Inflammatory Biomarkers and Stroke Subtype

Didn't your competent? stroke doctor start using colchicine and canakinumab years ago? Or don't you have functioning stroke doctor? I'd run away from such incompetence!

AHA: Colchicine Prevents Postop Afib December 2011 

Could Old Gout Drug Offer New CV Benefits? November 2015 

Anti-inflammatory therapy for preventing stroke and other vascular events after ischaemic stroke or transient ischaemic attack November 2017

• canakinumab (5 posts to August 2012)

The latest here:

Inflammatory Biomarkers and Stroke Subtype

Seemant Chaturvedi, MD https://orcid.org/0000-0001-8660-7644, and Gian Marco De Marchis https://orcid.org/0000-0002-0342-9780Authors Info & Affiliations

January 23, 2024 issue

102 (2)

https://doi.org/10.1212/WNL.0000000000208098

 Abstract

• Disclosure
• Publication History
• References

• Information & Authors
• Metrics & Citations
• Get Access
• References
• 
  

• • Share

Abstract

Inflammation is an established pathway in the formation, growth, and rupture of atherosclerotic plaques. Inflammation is thus essential to the pathogenesis of coronary heart disease and some types of ischemic stroke.¹ The benefit of anti-inflammatory therapies, such as colchicine² and the anti-IL1β canakinumab,³ is proven in patients with coronary heart disease, yet it remains unproven for patients with ischemic stroke. Compared with coronary heart disease, the etiology of stroke is more heterogeneous. Besides arterio-arterial atherogenic embolism, possible etiologies are penetrator artery occlusion, cardioembolism, and other mechanisms. Finding a stroke etiology remains elusive in up to 30%–40% of patients despite a full evaluation. Understanding whether the stroke etiology modifies the association between inflammatory markers and recurrence risk is an important step to improve selection of patients for randomized trials on anti-inflammatory agents. IL-6 and high-sensitive CRP (hs-CRP) have been implicated in a higher recurrence risk after ischemic stroke by both an individual participant data meta-analysis⁴ and a Mendelian randomization study,⁵ but granular, in vivo results stratified by stroke etiology are lacking.

Get full access to this article

Atherosclerotic Plaque Disruption and Healing

If it ever occurs the final result of this research should provide interventions that make sure your plaque is the extinct version. What is your stroke hospital doing to ensure this research is followed up and creates protocols?

Atherosclerotic Plaque Disruption and Healing

As with geologists, cardiovascular researchers have long studied the mechanisms governing atherosclerotic plaque formation, disruption, and thrombosis (i.e. the ‘volcanoes’ eruption’), and the ascertained knowledge has guided our traditional approaches to atherosclerosis therapy. Yet the ability to predict plaque instability and the development of acute coronary syndrome (ACS) or sudden coronary death remains weak, suggesting that other potential pathogenic mechanisms should also be explored.²

In our review article recently published in the New England Journal of Medicine,³ we explored the hidden side of the moon: mechanisms of atherosclerotic plaque healing and their clinical and potential therapeutic implications. We know from historical pathology studies that healed plaques can be frequently found at the non-culprit coronary sites of patients dying from sudden cardiac death, and even in subjects dying from other causes.⁴ These plaques can be considered as ‘inactive volcanoes’ within the vasculature, either ‘extinct’ or ‘dormant’. By definition, an ‘extinct volcano’ is a volcano that has not erupted for at least 10 000 years and is not supposed to erupt again in the future, while a ‘dormant’ one is a volcano that is not erupting, but is expected to erupt again.¹

As with volcanoes, the healing process can either pacify the disrupted plaque so that it remains silent for the rest of the patient’s life, or instead, stabilize it for a variable time period before a new disruption occurs. Both pathology and in vivo imaging studies in fact suggest that atherosclerotic plaques may undergo multiple episodes of disruption and healing, and that accumulation of new granulation tissue may contribute to an increase in plaque burden and to progressive luminal narrowing.^4,5

