials. In most of these meta-regression analyses, the use of statin and non-statin therapies, essentially by upregulating the LDL receptor expression, in order to reduce the LDL-C, is associated with very similar risk reductions of the major vascular events per change of LDL-C level.


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In the recent IMPROVE-IT study, a reduction in LDL cholesterol level from 70 mg/dL to 54 mg/dL was associated with a significant reduction in the primary and pre-specified secondary endpoints. This gives a lot of credence to the fact that whether you use a statin or you use another additional agent to help reduce the LDL cholesterol further, it is useful.

The FOURIER study showed that the LDL-C that can be low as 30 mg/dL or about 0.8 mmol/L is associated with better CV outcomes. There is much widening of the curves, as you can see both of the primary efficacy endpoint as well as for key secondary efficacy endpoints, and this tells you that it is very safe as well as very effective.

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How are Asians doing with regards to the LDL-C reduction? Are we managing our patients well enough? We have some patient data. We have the REALITY Asian Data that showed that most physicians do not change or uptitrate the dose of statin prescribed after the first visit. You can see that across the board from my own country, even in Malaysia, as many as 80% to 85% of patients were put on their first dose and the dose carries on forever.

Fifty-two percent of Asian patients at high CV risk did not achieve their consensus cholesterol treatment targets, particularly those with higher CV risk and also for those who we want to target LDL-C goes lower. Greater than 40% of patients who failed to achieve the target of LDL-C <100 mg/dL with the starting dose required 6% incremental LDL-C lowering to attain their goals. Fifty-six percent of patients whose statin doses were uptitrated failed to achieve their LDL-C targets.


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Fewer than 50% of patients achieve their LDL-C targets. These data indicate a need for more effective treatments to help more Asian patients achieve their guideline-recommended cholesterol treatment.

Only about half of the patients achieve LDL-C goals that we have set. For very high-risk categories, it would be as much as about 1 in 3 get their levels under control. This is on top of the varying regional and country differences, Hong Kong being better, but, across the board, you will find that most of the Asian countries do not achieve nearly as good targets as you would like them to be. This is on top of the widespread use of statin and also on use of additional therapies. You will find that only about 50% are able to achieve these targets.

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In conclusion, Asians are facing an epidemic increase in the incidence and prevalence of atherosclerotic CV disease, with higher stroke and MI rates. Half the global burden of disease is now occurring in the Asia-Pacific region. Lifestyles changes, increasing sedentary lifestyles, occupation, adoption of Western food habits, different adaptations towards metabolic syndromes might play important roles. The Asian risk profiles are not significantly different from the Western cohorts. The high LDL-C levels, high lipoprotein(a), a low HDL-cholesterol, widespread hypertension, high incidences of dysglycemic syndromes, and diabetes are important determinants and are still poorly recognized, managed, and treated.


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Younger patients are increasingly seen succumbing to premature episodes of fatal and nonfatal ACS and strokes. The treatment-to-target goals for LDL-cholesterol are still very suboptimal, so appropriate and aggressive statin doses with or without other LDL-lowering agents such ezetimibe or the newer PCSK9 inhibitors are needed to achieve this better, especially if the target LDL cholesterol cannot be achieved or when there are intolerable adverse side effects.

Very low LDL-C, even as low as 30 mg/dL or 0.8 mmol/L appears to be safe, but this needs to be assessed on a cost-benefit evaluation. Better commitment to guideline-determined management of atherosclerotic cardiovascular disease is critical to stem the epidemic of premature death and disability in Asia.

Thank you very much for participating in this Medscape activity. Please continue to follow the other video presentations.

Thank you.

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Interpreting Statistics in Outcome Trials

Tan Ru San, MBBS: Hello. I am Tan Ru San. I am a cardiologist from National Heart Center, Singapore. Welcome to today’s presentation titled “Interpreting Statistics in Outcome Trials”.

