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Statin Adverse Effects: Implications for the Elderly

http://www.geriatrictimes.com/g040618.html

by Beatrice A. Golomb, M.D., Ph.D.

Geriatric Times May/June 2004 Vol. V Issue 3

 

Statins, or 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (e.g.,

atorvastatin [Lipitor], simvastatin [Zocor]), are among the best-selling

prescription drugs in the world and are widely viewed as very safe and

effective. Their

benefits to coronary artery disease have been copiously documented and are

incontrovertible. In addition, statins have been shown to benefit survival in a

large study of middle-aged men with, or at high risk for, heart disease

(Scandinavian Simvastatin Survival Study Group, 1994). Nonetheless, all drugs

have

potential adverse reactions despite their potential benefits. Understanding

these

risks is vitally important, particularly in elderly patients in whom both

risks and benefits differ relative to younger patients.

 

Evidence suggests the balance of benefits to risks may be less favorable in

the elderly: Cholesterol becomes a less potent predictor of cardiovascular

problems, and adverse reactions from drugs, including statins, may become more

prominent. While patients at high risk for cardiovascular disease receive

mortality benefit from statins in studies predominating in middle-aged men

(Scandinavian Simvastatin Survival Study Group, 1994), no trend toward survival

benefit

is seen in elderly patients at high risk for cardiovascular disease (Shepherd

et al., 2002). A less favorable risk-benefit profile may particularly hold for

patients older than 85, in whom benefits may be more attenuated and risks

more amplified (Weverling-Rijnsburger et al., 1997). In fact, in this older

group, higher cholesterol has been linked observationally to improved survival.

This paper will review a selection of the risks and adverse effects of statins

that have special implications for elderly patients.

 

Muscle Problems

 

Muscle problems are the most common reported adverse effects of statins,

according to an observational database maintained by the University of

California

at San Diego Statin Study group. Perhaps the most feared adverse effect of

statins is rhabdomyolysis--a condition in which there is severe breakdown of

muscle tissue that may be toxic to the kidneys and result in kidney failure or

death. The muscle breakdown commonly leads to a strong elevation in blood levels

of muscle enzyme creatine kinase (CK). Creatine kinase levels often exceed 10

times the upper limit of normal in cases of frank rhabdomyolysis. Fatal

rhabdomyolysis occurred with increased frequency with cerivastatin (Baycol) when

used at higher doses or in combination with gemfibrozil (Lopid); cerivastatin

was

removed from the U.S. market in 2001. Rhabdomyolysis occurs with all statins,

although the actual frequency of occurrence is quite low.

 

Physicians are most familiar with rhabdomyolysis, and many suppose that for

muscle pain to be statin-associated, it must induce muscle symptoms throughout

the body coupled with elevation of CK levels. However, this reflects only one

manifestation of statin-associated muscle symptoms. Some patients have only

new focal pain or new fatigue, and may have mild or no elevation in CK levels.

In some instances these symptoms progress to rhabdomyolysis--one reason to take

these symptoms seriously--but many times they do not.

 

An important double-blind, crossover biopsy study showed that some patients

receiving statin therapy with non-CK-elevating muscle pain have objectively

documentable, partially reversible mitochondrial myopathy (Phillips et al.,

2002). Even in the absence of rhabdomyolysis or CK elevation, major effects on

function and quality of life may occur (Golomb et al., 2003). It is important to

note that in both our experience and that of others, muscle symptoms

precipitated by statins may not in all cases completely recover; this is

consistent with

the finding that, pathologically, the myopathy may not completely reverse.

 

Adverse muscle problems from statins, in addition to rhabdomyolysis, take a

variety of forms (Table http://i.cmpnet.com/CME/gt/content/g040618.jpg ).

Shortness of breath sometimes accompanies statin-associated muscle problems. The

" respiratory exchange ratio " --the ratio of carbon dioxide exhaled per oxygen

inhaled--is altered in people with statin myotoxicity (Phillips et al., 2004).

Occasionally, shortness of breath is the predominant symptom. Patients may

experience marked shortness of breath that occurs following initiation of statin

therapy and is sustained while statins are continued for which no etiology is

identified on extensive cardiopulmonary workup. These symptoms resolve

completely with statin discontinuation.