Recent optical coherence tomography studies showed an association between the presence of healed coronary plaques and higher non-target lesion, ischaemia-driven revascularization rates, in the absence of acute events.⁶ These data confirm our original observation that patients with healed plaques are more likely to evolve towards a long-standing chronic coronary syndrome (CCS), while those without evidence of healed plaques more frequently experience a recurrence of ACS.⁵ These observations have led us to propose the ‘double hit’ theory of atherosclerosis as a possible explanation of the pathogenesis of ACS.^3,5,7 This is somewhat reminiscent of what happened in oncology where, after studying oncogenes for decades, it was discovered that half of all human cancers were prompted by a mutation in oncogene suppressor genes. In atherosclerosis, the first hit is the acute destabilization of an atherosclerotic plaque by either rupture or erosion, whereas the second hit is an impaired healing capacity.³

Why are these findings important for patients with ischaemic heart disease? Because they may help to better predict the natural history of coronary atherosclerosis and, most importantly, they may pave the way towards novel therapeutic strategies. While traditional therapies have focused almost exclusively on preventing atherosclerosis progression and on treating its acute thrombotic complications, new therapies may point strongly towards strategies of improving healing. Patients with an effective healing capacity seem to have more potent endogenous fibrinolytic and thrombolytic systems as well as polarization of inflammation towards a reparative phenotype, including the production of anti-inflammatory cytokines and the overexpression of alternative M2 macrophages.³

Therapeutic options might come from existing drugs as well as from novel agents. Intensive antithrombotic therapy has already proved effective in promoting healing of coronary plaque erosion,⁸ and the beneficial effects of aggressive lipid-lowering agents (e.g. high-dose statins, proprotein convertase subtilisin–kexin type 9 inhibitors) on plaque stabilization have been largely documented.³

Promising results may come from the use of anti-inflammatory agents, such as interleukin-1β antagonists (e.g. canakinumab) or low-dose colchicine.^9,10 Recently, low-dose colchicine has been demonstrated to significantly lower the risk of cardiovascular events in a randomized trial involving patients with CCS compared to placebo.¹⁰ Although the mechanisms behind this benefit have not been elucidated, they may be at least in part related to an improvement in a plaque healing capacity. Another intriguing approach may be the modulation of macrophage polarization towards a reparative phenotype through CD31-targeting molecules or epigenetic therapies, including DNA methylation, histone modifications, or modulation of microRNAs and long non-coding RNAs.³

In conclusion, although primary prevention and traditional therapies provide a key to stemming the worldwide spread of the atherosclerotic disease epidemic and its thrombotic complications, the recognition of the healing process as an active player, rather than an innocent bystander, in the pathogenesis of ischaemic heart disease may provide ground for novel treatment options. We must strive to move beyond the classic approach of focusing on the mechanisms of plaque instability only, and try to elucidate the hidden protective mechanisms, with the aim of converting ‘poor healers’ into ‘good healers’.

During the Second World War, Sir Winston Churchill stated: ‘Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning’. In the current era, we might be at the same turning point in the war against atherosclerosis. Promoting plaque healing in addition to preventing plaque disruption might considerably potentiate our armamentarium in the battle against cardiovascular diseases.

 

New drug beats heart disease by reducing inflammation

How much would this help in preventing stroke?
Hopefully you can use this off-label.  They would rather pay for your heart attack or stroke. 

New drug beats heart disease by reducing inflammation 

By Dr. Manny Alvarez, Fox News

About every 40 seconds, an American has a heart attack, and almost 15 percent of those heart attacks are fatal. As the leading cause of death in the U.S., heart disease has been the subject of thousands of studies in the last several decades, and breakthroughs in the last 50 years have been significant.

First, diet, exercise, and smoking cessation were all proven to play an enormous role in heart health, helping physicians guide patients to less risky lifestyle choices.

