Source: Eur Urol  |  Posted 5 years ago

By Chris Berrie

BRUSSELS, BELGIUM -- May 18, 2006 -- Atorvastatin 80 mg/day significantly reduces the risk of recurrent stroke in patients with recent stroke or transient ischaemic attack (TIA) and no history of coronary heart disease (CHD), while substantially decreasing the risk of major coronary and CHD events and revascularisation procedures.

Principal investigator K. Michael Welch, MD, professor, department of neurology, and president, Roslyn Franklin University, North Chicago, Illinois, United States, presented the results of the large-scale, multicentre, double-blind, randomised, placebo-controlled, Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial here at the 15[^]th[] European Stroke Conference (ESC).

"Although in the early years it was difficult to relate cholesterol to stroke risk, when the statin trials began to be reported, it became clear that indeed the reduction of high cholesterol by statins reduced stroke," he said during his presentation on May 17[^]th[].

He pointed to the evidence from a meta-analysis of 26 trials for stroke outcomes in statin trials that showed the statins can significantly reduce stroke by 21% ([]P[] <.0001). Furthermore, the same study estimated that for every 10% reduction in low-density lipoprotein cholesterol (LDL-C) level there was a 15.6% reduction in the risk of stroke.

These previous studies largely concentrated on primary prevention in patients with no prior stroke or TIA, which included either secondary prevention following prior CHD or primary prevention for patients with no prior CHD. Therefore, the design of the SPARCL trial was for a patient population with prior stroke or TIA, but with no prior CHD.

These patients were recruited in 205 sites worldwide, with inclusion criteria of documented stroke or TIA within the previous 6 months, with no history of CHD, and with LDL-C levels between 100 and 190 mg/dL. The primary endpoint was for time to first occurrence of a fatal or nonfatal stroke.

Of the 6,670 patients screened, 4,731 were randomised to either placebo (n = 2,366, mean age, 62.5 years, male, 59.0%) or atorvastatin 80 mg/day (n = 2,365; mean age, 63.0 years; male, 60.3%).

Patients in the placebo and atorvastatin groups were well matched for baseline characteristics (respectively): current smoking, 19.3%, 19.1%; hypertension, 61.4%, 62.4%; diabetes, 16.9%, 16.7%; carotid stenosis, 21.7%, 20.9%. For their entry events, 31.8% and 29.9%, respectively, showed TIA, and 68.2% and 70.0%, stroke. The stroke patients were further divided into ischaemic (96.3%, 96.7%), haemorrhagic (3.0%, 2.7%), and others (0.4%, 0.9%).

Because age is such a major risk factor for stroke, Dr. Welch also stressed that the 6-month difference seen between the 2 treatment groups did indeed justify a prespecified adjustment for age.

The concomitant medications within the placebo and atorvastatin groups included mainly antiplatelet (94.1%, 93.6%) and antihypertensive (692%, 68.7%) agents, with the use of atorvastatin (13.0%, 5.1%) and simvastatin (11.0%, 4.7%) providing a net difference in statin use of 78%.

For the LDL-C during the 6 years of follow-up, while the mean baseline level (133 mg/dL) across all patients showed a 1% increase in the first month in the placebo arm, there was a drop in 53% with atorvastatin. Mean on-treatment LDL-C levels were 129 mg/dL for the placebo group, and 73 mg/dL for atorvastatin.

As the primary endpoint of time to fatal or nonfatal stroke at 6 years, and following prespecified adjustments for geographical region, entry event, time since entry event, gender and baseline age, the atorvastatin arm (265 events) showed a significant 16% risk reduction over placebo (311 events), with an adjusted hazards ratio (HR) of 0.84 (95% confidence interval [CI], 0.71-0.99; []P[] =.03).

When divided according to fatal stroke and nonfatal stroke, the former showed a significant risk reduction for atorvastatin (hazards ratio [HR], 0.57; 95% CI, 0.35-0.95; []P[] =.03), while the latter also showed a trend towards atorvastatin benefit (HR, 0.87; 95% CI, 0.73-1.03; []P[] =.11)

A post-hoc analysis for ischaemic stroke showed a similar significant benefit with atorvastatin (HR, 0.78; 95% CI, 0.66-0.94; []P[] =.01), while haemorrhagic stroke showed a slight but significant increase in HR for atorvastatin (1.66; 95% CI, 1.08-2.55; []P[] =.02), although Dr. Welch said that in terms of fatal haemorrhagic strokes, this difference was lost.

For the first secondary endpoint of time to stroke of TIA, again the atorvastatin group showed a significant 23% reduction in risk (HR, 0.77; 95% CI, 0.67-0.88; []P[] <.001), which was maintained when just considering TIA.

Dr. Welch then stressed that this patient population had no previous known CHD, and yet the secondary endpoint of time to a major coronary event showed the atorvastatin group with further significant benefit, with a 35% risk reduction (HR, 0.65; 95% CI, 0.49-0.87; []P[] =.003).

This significant benefit of atorvastatin was also maintained across the further selected secondary endpoints of major coronary (HR, 0.65; 95% CI, 0.49-0.87; []P[] =.003) and major cardiovascular (HR, 0.80; 95% CI, 0.69-0.92; []P[] =.002) events, and any CHD (HR, 0.58; 95% CI, 0.46-0.73; []P[] <.001) and any revascularisation (HR, 0.55; 95% CI, 0.43-0.72; []P[] <.001).

For all-cause mortality (HR, 1.00; 95% CI, 0.82-1.21; []P[] =.98) and cancer mortality (HR, 1.05; 95% CI, 0.72-1.53; []P[] =.80) there were no differences between the treatment arms, while cardiovascular mortality showed a beneficial trend for atorvastatin (HR, 0.78; 95% CI, 0.58-1.06; []P[] =.11).

Dr. Welch also stressed that the atorvastatin was very well tolerated, with only a slight increase in liver enzyme levels, with no changes in musculoskeletal adverse events.

He concluded that these data showed that to prevent 1 stroke, major cardiovascular, or revascularisation procedure event, there would be the need for a 5-year atorvastatin treatment of 46, 29, and 32 patients, respectively. Furthermore, this use of atorvastatin offered significant benefit over risk in terms of stroke and major coronary events ([]P[] =.002).

Thus, results from the SPARCL study support the initiation of atorvastatin 80 mg/day soon after a stroke or TIA.

This study was funded by Pfizer.

[[]Presentation title: The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Study. New Clinical Trials I; Abstract 1[]]