A New Way to Treat Heart and Stroke Risk: Treating the Arteries Themselves, Not Just the Numbers on Your Lab Report

Table of Contents

• Key Points
• Why This Research Matters: The Old Way vs. The New Way
• How the Study Was Conducted: Measuring Plaque with Ultrasound
• The Patients: Who Was in This Study?
• The New Treatment Approach: What Changed in 2003
• Key Findings: Plaque Progression Reversed
• The Cholesterol Puzzle: What LDL Levels Revealed
• Reducing Real-World Events: Stroke, Heart Attack, and Death
• Why the Old Approach Was Failing: The Limits of Guideline-Based Care
• Study Limitations: What This Research Could Not Prove
• What This Means for Patients: Practical Takeaways
• Frequently Asked Questions
• Source Information

Key Points

• In an observational study of 4,378 patients, measuring carotid plaque with ultrasound appears to improve treatment effectiveness.
• By 2005, over half of patients had plaque regression, compared with about 25% before 2002.
• Two-year risk of stroke, heart attack, or death in asymptomatic carotid stenosis fell from 17.6% to 5.2%.
• Some patients with LDL below guideline targets still had plaque progression, so lab numbers alone may not predict safety.
• Plaque regression is possible and can become the norm with intensive, plaque-guided therapy, but randomized trials are still needed.

Why This Research Matters: The Old Way vs. The New Way

For decades, doctors assumed that atherosclerosis—the buildup of fatty plaque inside artery walls that causes heart attacks and strokes—was an unstoppable, one-way street. Once plaque formed, conventional wisdom held that it could only get worse, never better.

That assumption began to crack in the mid-1970s, when researchers discovered that plaques formed in response to balloon injury in monkeys could actually regress—shrink away entirely—within months when the animals were switched from a high-cholesterol diet to a healthy one. In 1990, Dr. Dean Ornish showed that patients following a severely restrictive diet and intensive lifestyle program could achieve measurable reduction of coronary stenosis (narrowing of heart arteries) on angiography.

This study from researchers J. David Spence and Daniel G. Hackam at the University of Western Ontario takes that concept much further. The researchers set out to test a bold new idea: rather than treating risk factors (the numbers on blood tests and blood pressure cuffs), what if doctors treated the arteries themselves—measuring the actual plaque and adjusting medications until the plaque stopped growing or began to shrink?

The research team had been measuring something called carotid total plaque area (TPA) since 1990. This is a measurement of the sum of cross-sectional areas of all atherosclerotic plaques visible in the carotid arteries (the main arteries in your neck that supply blood to the brain), measured using ultrasound.

Their earlier work had already shown that TPA is a powerful predictor of future health problems. In their landmark 2002 study, patients in the top quarter (quartile) of plaque area had a 3.4-times higher risk of stroke, death, or heart attack over 5 years compared to those in the lowest quarter, even after accounting for age, sex, cholesterol, blood pressure, smoking, diabetes, homocysteine, and treatments for lipids and hypertension.

The same 2002 study revealed just how poorly standard care was working. Among patients treated according to consensus guidelines (the standard approach at the time), only 26% experienced plaque regression, 15% had no change, and a striking 59% had continued plaque progression in the first year of follow-up. Those whose plaque progressed had twice the risk of stroke, heart attack, or death. Perhaps most concerning, a high Framingham risk score (a standard tool for estimating cardiovascular risk) identified only 30% of patients who would go on to have events—while 70% of events occurred among patients in the top quarter of plaque area. In other words, relying only on traditional risk scores was missing most of the people who would actually get sick.

These findings were later validated in the Tromsø study, a population-based study of about 6,000 participants in Norway, which found that carotid total plaque area—but not common carotid intima-media thickness (IMT, a different ultrasound measurement of the artery wall)—significantly predicted coronary events.

How the Study Was Conducted: Measuring Plaque with Ultrasound

The study included all patients who had carotid plaque measurements taken in any two successive years between January 1, 1997, and December 30, 2007. This comprehensive data set captured the clinic's entire experience across the treatment paradigm change.

Plaque measurements were made using a high-resolution duplex ultrasound scanner. Two highly experienced registered vascular technologists performed all scans. The technologists knew the patients' blood pressure and smoking status but did not know what medications the patients were taking—an important detail that reduces bias in the measurements.