Then, in the 1980s, the first commercial statin was approved by the FDA, ushering in an era in which medication could be used alongside lifestyle changes to lower cholesterol levels, potentially reducing heart attack risk by over a third for some high risk patients.
STDS HIT RECORD HIGH IN US, 2M CASES REPORTED IN 2016
Despite these gains and the fact that statins are one of the most frequently prescribed drugs, heart disease is still the number one killer of Americans, but researchers are excited about the results of a study published last month in the New England Journal of Medicine that investigates the impact of a new drug on cardiovascular risk.
The trial is the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), and the drug, called Canakinumab, may be able to bring heart attack risk to an all-time low by targeting inflammation.
This study is the first in which a systemic anti-inflammatory, a drug that reduces inflammation throughout the body, has been shown to lower heart attack risk independent of cholesterol-lowering medications.
The purpose of the trial was to see whether reducing inflammation could reduce the risk of recurring cardiovascular events among people who had already had a heart attack and who had elevated levels of high sensitivity C-reactive protein (hsCRP), an indication of systemic inflammation.
The study was the culmination of more than 25 years of research. By treating all patients in the trial with standard care (high doses of statins) and then dividing them into groups that would receive either 50, 150, or 300 mg of Canakinumab (or a placebo), the researchers were able to accurately assess the impact of the new drug. More than 10,000 patients took part in the trial, some of whom were monitored for up to four years.

The results showed a 15 percent reduction in heart attacks and strokes for patients taking either 150 or 300 mg of the of Canakinumab, proving for the first time that inflammation plays a role in heart disease risk independent of cholesterol levels.
This discovery may change therapeutic practice for patients at high risk of heart attack or stroke. More studies are underway to establish the best strategies for using Canakinumab – which patients benefit most and how the drug can be used in combination with other therapies.
“These findings represent the end game of more than two decades of research, stemming from a critical observation: Half of heart attacks occur in people who do not have high cholesterol," Paul M. Ridker, M.D., the study's lead author, said. "For the first time, we’ve been able to definitively show that lowering inflammation independent of cholesterol reduces cardiovascular risk. This has far-reaching implications. It tells us that by leveraging an entirely new way to treat patients — targeting inflammation — we may be able to significantly improve outcomes for certain very high-risk populations.”
The need for invasive and expensive interventions, like bypass surgery and angioplasty, were reduced by more than 30 percent in patients taking Canakinumab, a far greater reduction than is usually found with the use of statins alone.

ESC: At Long Last, Inflammatory Hypothesis Confirmed in CVD by CANTOS Residual major CV event risk reduced by 15%

Since this is an orphan drug you better start saving your pennies, your insurance likely won't pay for it. They would rather pay for your heart attack or stroke. 
https://www.medpagetoday.com/MeetingCoverage/ESC/67529?xid=nl_mpt_DHE_2017-08-28&

• by Peggy Peck, Editor-in-Chief, MedPage Today August 27, 2017
• This article is a collaboration between MedPage Today® and:
  

Action Points

• Note that this large randomized trial demonstrated that the anti-IL-1 therapy canakinumab reduces the rate of myocardial infarction among those with prior MI and an elevated CRP.
• Be aware that deaths from infection were significantly more common in the canakinumab arm.