 

Muscle problems associated with statins may be more common among the elderly.

In the 2002 American College of Cardiology/American Heart

Association/National Heart, Lung, and Blood Institute Clinical Advisory on the

Use and Safety of

Statins, Pasternak et al. noted the following factors that may increase the

risk for statin-associated myopathy:

 

- advanced age (especially >80 years, women > men);

- small body frame and frailty;

- multisystem disease;

- multiple medications;

- perioperative periods; and

- concurrent use of certain medications.

 

These factors are especially common among the elderly, which places them at

increased risk for development of muscle problems with statins.

 

Muscle problems associated with statins may be more debilitating among the

elderly. When muscle problems occur, they may have more impact on the elderly.

Elderly patients more commonly have already declined in muscle strength and

function; and are often already on, or perched near, the steep part of the curve

relating muscle strength to physical function, independence and the ability to

perform activities of daily living. Thus, the same amount or proportion of

compromise in muscle function may have a substantially more profound impact on

quality of life in elderly patients. In addition, reductions in physical

function, indexed by reductions in lower extremity function, are linked to

self-reported disability, hospitalizations, admissions to nursing homes and

mortality

from all causes (Guralnik et al., 2000, 1995, 1994; Penninx et al., 2000).

Reductions in lower extremity function are associated with reduced physical

activity (McDermott et al., 2002), so that such patients may lose the protection

that exercise is reported to afford against a host of conditions.

 

Cognitive Loss

 

Cognitive problems also occur with statins and may also have more impact in

elderly patients. Two randomized trials that were designed to assess cognitive

effects of statins have shown worsening in cognitive function (Muldoon et al.,

2002, 2000). In addition, several case reports (King et al., 2003, 2001; Orsi

et al., 2001) and one large case series (involving 60 patients) (Wagstaff et

al., 2003) have reported deleterious cognitive effects of statins on memory

and cognitive function.

 

Although not expressly designed to assess cognition, results from the Heart

Protection Study (HPS) (Heart Protection Study Collaborative Group, 2002) and

PROSPER trial (Shepherd et al., 2002) did not show that statin therapy had

favorable or deleterious effects on cognitive measures that were tested. Several

factors may help to explain the discrepancy between findings from these large

and smaller trials targeted at testing cognition. First, different measures of

cognition were used that may not have tapped the areas in which problems

occur. The telephone survey measure in the HPS, for instance, would not have

captured visuomotor coordination and processing speed, which the other trials

suggested may be particularly affected.

 

Second, the large trials enrolled people at high risk for cardiovascular

disease who experience benefit from statins to nonfatal stroke, which may lead

to

improvements in cognition that may help to balance out harms to cognition from

other mechanisms. Although there are trends toward increases in fatal stroke

with statins in most of the large statin trials, those who have died cannot

complete cognitive surveys. The impact on total number of strokes was unaffected

in the PROSPER trial with its sole focus on the elderly population. In the

PROSPER trial, the number of reduced transient ischemic attacks and nonfatal

strokes was actually matched by a similar number of increased fatal strokes.

 

Finally, the HPS used what is termed an " active run-in. " For six weeks,

participants considered for enrollment were placed on simvastatin, and those who

were not fully compliant were dropped from the study. Participants who perceived

problems on the drug, including cognitive problems, may have dropped the

study themselves or skipped pills intentionally. In addition, participants who

developed memory problems may have had trouble remembering to take the pills

even

if they did not recognize deterioration in cognitive function. This run-in

process may have excluded participants who developed cognitive problems on the

drug, selecting only those who did not experience problems. Over one-third of

those who were interested in enrolling were excluded following this compliance

run-in.

 

Because statins reduce nonfatal stroke (and cognition is obviously not

measured in people who have experienced fatal stroke), benefits by statins for

cognitive function in those in whom a stroke was averted might be expected. It

must

be emphasized that the randomized trial evidence has, to date, uniformly

failed to show cognitive benefits by statins and has supported no effect or

frank

and significant harm to cognitive function.