The technique works like this: A plaque was defined as a local thickening of the carotid intima (the innermost layer of the artery) of at least 1 mm. The technologist scanned around each artery to find the view showing the largest extent of each plaque, then froze and magnified the image. Using a cursor, they traced around the perimeter of each plaque, and the scanner's microprocessor calculated the cross-sectional area. They repeated this for every visible plaque in the right and left common, internal, and external carotid arteries, and when visible (usually on the right side), the subclavian arteries. The sum of all plaque areas between the clavicle and the angle of the jaw was recorded as the total plaque area (TPA).

This measurement method proved highly reliable. The intraobserver reliability (how consistent one technologist was when repeating the same measurement) was 0.94, and the interobserver reliability (how consistent different technologists were with each other) was 0.85—both considered excellent.

The study used specific definitions to categorize patients each year:

• Progression: An increase in TPA from one year to the next of more than 5 mm²
• Regression: A decrease in TPA of at least 5 mm²
• Stable: A change of less than 5 mm² in either direction

The Patients: Who Was in This Study?

Between 1997 and 2007, 4,378 patients had serial plaque measurements in the clinic's given year. Of these, 47% were female. The mean age at the time of referral was 60 years (standard deviation 15 years), though this increased steeply over the study period—from age 50 to 62 years over the first 5 years—as the clinic shifted its focus to stroke prevention. Because stroke patients tend to be older, the clinic population aged significantly during the study period.

The baseline characteristics of these patients reflect a high-risk vascular prevention clinic population:

• Systolic blood pressure: 142 mm Hg (SD 23)
• Diastolic blood pressure: 82 mm Hg (SD 13)
• Total cholesterol: 5.35 mmol/L
• LDL cholesterol (the "bad" cholesterol): 3.48 mmol/L
• HDL cholesterol (the "good" cholesterol): 1.69 mmol/L
• Triglycerides: 2.32 mmol/L
• Total plaque area: 124 mm² (SD 140)
• 53% male
• 22% had experienced a previous stroke
• 31% had experienced a previous transient ischemic attack (TIA, or "mini-stroke")
• 10.4% had diabetes
• 13% still smoked; 45% were former smokers; 42% had never smoked
• 42% were already using a lipid-lowering medication
• 53% were already using a blood pressure medication

Patients came from three clinics: the Stroke Prevention Clinic, the Atherosclerosis Prevention Clinic, and the Premature Atherosclerosis Clinic, all at University Hospital in London, Ontario, Canada. Patients had been referred because of a transient ischemic attack or stroke, asymptomatic carotid stenosis (narrowing of the carotid artery without symptoms), a family history of premature vascular disease, or a personal history of premature or accelerated atherosclerotic disease affecting the coronary, carotid, aortic, or peripheral arteries.

The rate of plaque progression would be expected to increase steeply as the clinic population aged—and indeed it did initially, rising until about 2000. Then something unexpected happened, as described below.

The New Treatment Approach: What Changed in 2003

Beginning in 2001—when the researchers started to understand the implications of their soon-to-be-published 2002 findings—they began implementing a fundamental change in how they treated patients. By 2003, this new approach was fully in place.

Previously, patients were treated according to consensus guidelines: if your blood pressure was above target, you got blood pressure medication; if your LDL cholesterol was above target, you got a statin. The goal was to hit the numbers.

The new approach flipped this on its head. The goal became halting plaque progression or achieving frank regression, as measured by ultrasound. At baseline, therapy was intensified for anyone with a high plaque burden. During follow-up, therapy was intensified in any patient whose plaque was progressing—even if their blood pressure and LDL cholesterol were already at guideline targets.

Patients were also proactively involved in their own care. Doctors showed patients their plaque measurements and images to impress upon them that their high plaque burden for their age warranted intensive therapy. They expressed plaque burden as "arterial age" using a chart printed on ultrasound reports. During follow-up, patients could see for themselves whether their plaque was progressing. This visual feedback was used to motivate adherence to smoking cessation, exercise, medications, and a Mediterranean diet.

The medication strategy was intensive and stepped:

1. Patients with plaque progression received an increased statin dose to the maximum tolerated dose, regardless of LDL levels. This typically meant atorvastatin 80 mg or rosuvastatin 40 mg daily.
2. Patients already at the maximum tolerated dose of a statin had ezetimibe 10 mg daily added.
3. Those already using maximum statin plus ezetimibe were started on niacin (if not diabetic) or fibrates (for diabetic patients, or those unable to tolerate niacin due to flushing).
4. All patients with vascular disease were put on an angiotensin-converting enzyme (ACE) inhibitor—a type of blood pressure medication that also has protective effects on blood vessels. Those unable to tolerate ACE inhibitors due to cough or angioedema were switched to an angiotensin receptor blocker (ARB), unless contraindicated.
5. Blood pressure control was individualized based on each patient's renin/aldosterone profile (a blood test that helps predict which blood pressure medications will work best).
6. Some patients with insulin resistance (identified by high fasting insulin levels with normal blood glucose) were started on metformin or pioglitazone before diabetes even developed.
7. Virtually all patients used antiplatelet agents (like aspirin) unless they were anticoagulated for conditions such as atrial fibrillation.