BARCELONA -- Long-awaited evidence that targeting an inflammatory pathway can reduce heart attacks and stroke independent of lipids is now in hand -- canakinumab (Ilaris) reduced events by 15% compared with placebo.
But there is a two-fold catch: Because canakinumab is an immunotherapy, the drug carries a high price tag and use was associated with an increased risk of fatal infections.
Canakinumab is a human monoclonal antibody that targets the interleukin-1beta innate immunity pathway and it is currently approved as an orphan drug for treatment of two rare pediatric conditions -- systemic juvenile idiopathic arthritis and cryopyrin-associated periodic syndromes for which it is administered monthly and carries an annual price tag of $200,000.
Thus, the reception was mixed: Anthony DeMaria, MD, of the University of California San Diego School of Medicine, called the results "really big because it is a totally new mechanism." But while Stanford cardiologist Robert Harrington, MD, agreed that CANTOS provides evidence to validate the inflammation hypothesis, he suggested it is too soon to strike up the band.
In the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), 150 mg of canakinumab every 3 months reduced high-sensitivity C-reactive protein (hs-CRP) levels by an average of 37% compared with placebo and achieved a 15% reduction in cardiovascular events -- mostly MIs -- compared with placebo, Paul Ridker, MD, reported here at the European Society of Cardiology 2017 congress.
The CANTOS findings were simultaneously published online by the New England Journal of Medicine.
After a median follow-up of 3.7 years, the event rate was 4.5 per 100 person-years in the placebo group versus 3.86 events per 100 person-years in the canakinumab 150 mg group. Two other arms -- canakinumab 50 mg and 300 mg -- also achieved reductions in events (4.11 and 3.90 per 100 person-years, respectively) but only the 150-mg dose achieved a statistically significant reduction. There was no reduction in mortality.
The trial recruited patients who had a history of MI and a hs-CRP level of 2.0 mg/L or higher.
Reflecting on the finding, Ridker told MedPage Today that he had spent roughly 25 years investigating "one fundamental question: Why do half of all heart attacks and strokes occur in people with no known risks?"
Click here for video comments from study authors of the ESC late-breaking trials, and discussions by leading cardiologists from around the world.
His timeline for proving the inflammation hypothesis began more than 20 years ago, "when we published the first paper that said if you checked an inflammatory marker, what we now call CRP, you could identify people at high risk for heart attacks ... 19 years ago we published a paper showing that statins reduced inflammation, and about 8 0r 9 years ago we published a paper that showed if you had high CRP and low LDL, you had better be on a statin.
And through that whole process the fundamental question we asked remained: Can we lower event rates by reducing inflammation?"
The answer, based on CANTOS, is yes, Ridker concluded.
Moreover, he noted that, although there was no cardiovascular mortality benefit, there was 30% reduction in need for bypass surgery, angioplasty, and heart failure -- all of which means a significant improvement in quality of life. And treatment was also associated with a reduction in gout, rheumatoid arthritis, and osteoarthritis, he said.
Interestingly, the treatment had no effect on lipids, which suggests that the benefit was all attributable to the anti-inflammatory activity. But Ridker added that the inflammatory hypothesis in no way competes with the lipid hypothesis. "I think statins are the miracle drugs of the century, and all of these patients [in CANTOS] were on aggressive statin therapy."
Cancer Benefit
And canakinumab treatment had yet another benefit: There was an apparent decrease in risk of cancer, a finding that was elucidated in a Lancet paper also published today. In the cancer analysis, also authored by Ridker, total cancer mortality was lower only in the 300-mg group, but "[i]ncident lung cancer (n=129) was significantly less frequent in the 150 mg (HR 0.61 [95% CI 0.39–0.97]; P=0.034) and 300 mg groups (HR 0.33 [95% CI 0.18–0.59] P<0.0001."
And now the bad: Canakinumab was associated with a higher incidence of fatal infection than placebo -- the rate was 0.18 in the 3,344 patient placebo group versus 0.32 among the 6,717 patients who received any dose of the drug, which worked out to 23 deaths vs 78 deaths (P=0.02).
There was no significant difference in all-cause mortality (HR for all canakinumab doses vs placebo, 0.94; 95% CI 0.83-1.06; P=0.31).