 

Analogous to the case for muscle adverse effects, the impact of cognitive

adverse effects from statins, when they occur, may be more profound in the

elderly. Elderly patients have more commonly already experienced some decline in

cognitive function, and more commonly are in a vulnerable range in which

additional impairment can have an impact on independence and safety. Indeed, a

number

of studies show that even modest reductions in cognition in the elderly are

linked to increased mortality, even when the reductions remain within the

nondemented range, and even when other health factors have been controlled for

(Bassuk et al., 2000; Frisoni et al., 1999; Korten et al., 1999; Smits et al.,

1999). In this context, adverse cognitive effects must be taken seriously not

only

for their intrinsic impact on quality of life, but for their potentially

weighty implications for mortality.

 

Other Adverse Effects

 

A large variety of other adverse effects have been reported with statins,

including (but not limited to) gastrointestinal and neurological effects,

psychiatric problems, immune effects (e.g., lupus-like syndrome), erectile

dysfunction and gynecomastia (breast enlargement in men), rash and skin

problems, and

sleep problems.

 

Of particular note for the elderly population, the PROSPER trial found a

significant 25% increase in incident cancer in participants over age 70

randomized

to statin therapy versus placebo (Shepherd et al., 2002). Because statins

have been reported to cause cancer in animals, the significant increase in

cancer

cannot be dismissed as necessarily a fluke. While a similar increase has not

been seen in studies of statins in younger participants, older people have

poorer stores of the cancer-protecting antioxidant nutrients that low-density

lipoprotein cholesterol helps to transport to tissue (so that the increase in

risk may occur selectively in elderly). Even if the fractional change in risk

were similar, the elderly have a higher risk of cancer, increasing the number of

cancer events that would manifest.

 

Low cholesterol is also linked to infection, including development of

postoperative infection (Leardi et al., 2000) and predicts mortality and adverse

outcomes in hospitalized patients (Crook et al., 1999). While some of this could

be due to illness causing lower cholesterol, it may also be that low

cholesterol contributes to illness; indeed, animal studies suggest lipoproteins

may

serve to protect against bacterial endotoxin-induced death (Read et al., 1993).

 

Statins may produce irritability or short temper in some people, a problem

that occurs with statin therapy and resolves with its discontinuation (Golomb et

al., 2004). For elderly patients who depend on others for assistance,

irritability and its impact on the relationship with caregivers may have special

implications.

 

Heart failure may also occur in patients taking statin therapy. In some

people, the myopathic effects of statins may impair heart pumping function

(Silver

et al., 2003). However, in patients with reduced pumping function due to

coronary artery blockages, statins may help heart pumping by improving blood

flow

to the heart (Node et al., 2003). It depends on the person whether benefit or

harm dominates with statin therapy.

 

Discussion

 

Observational studies show that as age increases within the elderly age

range, high cholesterol flattens then reverses as a risk factor for mortality

(Weverling-Rijnsburger et al., 1997). Although it remains to be fully clarified

whether these findings have relevance to cholesterol-lowering treatment, the

exclusive major randomized trial of statins conducted in the elderly does

nothing

to dispel a possible causal association, as it did not show benefit of statins

to survival. The impact was completely neutral on mortality despite selecting

for an elderly population at only moderately older age and selecting for

particularly high risk of heart disease--the elderly group in whom greater

benefits and lower risks would be expected (Shepherd et al., 2002). There are

reasons

for concern that still older people--those elderly not selecting for high

cardiac risk and those who are frailer than clinical trials generally

select--might fare less well. Caution should be exercised in provision of

statins as with

all treatments in elderly patients. Any time a patient develops a new problem

or worsening of an existing problem, the medication list should be reviewed

and a possible contribution by medications should be considered. This principle

is by no means confined to statins. It is particularly true in elderly

patients who may be on many medications with interacting effects, and in whom

ability to withstand adverse drug reactions may be attenuated.

 

Acknowledgement

 

Dr. Golomb would like to thank Tram Dang for research assistance and Janis

Ritchie, R.N., for administrative assistance.

 

Dr. Golomb is on the faculty of the department of medicine and family and

preventive medicine at the University of California, San Diego. Her research

focuses on the risks and benefits of medical interventions.

 

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