A striking example from the article illustrates how quickly and dramatically plaque can regress with this approach. A 64-year-old man had soft plaque at the origin of the left external carotid artery. His plaque had progressed from 20 mm² one year to 28 mm² after stopping rosuvastatin because of muscle pain (myalgias) and cramps. After restarting rosuvastatin 5 mg daily along with CoQ10 200 mg daily to prevent the muscle symptoms, his plaque area regressed to just 0.19 mm² over 3.5 months. Not only did the plaque shrink dramatically, but it also became denser, with regression of the soft plaque and more calcification—suggesting the remaining plaque was more stable and less dangerous.

Key Findings: Plaque Progression Reversed

The results of this 10-year observational study were striking. Despite the fact that the clinic population was aging—which should have pushed the plaque progression rate steadily upward—the opposite happened after the paradigm change was implemented.

In the early years (1997 to 2001), as the clinic population aged, the proportion of patients with plaque progression increased, peaking at 61.7% in 2001. Only 19.6% of patients had regression that same year. But after the paradigm shift took hold, the trend reversed dramatically.

The year-by-year breakdown tells a powerful story:

• 1997-1998: 28.2% progression, 35.9% regression
• 1998-1999: 33% progression, 38.7% regression
• 1999-2000: 48.1% progression, 28.6% regression
• 2000-2001: 61.7% progression, 19.6% regression (the worst year)
• 2001-2002: 55.4% progression, 26.1% regression
• 2002-2003: 46.1% progression, 33.4% regression
• 2003-2004: 41.9% progression, 38% regression
• 2004-2005: 40.6% progression, 33.9% regression
• 2005-2006: 26.8% progression, 50.1% regression (the best year)
• 2006-2007: 28.4% progression, 40.5% regression

By 2006, the proportion of patients with plaque progression had fallen to just over a quarter (26.8%), and for the first time, more than half of the patients (50.1%) were experiencing actual plaque regression. The mean rate of plaque change had become negative—meaning the average patient in the clinic was now seeing their plaque shrink rather than grow.

The overall numbers are equally compelling. Before 2003, approximately half of all patients had plaque progression and about a quarter had regression. By 2005, this ratio had reversed: roughly half had regression and a quarter had progression. The annual rate of plaque progression after 2001 abruptly declined and has remained negative since 2005.

This improvement was not simply a matter of treating everyone more aggressively. The researchers carefully analyzed the lipid data to show that the changes in plaque behavior were attributable to the plaque-guided approach itself, not just a blanket intensification of therapy for all patients.

The Cholesterol Puzzle: What LDL Levels Revealed

One of the most interesting findings concerns the relationship between LDL cholesterol levels and plaque behavior before versus after the paradigm shift.

In the early years, the data looked exactly as you would expect: patients with plaque progression had higher LDL cholesterol levels, while those with regression had lower LDL levels. This is the classic relationship that supports the "lower is better" approach to cholesterol.

But by 2007, something remarkable had happened. Patients with plaque progression had LDL levels that were approximately half of what progressors had in the early years. Even more striking, by 2007 patients with progression actually had lower LDL levels than patients with regression (1.84 mmol/L vs. 1.87 mmol/L).

It's important to note that the LDL trends shown in Table 2 of the study reflect group averages, and the statistical significance varied by year. The differences reached significance in certain years—for example, the LDL difference between regression groups in 2004-2005 (P<0.05) and 2006-2007 (P<0.003). The researchers interpreted the overall pattern as evidence that the clinic was "trying harder to stop plaque progression and achieve frank regression using plaque measurement to guide therapy." Once plaque measurement became the treatment target, LDL levels were pushed much lower in patients whose plaque was still progressing, often beyond what guidelines would typically recommend at that time.

This finding has a subtle but important meaning for patients: a "normal" LDL level on a lab test does not necessarily mean your arteries are safe. Some patients need much more aggressive cholesterol lowering to halt plaque growth, and plaque imaging can identify who those patients are.