"Despite the scientific and clinical excitement associated with having a new mechanism of action to attack in the treatment of coronary artery disease," Harrington wrote, "a better understanding of the risks and benefits of this form of therapy is needed. Given that there was no observed effect on cardiovascular mortality in this trial, more information about the details of the myocardial infarctions (infarct size, Q-wave vs. non–Q-wave, and spontaneous or procedure-related) is needed to better assess the clinical benefit of canakinumab. We also need additional information about the fatal infections encountered in CANTOS. Furthermore, any discussion of the use of canakinumab in patients with a previous myocardial infarction must consider cost. Given monthly for approved indications, canakinumab is priced at approximately $200,000 per year in the United States. Such pricing may be suitable for rare diseases, but not for a common indication such as coronary artery disease, even if given every 3 months."
Price vs Benefit
Harrington is not the first to point out this difficulty with CANTOS -- on June 28 heart failure specialist Milton Packer, MD, wrote this in his MedPage Today blog: "My prediction: [canakinumab] may cost $64,000 for a 15-20% reduction in the risk of a major cardiovascular event, without decreasing cardiovascular death by itself.
"Is it worth it? If there was push back from payers for [evolocumab] Repatha, I can just imagine what will happen if Ilaris receives a cardiovascular indication."
Repatha is a PCSK9 inhibitor that aggressively lowers lipids and is approved for patients who fail statin therapy, including patients with heterozygous or homozygous familial hypercholesterolemia. But while the lipid reductions with the PCSK9 therapy are impressive, and the FOURIER trial found a 15% reduction in events with treatment, neither evolocumab nor alirocumab (Praluent), a PCSK9 inhibitor from Sanofi/Regeneron have achieved wide uptake as payers balk at the high price tags for the drugs.
Speaking at an ESC press briefing, Ridker said, "This is what personalized predictive medicine is all about." Once a patient has experienced an MI, there is always residual risk of recurrence. Thus, he suggested that residual risk can be divided into residual lipid-driven risk and residual inflammatory-driven risk.
Co-investigator, Peter Libby, MD, of Massachusetts General Hospital, put it this way: 30 days after an MI, when a patient is on statin therapy and stable, physicians could check LDL and then initiate more aggessive statin therapy if it is not well-controlled. Similarly, physicians should check hs-CRP, and if it is elevated -- 2.0 mg/L or higher -- initiating anti-inflammatory therapy targeting interleukin-1 beta would be an option.
That said, Libby noted that he was not recommending off-label use of canakinumab. "We need to wait for guideline committees to assess the evidence."
Ridker told MedPage Today he believed canakinumab might prove to be most useful if it were given to an identified high-responder group. He noted that after a single injection responders have a significant reduction in highly sensitive-CRP and it is those patients who would benefit from continuing on treatment. At that point, "I believe the benefit would outweigh the toxicity risk," he said.
"Maybe that first dose could be free," Ridker added.
And while canakinumab is the first anti-inflammatory agent to demontrate benefit, there may be others, Ridker said. For example, "we have a [National Heart, Lung, and Blood Institute] trial of methotrexate that is on-going. If that proves to be effective, it would be only pennies per treatment." At the press conference, Ridker said the methotrexate trial has "randomized about 4,000 patients, and we will need to get to 7,000 so it will be a few years before we have results."
Novartis, which developed canakinumab, may be sympathetic to that approach. Novartis Global Head Drug Development and Chief Medical Officer Vas Narasimhan, MD, and Jay Bradner, MD, president of the company's Institutes for BioMedical Research, told reporters that the company planned to go ahead with a filing with the FDA as early as October.
"We plan to move ahead with a cardiovascular filing" based on the CANTOS results, Narasimhan said. And while the filing will be based on the total results, "we plan to bring the findings in the hs-CRP responders to our meeting with the FDA." The company also plans to proceed with a phase III trial in non-small cell lung cancer in the first quarter of 2018.
Narasimhan said that, in CANTOS, patients whose hs-CRP declined to 1.8 mg/L or less had a much more robust response. In that subgroup, the number needed to treat to prevent a primary endpoint event was 50 at 2 years and 30 at 3.7 years.