Trials that target endpoints like blood pressure lowering and sugar lowering, cannot directly answer questions about the impact of intervention on clinical outcomes. Randomized controlled trials, with hard clinical outcomes, are the gold standard for demonstration of the effectiveness of an intervention in reducing crucial and relevant morbidity and mortality events. In the arena of outcome clinical trials, the relevant outcomes include nonfatal MI, nonfatal stroke, and CV death. Outcome trials must be adequately powered. Outcome trials are indeed a huge investment of resources in order to advance scientific understanding of the intervention and also to, importantly, assess the clinical effect of the intervention.


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The most important thing to interpret in outcome trials is the primary outcome criteria. Depending on the clinical question involved, this is often a composite outcome, either of efficacy and/or safety outcome events. Importantly, the primary outcome must be precisely defined and it must bear the following characteristics. It must be clinically important, biologically plausible, ie, relevant to the mechanism of action, rational, conforming to established convention where applicable and adjudicated.

The reason why the primary outcome is so important is because it forms the crucial basis for statistical calculation of the number of subjects required to be recruited in a trial such that we minimize two types of errors. Type I error rate (α) or significance level is less than 0.05 (detection of a treatment effect that is not present). Power -- 1 minus type II error rate (β) -- is more than 80% or 90% (failure to detect a treatment effect that is present).

Secondary outcomes include all non-primary outcomes. They are never the basis for statistical calculation in the clinical trial. Frequently, in a well-designed clinical trial, there is a hierarchy of secondary outcomes. These may be, either composite outcomes or individual components of either the primary or secondary outcomes.

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Similar to the primary outcomes, the essential outcomes should preferably be clinically important, biologically plausible, rational, and adjudicated. There should also, in a good clinical trial design, be a prespecified hierarchical order of analysis. That is, we should only proceed to analyze what differences of secondary outcomes if the primary analysis was significant and, subsequently, at each level of the hierarchy, we should proceed only if there were significant levels at the preceding higher level and stop when significance becomes not present. All these analyses should prespecified.

If you perform a post hoc analysis, that is an analysis that is not prespecified in the protocol, you run the danger of risking a Type I error, which is the risk of finding a significant result when it is not there due to multiple statistical analyses. An adjustment, therefore, has to be made for multiple comparisons.

What constitutes a significant difference in the clinical trial and how do we interpret the results?

Classically, the statistical significance is achieved when the prespecified statistical significance for the observed difference in the primary outcome event is observed between the interventional and control groups. In the control group, the expected event risk is important to assess, a priori, the type of significance that we can achieve. This expected event control group is dependent on the risk profile of the subpopulations and is estimated from prior studies, which can include smaller trials or registry data, solely for the purpose of statistical power calculation in this large randomized control trial.

How do we interpret the key secondary outcome results and other outcome results? We should look at the results in totality and determine which components drove the primary outcome results. Was there heterogeneity among the different results? We shall examine this in a subsequent example. In addition, we can strengthen our interpretation results if there was evidence for biological plausibility, particularly, does the outcome results parallel the pharmacodynamic effect that we observe in the trial or is there collaborative mechanistic studies that support the results of the outcome trials? We shall look at examples of this later as well.


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In the example, we will look at the lipid-lowering trial, FOURIER. The trial included approximatively 27,000 patients with known atherosclerotic disease, prior MI, prior stroke, or prior peripheral vascular disease, and LDL levels above 70 mg/dL on statins. The median follow-up was 2.2 years. You may have known that from prior presentations that the lipid levels were reduced by an average of 60%.

This reduction in LDL-C was associated with a significant reduction in the primary efficacy criteria, which is the composite of MI, stroke, CV death, hospitalization for unstable angina, or coronary revascularization.

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Evolocumab was associated with a significant reduction in MI and stroke. There was no significant reduction in CV deaths and total deaths. One of the explanations is that in this contemporary trial, the rate of evidence-based pharmacotherapies use is very high and this lowers the CV mortality risk significantly compared with prior trials. For instance, the CV mortality rate in the FOURIER trial was much lower than that of prior secondary prevention trials, as much as 3 times lower than in the 4S trial. The FOURIER trial was not powered for CV mortality. The absent a finding of a CV mortality significant difference should not negate the results of the primary endpoint. For instance, if the power study sufficiently for CV mortality in FOURIER, it would need many more times the patients that is currently recruited, which is technically implausible.

