A 66-year old woman with hypertension and a 40-pack year smoking history presents to the hospital with sudden onset of left-sided weakness and sensory loss. If her LDL is 105, should she be started on a statin in the hospital?
Hospitalists frequently care for patients with acute ischemic events, and the hospital physician must evaluate new and evolving evidence on indications for acute statin therapy with a critical eye to risks, benefits, and the quality of the data. An understanding of the mechanism of this class of medications illuminates the physiologic basis for the rationale behind acute therapy. The unique non-cholesterol mediated effects of statins offer intriguing potential for benefit across a number of disparate conditions, including myocardial infarction (MI), stroke, the perioperative period, and even sepsis.
How do statins work?
Statins, derived from the fungus Penicillium citrinum, act by blocking HMG Co-A reductase. Competitive inhibition of the rate-limiting step in cholesterol synthesis reduces production of mevalonate and other downstream products (collectively referred to as isoprenoids) and ultimately limits cholesterol production. An interesting additional mechanism of this medication class lies in the so-called “pleiotropic effects,” which include improved endothelial function, antithrombotic and anti-inflammatory properties. These effects are driven not by cholesterol reduction, but rather by reduced modulation of GTPbinding proteins through limiting production of isoprenoid intermediaries. In effect, blocking HMG Co-A reductase decreases the amplitude of signal driving the inflammatory and thrombotic cascades (see Figure). These pleiotropic benefits occur rapidly and are hypothesized to explain much of the short-term benefit in clinical outcomes.
The evidence base is strongest for using statin therapy for coronary disease. Use in acute MI hinges on the concept of modern plaque theory (“Plaque stabilization: can we turn theory into evidence?” Am J Cardiol 2006; 98:26P-33P). MI is no longer thought to be simply the end result of low incremental clogging of coronaries by cholesterol, but rather rupture of an unstable coronary plaque results in the acute infarction. These plaques contain a dynamic slurry of cholesterol esters, extra-cellular cholesterol, cytokines, and other inflammatory mediators. Rupture exposes intensely thrombogenic material to the circulating bloodstream and results in thrombotic occlusion. While reduction in arterial cholesterol burden takes months to years, pleiotropic effects of statins may rapidly stabilize vulnerable plaques.
The 2001 MIRACL trial, the first major study on acute initiation of statins following MI, used a high-dose, high-potency statin started in the first few days after the event and demonstrated a 16% relative risk reduction for recurrent ischemia (“Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes. The MIRACL study: a randomized controlled trial.” JAMA 2001; 286:1711-1718). These findings were confirmed by the 2004 PROVE-IT trial which found similar risk reduction when comparing high-intensity to low-intensity statin therapy (“Intensive versus moderate lipid lowering with statins after acute coronary syndromes.” NEJM 2004; 350:1495- 504). Benefit was seen in as little as 30 days. While the 2004 A to Z trial did not find similar benefit to statins, some have hypothesized the failure to show improvement may be due to less dramatic reduction in inflammatory markers. A meta-analysis of 13 studies found a 19% risk reduction with early acute statin initiation (“The effect of early, intensive statin therapy on acute coronary syndrome: a meta-analysis of randomized controlled trials.” Arch Intern Med 2006; 166:1814-1821). Target LDL after MI is less than 100 mg/dl with an optional goal of less than 70 mg/dl, and ACC/AHA guidelines recommend consideration of statin therapy after MI regardless of initial lipid levels.
Lipids and stroke
In contrast to the relationship between high cholesterol and coronary disease, the epidemiologic association between lipids and stroke is relatively weak. However, the concept of the unstable plaque is as relevant to stroke as it is to MI. The landmark trial was the 2006 SPARCL trial that also used a high-dose, highpotency statin relatively early after the index stroke. (“SPARCL investigators: High-dose atorvastatin after stroke or transient ischemic attack.” NEJM 2006; 355:549-59). Over the course of five years, the statin group had a 16% relative risk reduction in second strokes. No change in mortality was seen, and there was a small increase in hemorrhagic strokes. In sum, the results suggest that for 1,000 patients treated for a year after stroke, 4.8 ischemic strokes and 3.5 MIs would be prevented, although at the cost of 1.9 extra hemorrhagic strokes (“Intensive statin therapy after stroke of transient ischemic attack: a sparcling success?” Stroke 2007;38:1110-1112).