New wonder drug hailed as biggest breakthrough in fight against heart attacks and cancer - attacks inflammation

Well well, finally getting to the root cause of atherosclerosis, cholesterol was never the problem.  25% of your bodys' cholesterol is in your brain, why the hell would you take drugs that reduce that?  But I'm not medically trained so nothing I say can be trusted. Urgent trials needed for stroke which will never occur. Start saving your money for this, your insurance won't pay for this.
New wonder drug hailed as biggest breakthrough in fight against heart attacks and cancer - attacks inflammation

A new class of drugs which could prevent thousands of heart attacks and deaths from cancer has been hailed as the biggest breakthrough since statins.

Scientists last night said the discovery ushered in “a new era of therapeutics” which work in an entirely different way to conventional treatment.

As well as cutting the risk of a heart attack by one quarter, the drugs halved the chances of dying from cancer and protected against gout and arthritis.

Heart attack: Symptoms and treatment

Cholesterol-busting statins are given to millions of adults deemed to be at risk of heart disease.

But half of heart attacks occur in people who do not have high cholesterol at all.

Now scientists have found that reducing inflammation in the body can protect against a host of conditions - with a “really dramatic effect” on cancer deaths.

The drug canakinumab, given by injection every three months - cut repeat heart attacks by one quarter. Statins cut the risk by around 15 per cent.

Experts said the findings have “far-reaching” implications for the 200,000 people a year in Britain who suffer a heart attack.

   

And they called for urgent trials to further examine the impact of the medication on cancer.

Professor Paul Ridker of Harvard Medical School, presenting his findings at the European Society of Cardiology congress in Barcelona yesterday, said it opens up a “third front” in the war on heart disease.

The landmark study tracked 10,000 heart attack victims who were given canakinumab, a drug which targets inflammation.

Typically, around a quarter of survivors will go on to have another event within five years, despite taking statins.

The four-year study found those given the new treatment saw a 24 per cent reduction in heart attacks and 17 per cent fall in angina, while those on the highest dose saw cancer deaths fall by 51 per cent.

Speaking at the world’s biggest gathering of heart experts, Harvard scientists said the approach promises to “usher in a new era” of treatment.

statins

Dr Ridker, from the Brigham and Women's Hospital in Boston, said: “These findings represent the end game of more than two decades of research, stemming from a critical observation: Half of heart attacks occur in people who do not have high cholesterol.”  

“For the first time, we’ve been able to definitively show that lowering inflammation independent of cholesterol reduces cardiovascular risk," he said.

He said the findings had “far-reaching implications,” opening up a new generation of treatment. “In my lifetime, I’ve gotten to see three broad eras of preventative cardiology,” the heart expert said.

“In the first, we recognized the importance of diet, exercise and smoking cessation. In the second, we saw the tremendous value of lipid-lowering drugs such as statins. Now, we’re cracking the door open on the third era.”

The findings were presented at the European Society of Cardiology Congress in Barcelona and published in the New England Journal of Medicine. Inflammation is one of the body's natural responses to infection or injury. But it also plays a major role in causing heart attacks and strokes.

Experts said high levels of inflammation were associated with a variety of conditions linked to ageing, including cancer, rheumatoid arthritis, osteoarthritis and gout - all of which reduced among patients put on the treatment.

The new treatment - which works by blocking part of the immune system called interleukin-1 - currently costs around £40,000 annually to treat a patient with the drug, compared to just £20 for statins.

But experts say the price would come down if widely adopted. And they said the cost would be offset by the millions of pounds saved from not having to perform heart bypasses and other major forms of surgery. Leading British medics last night hailed the findings as “exciting" and incredibly important”.

Dr Derek Connolly, consultant interventional cardiologist at Birmingham City Hospital, said:  “The drug is likely to be given to patients alongside statins - in a 'twin attack' against cholesterol and inflammation. “You need lots of bricks to build a wall - this is another brick in the wall.”

Professor Jeremy Pearson, Associate Medical Director at the British Heart Foundation, said: “Nearly 200,000 people are hospitalised due to heart attacks every year in the UK. 

