A Review on Statins as Medication Against Coronary Heart Disease

Coronary heart disease (CHD), also known as coronary artery disease and arteriosclerotic heart disease is defined by the narrowing of the small blood vessels that provide blood and oxygen to the heart.1 The disease starts with the condition call atherosclerosis which develops with a combination of fatty material (cholesterol), calcium and scar tissue (plaque) that builds up in the arteries for sustaining the heart muscle (myocardium) call the coronary arteries.2 This build up on the walls of the arteries causes them to narrow constricting blood flow to the heart. This causes symptoms such as chest pain or angina, shortness of breath, jaw pain, back pain or arm pain especially on the left side either during exertion or rest, palpitations, dizziness, light-headedness or fainting, weakness on exertion or at rest, heart attacks (myocardial infarction) and even a fatal rhythm disturbance (sudden cardiac arrest).1

CHD afflicts about 14 million men and women in the United States.2 CHD kills more than 110,000 people in the United Kingdom annually, causes angina (or chest pain) for more than 1.4 million people and heart attacks for 275,000 people each year.3 It is considered the most fatal disease in the United States and United Kingdom and claims more lives than all the remaining top seven diseases combined kills.2

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This disease may be hereditary or due to tobacco abuse (smoking or even chewing tobacco), obesity, high blood pressure or hypertension, diabetes, lack of regular exercise, menopause (for women), high-fat diet, emotional stress, type A personality (impatient, aggressive, competitive), high levels of low-density lipoprotein (LDL) considered the bad cholesterol and low levels of high-density lipoprotein (HDL) known as the good cholesterol.2 The risk of getting CHD drastically increases for men in the age of 40. The risk increases for both men and women as their age increases. Inflammation-related substances at high levels such as C-reactive protein, fibrinogen and homocysteine also increase the risk of heart disease.1

CHD is currently treatable and is variable depending on the symptoms and the severity of the disease. When CHD has no apparent symptoms (a condition called silent ischemia), the remedy prescribed is either medication or angioplasty (opening the narrowed blood vessels) with stenting. Studies have confirmed that both approaches are equally beneficial but angioplasty is a life-saving procedure to stop a heart attack. Angioplasty, stenting, coronary atherectomy and coronary radiation implant or coronary brachytherapy are collectively known as the precutaneous coronary interventions. Surgeries utilized in curing CHD are coronary artery bypass surgery (clogged arteries are bypassed) and minimal invasive heart surgery (opening the heart without having to stop it). Other medications include ACE inhibitors for blood pressure lowering; blood thinners (antiplatelet drugs) for reducing the risk of blood clots; beta-blockers for lowering heart rate, blood pressure and oxygen use by the heart; calcium channel blockers for relaxing arteries, lowering blood pressure and reducing strain on the heart; diuretics for blood pressure lowering; nitrates (like nitroglycerin) for stopping chest pain and improving blood supply to the heart; and statins for lowering cholesterol.1

 

This review focuses on the current researches on the ability of statins to prevent coronary heart disease and its other symptoms by lowering low-density lipoprotein cholesterol. The sheer amount of studies performed on this topic makes it necessary to provide a bird’s eye view of current trends and findings that may be helpful for physicians and the public alike to reduce the victims of the deadliest disease of the country. This review will delve into eight separate research papers related to the topic to be used as the primary sources.

Discussion

Cholesterol is an important component for the normal function of all cells in the body because it is typically found in the cell membrane. However, excessive amounts of cholesterol especially the low-level lipoprotein cholesterol (LDL-C) provides for the development of artherosclerosis.4

Statins are a class of drugs that can work to reduce cholesterol levels in the blood by lowering cholesterol production by the liver. They block the enzyme that works to make the cholesterol which is known as the methylglutaryl-coenzyme A reductace (HMG-CoA reductase) so statins are known as the HMG-CoA reductase inhibitors.4

Currently under research are non-cholesterol related actions of statins that may also prevent atherosclerosis. These include improvement of endothelial function, modulation of inflammatory responses, maintenance of plaque stability and prevention of thrombus formation.5

There are many types of statins available. In the United States, those approved for use are lovastatin (Mevacor), simvastatin (Zocor), pravastatin (Pravachol), atorvastatin (Lipitor), fluvastatin (Lescol) and rosuvastatin (Crestor).4 Other types are cerivastatin (which was withdrawn from the market because of serious side effects), mevastatin (a naturally-occuring compound found in red yeast rice), pitivastatin (Livalo, Pitava) and Ezetimibe+Simvastatin (Vytorin).5 The types vary in LDL-lowering potency (cerivastatin is the most potent), interaction with other drugs for CHD and derivation (either synthetic, fermentation-derived, naturally-occurring or combination therapy). The reviews mentioned pravastatin6, atorvastatin7, 8, 9, 10,12, rosuvastatin10,12 and simvastatin11,12, with atorvastatin as the most commonly used subject of the studies.

