Blog from the 2011 Keynote address of the 25th Annual Internal Medicine Research Day

Presenter: David Goff Jr., MD PhD (Wake Forest University School of Medicine)

Blogger: Tejas Desai, MD (East Carolina University – Brody School of Medicine)

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Dr. Bolin introduces Dr. Goff as a critical investigator in the role of hypertension in cardiovascular disease. Dr. Goff outlines the keynote presentation: 1) discuss the historical research about high blood pressure and 2) outline the new directions in high blood pressure research.

Dr. Goff starts with a meta-analysis in the Lancet (2002): for each age group (50’s – 80’s), the risk of stroke increases with increasing systolic or diastolic blood pressure. The relationship is linear — the risk of stroke does not drop precipitously at a systolic blood pressure of 140 or lower. A similar patterns is seen with blood pressure and ischemic heart disease. There has been a lot of interest in pulse pressure and it’s ability to predict heart disease and stroke. In the MRFIT patients, those individuals with higher systolic or diastolic pressures had greater risk of stroke. However, those with the highest systolic and diastolic do not have the highest risk of stroke; instead, the group with the highest systolic and lowest diastolic (the greatest pulse pressure) have the highest risk of stroke. In the Lancet 2002 study, the investigators looked at the following pressures to determine which had the greatest predictor of stroke and heart disease: systolic and diastolic pressure, pulse pressure, mean arterial pressure, and the mid-blood pressure (the simple average of the systolic and diastolic pressure). Pulse pressure is a poor predictor of stroke but mid-blood pressure and mean pressure predict stroke the best.

Moving on, Dr. Goff indicates that high blood pressure is common — about 1 billion people worldwide. Since 1990 in the US, the prevalence of high blood pressure in almost all ethnic/racial groups is increasing. High blood pressure is becoming a particular problem in the older population: 75% of people age 75 or older will have high blood pressure.

Benefits of blood pressure treatment: A meta-analysis in 1994 showed a 38% reduction of stroke risk in patients with blood pressure control; 16% reduction of heart disease with blood pressure control. Observational studies had shown a 20-25% reduction of heart disease with BP control. As a result, many investigations were performed to determine why the meta-analysis only showed a 16% reduction — does anti-hypertensive medications have a negative effect on heart disease risk? Subsequent studies have not shown that any one particular drug reduces heart disease less than another.

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For decades, we’ve been trying to achieve lower blood pressures. Lower blood pressures have been shown in observational studies to decrease risk of stroke (35-40%) and heart disease (20-25%). In the SHEP trial, a good portion of patients with lower blood pressure had a lower risk of congestive heart failure. On average, most patients would need 2 medications to achieve blood pressure control that mitigates their risk of stroke or heart disease. Lfestyle interventions can also cause large changes in risk: physical activity, decreasing alcohol consumption, weight loss, DASH diet.

Weight loss was shown to decrease blood pressure as early as 1988.
Sodium reduction leads to 3.5 mm Hg decrease in systolic pressure and 1.5 mm Hg in diastolic pressure.
DASH diet is high in fruits, vegetables, and nuts. In the DASH-Sodium trial, there was a decrease of 9 mm Hg in systolic blood pressure, which results in a 25% reduction on cardiovascular mortality and 15% decrease in total mortality. Dr. Goff indicates that these are excellent results, especially in the context of limited side effects from the DASH diet itself.
Three meta-analyses have shown that physical activity (30 minutes for most days of the week), irrespective of weight loss, will lower systolic blood pressure.

Prevention of high blood pressure: MRFIT study showed a lower 16-year mortality if the blood pressure decreases by 6-8 mm Hg. NHANES II (1970-1980’s) showed a substantial decrease in blood pressure in many groups. However, recent data, including NHANES III, show that most groups have higher blood pressures, perhaps due to the increasing prevalence of obesity. About 1/3 of the adult US population is now obese, and studies have shown that the degree of high blood pressure is proportional to the degree of adiposity.

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Drs. Goff and Bolin are currently working to elucidate how low one should push the systolic blood pressure (SPRINT Trial). Lowering the systolic pressure below 120 is now the hot area in the field. Dr. Goff, who was a part of the ACCORD trial, showed that intense glucose control did not decrease cardiovascular events (contrary to what was believed initially). ACCORD also had a blood pressure component. The subgroup analyses looked at whether cardiovascular risk was any lower in those with a treated blood pressure of less than 120 mm Hg versus those with a treated pressure of less than 140 mm Hg. Follow-up was 8 years, with a median follow-up of 5 years. Dr. Goff showed a graph of how quickly the targeted blood pressures were achieved (very quickly). For the primary outcome (cardiovascular death, non-fatal and fatal), the hazard ratio was 0.88 (a 12% reduction) — but not statistically significant and not informative either (i.e., there was no indication of a beneficial trend toward blood pressure lower than 120 mm Hg). For total mortality, the hazard ratio was actually greater than 1 (1.07), but not statistically significant. The results are different when the outcome looked at is stroke – hazard ratio 0.59 (40% reduction) and this was statistically significant. Most of the strokes were non-fatal, but stroke was not a primary outcome in the ACCORD trial.

As a result, Dr. Goff concluded that there is no conclusive evidence that lowering BP to less than 120 is beneficial. Of course, there were many caveats to this conclusion, among which the small sample size, poor power, etc. The NHLBI is now launching forward with a trial that will look at lowering blood pressure to 120 versus 140: SPRINT.

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**Note: The Division of Nephrology and Department of Internal Medicine at East Carolina University is a major participant in SPRINT. As of this blog, ECU has the second largest enrollment of patients in this trial.**

SPRINT began enrolling in 11/2010. The outcomes are risk of cardiovascular disease and chronic kidney disease. There is also a component looking at memory and cognitive decline with different blood pressure targets: SPRINT-MIND. The idea behind SPRINT-MIND is that vascular dementia may be mitigated by lowering blood pressure to below 120 mm Hg, though this has not been demonstrated in any of the trials that Dr. Goff had mentioned during his presentation. Hopefully, SPRINT will show the same 20-25% reduction in events that we have seen in observational studies. Total enrollment will be 9,250 patients (the ACCORD sample size was about 50% this number). SPRINT also recruits patients with chronic kidney disease (uncommon in previously published trials). SPRINT will also recruit 3,250 patients age 75 or over (especially for the SPRINT-MIND component of the trial). Recruitment is for 2 years, follow-up is 4-6 years.

Some more details about SPRINT-MIND. A sub-study will use MRI to look at changes in brain structure and cerebral blood flow over the study duration in both arms.

Chronic kidney disease is a major component of SPRINT. In most blood pressure studies, patients with CKD have been under-represented or excluded entirely. As a result, investigators are not confident that lowering blood pressure actually has reno-protective effects. The common thinking that blood pressure control does protect kidney function has been established in trials that have performed sub-group analyses with small sample sizes or observational studies; no randomized trials have addressed this issue in CKD patients.

SPRINT is a multi-center trial: 87 centers across the US, divided into 5 networks (Dr. Goff leads one network at Wake Forest, of which ECU is one of the centers).

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