The results are supported if there is a mechanistic study that supports the mechanisms of actions of the drug. The Glagov trial recruited about a thousand patients with known coronary disease and underwent intravascular ultrasound at baseline and after about 76 weeks. In this trial, in the treatment group, with statins and evolocumab, there was a significant reduction in plaque atheroma volume. Hence, there is a definitive demonstration of regression of coronary blood atherosclerosis and this can underpin the secondary atherosclerotic benefits that we see in the FOURIER trial.


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How about for the other PCSK9 inhibitors? The ODYSSEY study is a trial that was designed to look at the lipid-lowering effect of alirocumab after 6 months. Indeed, the trial reduced LDL-C levels by 60%. The post-hoc analyzed CV endpoints.

Although the trial was not powered to evaluate an effect on CV outcomes, a reduction in CV events has been noticed in a post-hoc analysis; However, because it was not specified in the protocol, this is considered post hoc, and runs the risk of type I errors; Therefore, the definitive demonstration of outcome benefits with alirocumab should await the results of the ODYSSEY outcome trials.

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In summary, in the FOURIER trial, the inhibition of PCSK9 with evolocumab to a very low level of LDL provides CV benefits. Patients with atherosclerotic disease will benefit from LDL lowering with this agent. The primary outcome was driven by significant reductions in nonfatal MI, nonfatal stroke, and coronary revascularization. There was no difference found for CV death and hospitalization for unstable angina, because the study was not powered for the detection of differences of CV death and all-cause death.

In the ODYSSEY long-term trial, alirocumab added to statin therapy reduced CV events; however, this is a post hoc analysis and, therefore, definitive evidence for outcome benefits await the results of the outcome study, ODYSSEY outcome trial.

The learning points for today are that outcome trials provide definitive evidence for the benefit of intervention. The prespecified primary outcome result is the key determinant of the success of treatment. Secondary outcomes add to the understanding of the primary outcome results; however, the absence of significant difference of secondary outcome should not negate the primary outcome results. Prespecified analyses are obligatory. Post hoc analyses incur the risk of Type I errors; that is, finding a result when it is not there. Baseline study population risk characteristic are important both for statistical power calculation as well as interpretation of the results.


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Abbreviationsα = type I errorβ = type II errorACC = American College of CardiologyACS = acute coronary syndromeAE = adverse eventAMI = acute myocardial infractionApo = apolipoproteinASCVD = atherosclerotic cardiovascular diseaseATT = Achilles tendon thicknessBSL = baselineCAD = coronary artery diseaseCHD = coronary heart diseaseCI = confidence intervalCKD = chronic kidney diseaseCV = cardiovascularCVD = cardiovascular diseaseD = dayDALY = disability-adjusted life yearDM = diabetes mellitusEAS = European Atherosclerosis SocietyESC = European Society of CardiologyFH = familial hypercholesterolemiaFHx = family historyFU = follow-upHbA1c = glycated hemoglobinHeFH = heterozygous familial hypercholesterolemiaHR = hazard ratioIQR = interquartile rangeITT = intention-to-treatIVUS = intra-vascular ultrasoundLDL = low-density lipoproteinLDL-C = low-density lipoprotein cholesterolLLT = lipid-lowering therapyMACE = major cardiovascular eventMI = myocardial infarctionNS = not significantOR = odds ratioP-Y = patient-yearPCP = primary care physicianPCSK9 = proprotein convertase subtilisin kexin 9Q2W = once every 2 weeksRCT = randomized clinical trialRR= relative riskSAE = serious adverse eventSBP = systolic blood pressureSC = subcutaneousSCS = significant carotid stenosisSD = standard deviationWHO = World Health Organization

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