The research papers looked into the primary role of statins which is to lower LDL-C and total cholesterol but in different patient conditions. Atorvastatin was found to have LDL-C from 174 mg/dL to 72 mg/dL in one study with adult (18 years old or older) patients who experience unstable angina or non-Q-wave acute myocardial infarction.7 The results of another research showed a reduction of more than 30% of LDL-C and more than 20% of total cholesterol for simvastatin (at 40mg dose), atorvastatin (at 10mg dose) and rosuvastatin (at 5mg and 10mg doses) with patients undergoing treatment for 12 weeks or more.12 Pravastatin was found to have reduced 17% of total cholesterol levels and 28% of LDL-C level.6 LDL-C levels were reduced by 29% over a four year period for atorvastatin.8 In a comparison study between rosuvastatin and atorvastatin, it was also found that rosuvastatin (at 11mg dose) significantly reduced LDL-C, non-HDL-C and total cholesterol levels more than atorvastatin (at . The former also allowed for higher rates of attainment of goals set by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III in managing LDL-C.10 All these studies overwhelmingly confirm that statins, as inhibitors of cholesterol production, are effective in reducing harmful cholesterol that may lead to CHD.

More than the cholesterol-reducing effect of statins, the studies sough to relate post-hoc statin treatment with various symptoms.

One study compared pravastatin (at 40 mg/dL dose) and usual care in treating moderately hypercholesterolemic (with high levels of cholesterol) hypertensive (with high blood pressur) patients. The measures used were divided into primary outcome (all-cause mortality with follow-up of up to eight years) and secondary outcome (non-fatal myocardial infarction or fatal CHD combined, cause-specific mortality and cancer). It showed that although pravastatin was more effective in reducing cholesterol levels than usual care, there was no statistically significant difference between the two in preventing both primary and secondary outcomes.6 This somehow reveals that reduction of cholesterol may not reduce CHD events from occurring and afflicting the patient compared to usual care methods.

A different study sought to determine whether atorvastatin (at 80mg/dL dose) treatment initiated after 24 to 96 hours after an acute coronary syndrome could reduce death and non-fatal ischemic events (non-fatal acute myocardial infarction, cardiac arrest with resuscitation or recurrent symptomatic myocardial ischemia with objective evidence and requiring emergency re-hospitalization). The results showed that 14.8% of those treated with atorvastatin still experienced either non-fatal ischemic events or even death while 17.4% of the placebo group experienced these. Further investigation revealed that no statistical difference was found between the atorvastatin and placebo groups for death occurrences. On the other hand, risks of ischemic events and stroke were more significantly reduced in the atorvastatin group than the placebo group.7 This shows that reduction of cholesterol levels may not have prevented mortality but did, as a treatment, prevent some of the symptoms compared to no treatment at all.

Atrovastatin (at 10mg/dL or 80mg/dL dose), in another research, was correlated to the hospitalizations for heart failure. The treatment was applied to patients with stable coronary disease with 7.8% with a history of heart failure (HF). To keep the results reliable, patients with ejection fraction less than 30% and advanced HF were excluded from the research. Hospitalization incidence for HF was found at 2.4% in the 80mg/dL group and 3.3% in the 10mg/dL group overall. Breaking down the group, there was a 17.3% rate for 10mg/dL group with HF history and 10.6% for 80mg/dL group with HF history as well. For patients without HF, rates were at 1.8% for the 80mg/dL group and 2.0% for the 10mg/dL group. It is noteworthy that the reason for hospitalization was evidenced by preceding angina or myocardial infarction. Intensive treatment (at 80mg/dL) of atorvastatin reduced HF occurrences requiring hospitalization only with patients with a history of HF.9 This further shows the relationship of cholesterol reduction to the occurrence of heart failure – a symptom of CHD.

Other researches, instead of focusing on the symptoms, took into account the effect of factors for acquiring CHD on statin treatment.

One study tried to associate aggressiveness of treatment with cardiovascular risk since although the benefits of secondary prevent by statins is well known, some physicians and patients do not use them optimally where in fact they could benefit more from them. 19.1% of the patients in the study were prescribed statins for secondary prevention. From this number, 37.7% had low baseline risk; 26.7% were at the intermediate baseline risk and 23.4% had high baseline risk. However, statin prescription reduced by 6.4% each year as age of patients increase thereby increasing also the mortality risk of patients by 1%. Prescription for this drug was inversely related to cardiovascular risk and probability of death – even though the most benefits from taking statins as treatment is at that advanced stage.13 This shows that the factor of age not only increases the risk of having CHD but hinders proper and effective treatment.

Atorvastatin was also tested with patients with type 2 diabetes which increased the risk of CHD. It was found that in the group without prior myocardial infarction or interventional procedure, 10.4% of the atorvastatin group and 10.8% of the placebo group suffered the primary end point measure (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, coronary artery bypass surgery, resuscitated cardiac arrest and worsening or unstable angina that requires hospitalization). For those with previous myocardial infarction or interventional procedure, 26.2% of the atorvastatin group and 30.8% of the placebo group reached the primary end point. Relative risk reduction by atorvastatin was at 27% overall, 19% for patients without prior myocardial infarction or interventional procedure and 36% for patients with previous myocardial infarction or interventional procedure. However, the reduction of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, coronary heart bypass surgery, resuscitated cardiac arrest and worsening or unstable angina that requires hospitalization was not significantly different between the placebo and atorvastatin groups.8 This means that for type 2 diabetes patients, treatment with or without atorvastatin will produce the same results when it comes to reducing risk for these CHD events.