Reducing Real-World Events: Stroke, Heart Attack, and Death

The ultimate test of any treatment strategy is whether it prevents the things patients actually care about: strokes, heart attacks, and premature death. The researchers had previously published data on 468 patients with asymptomatic carotid stenosis (narrowing of the carotid artery of at least 60% by Doppler ultrasound), and these results were dramatic.

After implementing the more intensive, plaque-guided medical therapy:

• Plaque progression slowed dramatically: The rate of carotid plaque progression during the first year of follow-up fell from 69±96 mm² before 2003 to 23±86 mm² after (P<0.0001).
• Microemboli (tiny blood clots traveling to the brain) decreased by two-thirds: The prevalence on transcranial Doppler fell from 12.6% of patients to 3.7% (P<0.0001).
• Two-year stroke risk plummeted: From 8.8% to 1% (P<0.01).
• Two-year heart attack risk plummeted: From 8.6% to 1% (P<0.01).
• The combined outcome of stroke, death, heart attack, or carotid endarterectomy (surgery to clean out the artery, needed because of new neurological symptoms on the side of the stenosis) fell from 17.6% of patients to 5.2% (P<0.0001).

These are enormous reductions—far larger than those typically seen in clinical trials of individual medications. To put this in perspective, virtually all positive randomized trials of cardiovascular prevention in high-risk patients show relative risk reductions in the range of only 9% to 30%, meaning that even with the best guideline-based care, 70% to 80% of events are not prevented. The improvement seen with the plaque-guided approach in this study is on a different scale entirely.

Why the Old Approach Was Failing: The Limits of Guideline-Based Care

The article includes a sobering review of how poorly traditional risk factor management works in the real world, which helps explain why a paradigm change was so badly needed.

Difficulties with blood pressure management:

• Until recently, only one-third of patients with hypertension in the real world were controlled to target levels.
• Antihypertensive medication is prescribed in only 25% to 50% of cases of hypertension in North America and Europe.
• Global rates of hypertension control to <140/90 mm Hg range from just 5.4% in Korea to 58% in Barbados.
• Long-term persistence with antihypertensive therapy is only about 50%—half of patients stop taking their blood pressure medications over time.

Difficulties with cholesterol management:

• Only 40% to 50% of high-risk patients achieve LDL cholesterol targets in the United States and Europe.
• Even in a well-organized health maintenance organization, persistence with statins in secondary prevention (patients who already have vascular disease) was only 60%.
• In less structured systems, persistence with statins over 2 years is only about 40% in secondary prevention and just 25% in primary prevention.
• A community-based study found that only 21% of high-risk patients achieved goals for blood pressure, LDL cholesterol, and blood glucose simultaneously.

The STENO-2 trial, a well-known study of intensive multifactorial intervention in diabetic patients, achieved only a 50% reduction in cardiovascular events even with long-term, intensive treatment over 14 years. And in the JUPITER trial, treating all at-risk patients with intensive therapy for primary prevention was found not to be cost-effective.

The article also argues that the current approach—relying on population-wide risk scores—is insufficient. A recent report by Lee and colleagues showed a substantial worsening in the risk factor burden in Canada, further underscoring the need for a targeted, high-risk strategy based on actual disease measurement.

Study Limitations: What This Research Could Not Prove

The authors are transparent about the limitations of their study. It is essential to understand these before drawing conclusions.

Not a randomized trial: The research design was observational, not randomized. This means the researchers observed trends in patients who were accrued over the course of 10 years, rather than randomly assigning patients to two different treatment strategies. While the results are strongly suggestive, they cannot definitively prove that the plaque-guided approach caused the improvement—other factors could theoretically have contributed.

A referred, specialized population: All patients were referred to a prevention clinic at a university hospital. The results therefore may not apply directly to different patient populations, such as those seen in primary care settings or those without access to specialized vascular prevention services.

Group-level analysis: The changes reported for each time period are group changes. Not every patient had serial examinations in all years, so the year-by-year numbers reflect different patients at different times. The changes in plaque area were also not analyzed in a way that took individual patient characteristics into account.

Limited smoking analysis: Because only 16% of patients were still smoking at baseline, the study had limited ability to assess the effect of this approach on smoking cessation, particularly in the way reported by other researchers such as Bovet and colleagues.

Confounding by age: The increase in age and risk factor burden over time should have promoted more plaque progression, not regression. The fact that regression was observed despite this aging effect actually strengthens the conclusions—but it also means the true effect of the treatment change might be even larger than it appears, or partly counteracted by aging effects in ways that are difficult to fully disentangle.