Stroke is considered a coronary equivalent and the American Stroke Association recommends administration of statin therapy with intensive lipid lowering effects after stroke. Of course, not all data for statins after CVA is in agreement, and the results of the 2007 FASTER trial of statins immediately following TIA failed to find benefit at 90 days (“Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): a randomized controlled pilot trial.” Lancet Neurol 2007; 6:961- 69). It is an open question as to whether this variability is due to differences within the statin class or variability in study design. A meta-analysis with various statins following stroke suggests that 174 patients would need to be treated to prevent one second stroke from occurring (“Statin therapy in stroke prevention: a meta-analysis involving 21,000 patients.” Am J Med. 2008; 121:24-33).
Perioperative risk reduction
Surgery is a major physiologic stress with increased sympathetic tone, hypercoagulability and release of inflammatory mediators. Rates of ischemic events as high as 34% have been documented after vascular surgery and the pleiotropic effects of statins create the potential for reduction of perioperative adverse events. Indeed, reduction of circulating cytokines such as IL-6 and IL-8 have been demonstrated with statins prior to coronary bypass surgery.
A meta-analysis of statins in surgery revealed a 38% relative risk reduction (1.9% vs. 3.1%) in early mortality after cardiovascular surgery and 59% relative risk reduction (1.7% vs. 6.1%) in mortality after vascular surgery, largely due to reduction in perioperative MI and CVA rates. (“Improved postoperative outcomes associated with preoperative statin therapy.” Anesthesiology 2006; 150:1079-80). These findings are supported by a 2004 randomized controlled trial in elective vascular surgery that demonstrated a reduction in the rates of MI, CVA, and death from 26% in the placebo group to 8% in the statin group (“Reduction in cardiovascular events after vascular surgery with atorvastatin: a randomized trial.” Journal of Vascular Surgery 2004; 39:967-76). For high-risk patients undergoing high-risk surgery, these findings suggest statin initiation is reasonable.
All therapies that have benefit likely also have at least some potential for adverse effects, and statins are no exception. Myalgias are seen in 15% of patients, CK elevations in 0.9%, and hepatotoxicity in 1.4% of patients on statins. A review of clinical trials found only elevation in hepatic transaminases occurred significantly more often with statin treatment than placebo (“Risks associated with statin therapy: a systematic overview of randomized clinical trials.” Circulation 2006; 114:2788-2797). Major complications such as florid rhabdomyolysis or liver failure are rare. Risk of side effects rises with dose and particularly when there is a drug-drug interaction at cytochrome P450. Selected drugs that increase risk include cyclosporine, azole antifungals, fibrates, niacin, macrolides, warfarin and digoxin.
Potential future indications
Overwhelming infection due to sepsis is a leading cause of death in the U.S., and much of the morbidity can be attributed to an over-vigorous host inflammatory response. Therapies such as steroids or recombinant activated protein C target this to reduce mortality in sepsis. If statins, via pleiotropic effects, are also able to modulate the intensity of the inflammatory and thrombotic cascade, then could there be a role for this class of medications in sepsis as well?
Data from animal models imply benefit if started before or immediately after the infectious challenge. Retrospective observational and prospective cohort studies have mixed results, but some have suggested benefit in reducing mortality in humans. Of course, these studies include patients already on statin therapy and have to be interpreted in the context of the biases inherent in observational studies. A randomized controlled trial is ongoing but, at this time, sepsis is an intriguing but unproven indication for statins.
Statins represent a fascinating class of medications that benefit by long-term reduction in total body cholesterol burden. They also may act in the acute setting via pleiotropic mechanisms which improve endothelial function and reduce the intensity of the thrombotic and inflammatory signaling cascade. This suggests future lines of investigation and helps to explain the observed benefit in MI or stroke as well as the rationale for starting therapy for high-risk patients undergoing high-risk surgery.
Back to the case
For our 66-year old patient with ischemic stroke and LDL of 105 mg/dl I would recommend initiation of a high-dose, highpotency statin. Her LDL cholesterol is not at goal of 100 mg/dl. We should recognize that some of the improvements in outcomes seen in statin therapy may not be cholesterol mediated and early initiation has been shown to provide additional benefit even at low cholesterol levels. The hospitalization for an acute ischemic event offers the chance to start therapy which may pay dividends in a timeframe measured in months. In addition, therapy initiated in the hospital is likely to be continued by the patient after discharge. Secondary prevention, including statin therapy, for a patient such as the one in the case study should begin during hospitalization for the index stroke.