Is statin discontinuation an option in patients who have had a stroke?

SYNOPSIS

BACKGROUND

There is clear evidence that long-term statin therapy can prevent the recurrence of vascular events, but in clinical practice, many patients discontinue statin therapy.

OBJECTIVE

To evaluate the effect of statin interruption on clinical outcome in patients discharged after an acute ischemic stroke.

DESIGN AND INTERVENTION

The present study was conducted at an Italian community hospital and enrolled consecutive stroke patients who were discharged from January 2000 to June 2005. Inclusion criteria were absence of any major concurrent illness, absence of any clinical and laboratory evidence of coronary heart disease (CHD) or of any other major cardiac affect or cardiac embolism, and discharge on statin therapy. After exclusions, 631 patients (51% male; mean ± SD age 70.2 ± 7.6 years) were enrolled. All participants were followed up for 12 months. Adherence to prescribed medications was evaluated by telephone interview at 1, 6 and 12 months after discharge. Switching from one cardiovascular agent to another of the same class was considered adherence to the prescribed therapy. Univariate and multivariate Cox proportionalhazards regression analyses were performed to identify risk factors for occurrence of the primary end point, and to identify clinical and demographic variables associated with statin therapy discontinuation during the follow-up period.

OUTCOME MEASURES

The primary end point was death from any cause within 12 months of discharge.

RESULTS

At discharge, 409 (77.6%) patients received a prescription for atorvastatin and 222 (22.4%) patients received a prescription for simvastatin. During the follow-up period, 246 (38.9%) patients discontinued statin therapy; the discontinuation rates were similar for both statins (P=0.544). Seventy-one (28.8%) patients stated mild adverse effects—such as dyspepsia, fatigue, headache and myalgia—as the reason for statin interruption. No instance of major adverse event was reported. In the remaining 175 (71.2%) cases, neither the patient nor the primary care physician could provide any specific medical reason for statin discontinuation. Multivariate analysis identified increasing age (hazard ratio [HR] 1.006 per year, 95% CI 1.004-1.009; P= 0.01) and female sex (HR 1.07, 95% CI 1.03-1.11; P= 0.02) as risk factors for statin discontinuation. By contrast, patients with diabetes were more likely to continue statin therapy (HR 0.86, 95% CI 0.79-0.91; P=0.03). A total of 116 patients died within 1 year of discharge. Ninety-two (79.3%) of these patients had discontinued statin therapy compared with 154 (29.9%) patients who survived (P=0.0001), and statin interruption was identified as an independent predictor of 12-month all-cause mortality (HR 2.78, 95% CI 1.96-3.72; P=0.003). Other independent predictors of death within the first year after the stroke event were increased age, obesity, diabetes, stroke severity on admission, and antiplatelet therapy discontinuation.

CONCLUSION

A considerable proportion of patients with acute ischemic stroke are at increased risk of death within the first year after the index event because they discontinue statin therapy, often without a specific medical reason.

COMMENTARY

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, otherwise known as statins, are the principal therapeutic agents for patients with hypercholesterolemia or CHD. Early statin trials focused mainly on patients with CHD rather than with stroke because of the closer epidemiological association between elevated serum cholesterol levels and increased risk of CHD.¹ Indeed, until recently, the only evidence for the beneficial effects of statin therapy in stroke came from trials of primary stroke prevention in patients with cardiovascular risk factors or CHD. In the recent Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial, however, the use of a high-dose statin (atorvastatin 80 mg) was found to reduce the relative risk of secondary strokes by 16% in patients without a history of CHD, despite a slight increase in the incidence of hemorrhagic strokes.² A somewhat surprising finding of the SPARCL trial was that statin therapy reduced the incidence of major coronary events by 35%. These results indicate that, in patients with stroke or transient ischemic attack who have cardiovascular risk factors, the benefits of statin therapy reside not only in stroke prevention—they might also extend to primary prevention of CHD. In essence, the findings of the SPARCL trial suggest that stroke—like diabetes—confers a risk for future cardiovascular events that is equivalent to that conferred by a history of CHD.

It is, therefore, not surprising that in this study by Colivicchi et al., discontinuation of statin therapy in patients with ischemic stroke resulted in worsening clinical outcomes, especially among patients with particularly high risk of CHD, such as the elderly or obese and those with diabetes. Interestingly, the cause of mortality in this study was not defined in terms of stroke or CHD deaths, although—on the basis of previous clinical trials—both stroke and CHD deaths probably contributed most of the all-cause mortality reported in the first year after stroke.

The current findings are in agreement with those from another recent trial that showed that withdrawal of statins in patients presenting with ischemic stroke was associated with an increased risk of death or worsening neurological deficits at 90 days.³ What was even more striking was the 19-fold increase in early neurological deterioration and the larger infarct size in patients who discontinued statin use, as opposed to those without previous treatment with statins. These findings suggest that there is a rebound effect from statin withdrawal that is much more detrimental than not receiving statin therapy. Indeed, statins might exert cholesterol-independent or ‘pleiotropic’ effects by upregulating endothelial nitric oxide synthase (eNOS) and suppressing inflammation and oxidative stress.^1,4 Abrupt cessation of statin therapy has been associated with a decrease in nitric oxide release through a rebound increase in Rho GTPase, which negatively regulates eNOS expression.⁵

On the basis of current clinical data, all stroke patients should be on statin therapy regardless of serum cholesterol levels, not only to prevent secondary strokes, but also to prevent subsequent CHD events. As the study by Colivicchi et al. has indicated, cessation or interruption of statin therapy after ischemic stroke leads to an almost three-fold increase in first-year mortality.