Not applicable to IMT: The approach described cannot be based on measurement of carotid intima-media thickness (IMT), a simpler ultrasound measure. The annual change in IMT (about 0.015 mm) is below the resolution of the ultrasound method (0.3 mm). Only plaque area measurement provides a change signal large enough to guide therapy in real time.

Most importantly, the authors note: "These preliminary results are intriguing and promising but cannot lead to a widespread change in practice until validated in a randomized clinical trial, which is now being designed."

What This Means for Patients: Practical Takeaways

The core message of this research is captured in the authors' memorable analogy: "Treating atherosclerosis without measuring plaque would be like treating hypertension without measuring blood pressure."

No doctor would prescribe blood pressure medication without ever checking your blood pressure to see if it was working. Yet in the management of atherosclerosis, doctors have typically prescribed statins and other medications based on risk-factor targets, without ever directly checking whether plaque is actually growing, stable, or shrinking.

For patients, several practical lessons emerge:

1. Ask about plaque imaging. If you have had a stroke, TIA, or have been told you have carotid stenosis or are at high cardiovascular risk, ask your doctor whether carotid ultrasound to measure total plaque area is available. This measurement can tell you whether your current treatment is actually working.
2. An "acceptable" LDL level may not be enough. This study found that some patients continued to have plaque progression even with LDL levels at or below guideline targets. The goal should be to stop plaque progression, not just to hit a number.
3. If your plaque is progressing despite standard treatment, more intensive therapy may help. The study used maximum-tolerated statin doses, then added ezetimibe, then niacin or fibrates, plus ACE inhibitors and individualized blood pressure therapy. Many of these combinations go beyond what standard guidelines recommend.
4. Lifestyle matters, and seeing your plaque can motivate change. The researchers found that showing patients their plaque images motivated them to stop smoking, exercise more, take their medications, and follow a Mediterranean diet. Seeing is believing.
5. Plaque regression is possible and might be more common than previously thought. Before this study, regression was considered a novelty. Now, in an aggressively treated clinic population, regression became the norm—more than half of patients achieved it by 2005.
6. Sustained medication adherence is crucial. The study's review of real-world data shows that half of patients stop blood pressure medications and 40-60% stop statins within two years. This "treatment gap" is a major reason real-world results lag behind clinical trials. Staying on your medications is one of the most powerful things you can do.

The researchers also anticipate a future where a randomized clinical trial confirms these findings. In the meantime, the evidence suggests that a paradigm shift may be underway. The current approach to cardiovascular prevention—measuring cholesterol and blood pressure, treating to targets, and hoping for the best—is being supplemented by a new strategy that directly measures the disease itself and treats the arteries, not just the risk factors that contribute to the disease.

As the authors note, "Our observations support the hypothesis that measuring plaque improves therapy in cardiovascular prevention clinics." The validation of this approach in a prospective clinical trial will be eagerly awaited by both physicians and patients.

Frequently Asked Questions

How is carotid plaque measured during an ultrasound?

A high-resolution duplex ultrasound scanner is used. A plaque is defined as a local thickening of the carotid intima of at least 1 mm. The technologist traces around each plaque, and the scanner calculates the cross-sectional area. All plaque areas are summed to get the total plaque area. This method has excellent reliability.

What changed in the treatment approach from 2003 onward?

Instead of only treating blood pressure and cholesterol to guideline targets, doctors began measuring plaque with ultrasound and intensifying therapy if the plaque was growing. They used maximum tolerated statin doses, plus ezetimibe, niacin or fibrates, ACE inhibitors, and individualized blood pressure control to stop plaque progression or achieve regression.

Is a normal LDL cholesterol level enough to protect your arteries?

Not necessarily. By 2007, patients whose plaque progressed had LDL levels of 1.84 mmol/L, which was lower than the 1.87 mmol/L in patients with regression. The study suggests that some people need much more aggressive cholesterol lowering to halt plaque growth, and plaque imaging can identify those patients.

Can existing plaque in the carotid arteries actually shrink?

Yes. Regression was defined as a decrease in plaque area of at least 5 mm². By 2005, more than half of patients achieved regression with intensive therapy. One example showed a plaque shrinking from 20 mm² to 0.19 mm² over 3.5 months after restarting rosuvastatin with CoQ10.

Is the evidence strong enough to change standard care everywhere?

The authors say these results are intriguing but cannot lead to a widespread change in practice until validated in a randomized clinical trial, which is being designed. This was an observational study in a specialized referral clinic, so the findings may not apply to all patient populations.

Source Information

This patient-friendly article is based on peer-reviewed research published in the journal Stroke.

• Original article title: Spence 2010 Treating Arteries Instead of Risk Factor