Another study linked various factors to CHD events and response to simvastatin theraphy. Patients with lowest high-density lipoprotein cholesterol (HDL-C) (at <1.00 mmol/L or 39ml/dL) and highest triglyceride (at >1.80 mmol/L or 159 mg/dL) quartile (lipid triad) showed increased features of metabolic syndrome (body mass index, hypertension, diabetes), and previous occurance of myocardial infarction, revascularization and beta-blocker use compared to patients with the highest HDL-C (> 1.34 mmol/L or 52 mg/dL) and lowest triglyceride (< 1.11 mmol/L or 98 mg/dL) quartile (isolated LDL-C elevation). Occurrences of major coronary events were highest for the lipid triad group on placebo at 35.9% and showed the greatest reduction (relative risk 0.48, 95% CI 0.33 to 0.69) after treatment with simvastatin. Treatment effect was also greater in the lipid triad group than the isolated LDL-C elevation group. In summary, patients with elevated LDL-C, low HDL-C and elevated triglycerides were more likely to exhibit characteristics of metabolic syndrome, higher probability of CHD events without treatment and receive the greatest benefit with treatment using simvastatin.11 This study confirmed that the cholesterol factor was treatable using statins by loweing harmful cholesterol levels.

One result that must be looked into is that from one study showing the side effect of statin treatment. This study showed that abnormal liver transaminases were more common in the group of patients treated with atorvastatin compared to the patients given placebos at 2.5% to 0.6%.7 Since statins prevent the normal function of the liver in producing cholesterol, this is an inevitable side effect. Other documented side effects of statins include headache, nausea, vomiting, constipation, diarrhea, rash, weakness and muscle pains. Some serious but rare side effects are liver failure and rhabdomyolysis. In rhabdomyolysis, damage to muscles occurs. This may begin with muscle pain but may progress to loss of muscle cells, kidney failure and even death. This usually happens when statins are used together with other medication that may directly cause rhabdomyolysis or may interact with statin preventing their degradation and increasing the levels of statins in the blood – making it more toxic.4

Since as was found in the researches, not all symptoms are cured by statins, other medication might be taken by the patient. Statins also have well-documented drug interactions. One is the elimination of statins by the liver where liver enzymes (cytochrom P-450) expel statins from the body (except for pravastatin and rosuvastatin). If a drug can inhibit the action of this enzyme, it may bring overall statin levels to high and dangerous levels that could eventually lead to rhabdomyolysis. Some of these drugs are protease inhibitors, erythromycin, itraconazole, clarithromycin, dilitiazem, verapamil and grapefruit juice. Another drug interaction is between the statins and niacin or fibric acids such as gemfibrozil, clofibrate and fenofibrate. These drugs can cause rhabdomyolysis and liver failure by themselves and the likelihood of these two conditions to develop is increased significantly if these drugs are used together with statins. Another known interaction is that between statins and cholestyramine and colestipol. These drugs bind statin to intestine walls thereby decreasing their ability to absorb nutrients.4

Looking at all researches in general, it is noteworthy that the time covered by each of the studies were different, ranging from 12 weeks to up to eight years. However, one study found that the duration of treatment had no effect in the amount of benefit received from the treatment.12 Therefore, the length of time that a patient is exposed to the treatment is irrelevant to the overall effect on the cholesterol concentration in his body – for as long as the treatment is continuous.

Another apparent fact in looking into all researches is that there is a difference in the number of respondents per study ranging from the hundreds to the thousands. This sheer number is not surprising given the number afflicted by the disease. However, the problem of homogeneity arises. To keep an experiment controlled, all factors except the ones to be tested must be constant. The differences in the conditions of the patients especially the baseline or starting cholesterol value are staggering and may cause a problem to the study. Certain computations are performed to adjust the results in lieu of differences in gender, age, social standing and progression of disease. But as for baseline, cholesterol concentration, one study also found that this has effect in the amount of benefit received from statin treatment.12

Of course, in all researches, problems may occur. For instance, one study was unable to answer one of its objectives. The research sought to determine the benefits of statins on patients with different levels of risks. However, since the study found that the statin prescription was dependent on (and diminished with) baseline risk, it was unable to determine the maximum benefits of statin treatment to patients with the highest risk.13 Another study which had a conclusion that was opposite the original hypothesis explained that the reasons behind this contradiction were methodological in nature – problems with the research design, complexity and breadth of the primary end point measurement, types of subjects enrolled for the research and changes to the protocol.8

Conclusion

Based on all the information gathered for this review, it can be concluded that statins, in general, are very effective in performing their role of reducing cholesterol levels in the body. It can also be concluded that statins may or may not be directly related in preventing the occurrence of the symptoms of CHD. It can also finally be concluded that there are factors such as age, condition and cholesterol concentration that could affect the efficacy of statin treatment. Finally, it can be concluded that statins are effective medication that could benefit patients with coronary heart disease.

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