“Cholesterol-lowering drugs like statins are given to these people to reduce their risk of another heart attack and this undoubtedly saves lives. But we know that lowering cholesterol alone is not always enough. “These exciting and long-awaited trial results finally confirm that ongoing inflammation contributes to risk of heart disease, and could help save lives.  

“The findings suggest that existing anti-inflammatory drugs, such as canakinumab, could be given along with cholesterol-lowering drugs to treat survivors and further reduce their risk of another heart attack.”

Novartis, the company which produces the drug, said they now intend to apply for a licence for the treatment for heart attack victims, and to embark on a new phase III trial about the use of the drugs to protect against cancer.

Spotlight shifts—again—to anti-inflammatories for cutting CV risk

So talk to your doctor on this, I'm sure the statin makers will criticize it.
http://www.theheart.org/article/1438055.do?utm_medium=email&utm_source=20120826_ESC2012_world_2&utm_campaign=newsletter
  It's time to shift some of the attention paid to lipid-lowering drugs onto therapies that fight vascular inflammation, according to a number of experts speaking on the opening day of the European Society of Cardiology (ESC) 2012 Congress.

Statin and aspirin studies tracking markers of inflammation show that "the magnitude of this disease associated with inflammation is at least as large as that of lipids or blood pressure," Dr Paul Ridker (Brigham and Women's Hospital, Boston, MA) told heartwire here.

Ridker points out that the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER)—for which he was primary investigator—showed that rosuvastatin (Crestor, AstraZeneca) reduced major adverse events 44% compared with placebo in patients with low LDL cholesterol but a high level of C-reactive-protein (CRP), a common marker of systematic inflammation. JUPITER showed a 50% decrease in LDL and a 37% decrease in CRP at 12 months, and the risk reduction was greater in patients with greater CRP reduction.

In his ESC talk, Ridker described two new studies getting under way looking at anti-inflammatory agents for reducing CV risk.

"Statins are weak anti-inflammatory drugs, but we've shown this enormous effect with a weak anti-inflammatory drug, so I said, 'Wow, what might happen with a real anti-inflammatory drug?' " Ridker said. "We've done dozens of lipid-lowering trials and dozens of hypertension trials, but we haven't done a single inflammation-reduction trial. But now we have two, which is very exciting."

The Cardiovascular Inflammation Reduction Trial (CIRT), announced last week [1], will compare methotrexate, given 10 to 20 mg weekly for three to four years, with placebo in about 7000 adults who have had an MI within the past five years, have type 2 diabetes or metabolic syndrome, and are already on a statin. The end point will be a reduction in recurrent MI, stroke, and cardiovascular death among stable post-MI patients with type 2 diabetes or metabolic syndrome. Methotrexate is already widely available as generic drug indicated for rheumatoid arthritis and also sometimes used in higher doses to treat certain types of cancer.

Ridker and colleagues will begin site selection for CIRT in November to begin patient recruitment in March 2013, but he has already begun to talk up the significance of the study. "This is the most exciting new biology in the field," he said. "And [the National Institutes of Health] NIH is trying to back what is the most important science."

Novartis is also betting that directly attacking inflammation will make a big impact on cardiovascular events in patients already on a statin. The company is backing the CANTOS trial of canakinumab (Ilaris), a high-affinity human monoclonal anti-human interleukin-1 (IL-1) antibody currently used for the treatment of IL-1-driven inflammatory diseases (cryopyrin-associated periodic syndrome).

The study will compare three doses of canakinumab with placebo in about 17 200 stable post-MI patients with elevated high-sensitivity CRP levels. The primary end point will be first occurrence of a major adverse cardiovascular event, a composite of cardiovascular-related death, nonfatal MI, and stroke over a follow-up of three years. There will also be a substudy measuring the change from baseline in the patients' carotid plaque burden in the bifurcation region of the index carotid artery and another study measuring the change from baseline of the patients' insulin secretion rate.

The study began in April 2011 and is expected to be completed in the summer of 2016.