ASCOT: Amlodipine Cuts Stroke, Not Dementia Over Decades

Damian McNamara

June 17, 2020

Patients who took amlodipine as part of an antihypertensive regimen experienced significantly fewer strokes over two decades, new long-term results from the ASCOT study show. This group showed an 18% decrease in stroke incidence compared with others taking an atenolol-based regimen.

However, neither therapy was associated with an overall decrease in dementia incidence in the multicenter, randomized study.

Investigators also compared atorvastatin to placebo in a separate analysis. The statin did not significantly reduce either stroke or dementia rates.

"I was surprised that we still saw a beneficial effect of an amlodipine-based regimen on stroke incidence after 20 years of follow-up," study author William Whiteley, BM, BCh, PhD, told Medscape Medical News.

Whiteley presented these long-term results from the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) May 13 during a clinical trials webinar of the ESO-WSO 2020 Congress. The event was sponsored by the European Stroke Organisation and the World Stroke Organization.

"The results support many national guidelines — such as NICE in the UK — for the use of calcium channel blockers as first-line treatment for hypertension" in appropriate patient populations, said Whiteley, a Scottish senior clinical fellow in the Centre for Clinical Brain Sciences at the University of Edinburgh.

Aiming for a More Definitive Answer

Prior observational cohort studies point to an association between midlife stroke risk factors and an increased dementia risk. However, cohort studies can be confounded by other factors that place people at higher risk for dementia, Whiteley said.

Furthermore, randomized controlled trials of LDL cholesterol-lowering therapies and blood pressure-lowering therapies with shorter-term follow-up can have other shortcomings. "We only see a neutral or modest effect on dementia" in these studies, he added. "We only follow people for a short time, and often not into the years where the dementia risk is highest."

"Our goal was to do a long-term follow-up to ages where dementia incidence is highest, where we might hope to see a greater effect," said Whiteley, who is also a senior clinical fellow in the Nuffield Department of Population Health at the University of Oxford, UK.

Whiteley and colleagues focused on the ASCOT subpopulation of 8580 UK participants from a total of 19,342 patients in the overall trial. The researchers enrolled people with hypertension, three or more vascular risk factors and no coronary heart disease from 1998 to 2002. They randomly assigned participants to an amlodipine- or atenolol-based regimen in a study that lasted 5.5 years.

That group of the trial (ASCOT-Blood Pressure Lowering Arm) was stopped early in 2004 when a reduction in all-cause mortality was seen with the amlodipine-based regimen, although the primary endpoint, a 10% reduction in nonfatal myocardial infarction and fatal coronary heart disease, was not statistically different between the groups, something the researchers attributed to the early stop.

At the same time, ASCOT investigators also compared atorvastatin vs placebo (ASCOT-Lipid Lowering Arm) in a factorial 2 x 2 design among participants whose total cholesterol was 6.5 mmol/L or less. That group of the study was stopped at 3.3 years "because of overwhelming benefit on myocardial infarction," he said.

The researchers tracked all stroke and all dementia diagnoses using coding in national health records, and noted deaths, general hospitalizations, mental health consultations, prescriptions, and more.

A majority, 81%, of the study participants were men and 90% were of European ancestry. At baseline, mean systolic BP was 162 mm Hg and mean diastolic BP was 92 mm Hg. Total cholesterol was 5.9 mmol/L.

UK ASCOT

The amlodipine-based regimen for 5.5 years was associated with a significant 18% reduction in recorded stroke events over follow-up (443 strokes in the amlodipine-based group vs 552 in the atenolol-based group; adjusted hazard ratio, 0.82; P = .003).

"But we didn't see any [significant] reduction in dementia incidence," Whiteley added (450 cases in the amlodipine-based group vs 465 cases in the atenolol-based group; adjusted HR, 0.94; P = .323).

"There was an unexplained significant interaction between higher baseline total cholesterol and greater reduction in stroke incidence with allocation to amlodipine over those 20 years of follow-up," he noted.

Regarding the nested comparison of atorvastatin vs placebo, "We found no evidence that that allocation to atorvastatin for 3.3 years had any legacy effect on later recorded stroke or dementia in follow-up," Whiteley said.

The 8% reduction in all strokes over 20 years was not significant (adjusted HR, 0.92; P = .341). In addition, there was no significant decrease in dementia rates associated with atorvastatin (adjusted HR, 0.98; P = .837).

They also used the trial as an observational cohort, "given that we had a large number of dementia cases, and detailed measurement of vascular risk at baseline."

According to that analysis, mean total cholesterol and mean BP at baseline were not associated with dementia incidence over 20 years either. However, the researchers found a statistically significant association between greater BP variability and increased dementia incidence, even after adjustment for mean BP.

As expected, participants who experienced a stroke during the follow-up time were at increased risk of dementia (adjusted OR, 1.67).

Whiteley intends to further investigate the beneficial effects of an amlodipine-based regimen on stroke incidence going forward. He also noted that this "data driven learning health system" approach to research was difficult and will need many improvements.

Vascular Risk Not the Only Factor

"Longitudinal data are very welcome," Vladimir Hachinski, MD, professor of neurology and epidemiology at Western University in London, Ontario, Canada, told Medscape Medical News when asked to comment on the study.

"There are clear positive trends, stronger for stroke than dementia. This is not surprising, since the typical patient diagnosed with Alzheimer's disease has an average of eight pathologies, of which the vascular is the only treatable one that one could expected to be modified by antihypertensives and statins," he added.

Unanswered questions include whether the taking of medications was monitored or self-reported in the study, and whether the researchers assessed "the momentum of the risk factor, meaning the level multiplied by the duration, similar to pack/years for smoking."

Nevertheless, Hachinski added, "Neurologists should continue to use antihypertensive and statins. The antihypertensives should be given at bedtime. There is evidence that doing so cuts major vascular outcomes such as stroke and heart attacks by half."

Clinical trials webinar of the ESO-WSO 2020 Congress, sponsored by the European Stroke Organisation and the World Stroke Organization. Presented May 13, 2020.

Whiteley and Hachinski have disclosed no relevant financial relationships.

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