Evolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin–kexin type 9 (PCSK9) and lowers low-density lipoprotein (LDL) cholesterol levels by approximately 60%. Whether it prevents cardiovascular events is uncertain.
We conducted a randomized, double-blind, placebo-controlled trial involving 27,564 patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or higher who were receiving statin therapy. Patients were randomly assigned to receive evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or matching placebo as subcutaneous injections. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. The median duration of follow-up was 2.2 years.
At 48 weeks, the least-squares mean percentage reduction in LDL cholesterol levels with evolocumab, as compared with placebo, was 59%, from a median baseline value of 92 mg per deciliter (2.4 mmol per liter) to 30 mg per deciliter (0.78 mmol per liter) (P<0.001). Relative to placebo, evolocumab treatment significantly reduced the risk of the primary end point (1344 patients [9.8%] vs. 1563 patients [11.3%]; hazard ratio, 0.85; 95% confidence interval [CI], 0.79 to 0.92; P<0.001) and the key secondary end point (816 [5.9%] vs. 1013 [7.4%]; hazard ratio, 0.80; 95% CI, 0.73 to 0.88; P<0.001). The results were consistent across key subgroups, including the subgroup of patients in the lowest quartile for baseline LDL cholesterol levels (median, 74 mg per deciliter [1.9 mmol per liter]). There was no significant difference between the study groups with regard to adverse events (including new-onset diabetes and neurocognitive events), with the exception of injection-site reactions, which were more common with evolocumab (2.1% vs. 1.6%).
In our trial, inhibition of PCSK9 with evolocumab on a background of statin therapy lowered LDL cholesterol levels to a median of 30 mg per deciliter (0.78 mmol per liter) and reduced the risk of cardiovascular events. These findings show that patients with atherosclerotic cardiovascular disease benefit from lowering of LDL cholesterol levels below current targets.
Mr. Winston, a 50-year-old bus driver, presented to your office with a 4-week history of pain in his left leg and lower back. He described a combination of severe sharp and dull pain that originated in his left buttock and radiated to the dorsolateral aspect of his left thigh, as well as vague aching over the lower lumbar spine. On examination, passive raising of his left leg off the table to 45 degrees caused severe pain that simulated his main symptom, and the pain was so severe that you could not lift his leg further. There was no leg or foot weakness. His body-mass index (the weight in kilograms divided by the square of the height in meters) was 35, and he had mild chronic obstructive pulmonary disease as a result of smoking one pack of cigarettes every day for 22 years. Mr. Winston had taken a leave of absence from his work because of his symptoms. You prescribed 150 mg of pregabalin per day, which was gradually increased to 600 mg daily because the symptoms had not abated.
Now, 10 weeks after the initial onset of his symptoms, he returns for an evaluation. The medication has provided minimal alleviation of his sciatic pain. He has to return to work and is concerned about his ability to complete his duties at his job. He undergoes magnetic resonance imaging, which shows a herniated disk on the left side at the L4–L5 root. You discuss options for the next steps in managing his sciatica. He is uncertain about invasive procedures such as lumbar disk surgery but feels limited by his symptoms of pain.
- Option 1: Undergo Lumbar Disk Surgery
- Option 2: Receive Nonsurgical Therapy
Mr. Winston’s case represents a common scenario in the management of symptomatic lumbar disk herniation. In this particular case, the patient’s symptoms and the physical examination are consistent with nerve-root compression and inflammation directly from an L4–L5 herniated disk on his left side. The patient does not have weakness but has ongoing pain and has been unable to work for the past 10 weeks despite receiving pregabalin. Two questions emerge: first, does lumbar disk surgery (microdiskectomy) provide outcomes that are superior to those with continued nonoperative therapy in patients with more than 6 weeks of symptoms; and second, does lumbar microdiskectomy improve the likelihood of return to work in patients with these symptoms?
The highest quality data on the topic come from the Spine Patient Outcomes Research Trial (SPORT).1 The results of the randomized, controlled trial are difficult to interpret because adherence to the assigned treatment strategy was suboptimal. Only half the patients who were randomly assigned to the surgery group actually underwent surgery within 3 months after enrollment, and 30% of the patients assigned to nonoperative treatment chose to cross over to the surgical group.2 In this study, the patients who underwent surgery had greater improvements in validated patient-reported outcomes. The treatment effect of microdiskectomy was superior to that of nonoperative treatment at 3 months, 1 year, and 2 years. Moreover, in an as-treated analysis, the outcomes among patients who underwent surgery were superior to those among patients who received nonoperative therapy. Overall, the results of SPORT support the use of microdiskectomy in this case.
Results of clinical trials are based on a comparison of treatment options in study populations and may or may not apply to individual patients. SPORT did not specify what type of nonoperative therapy was to be used. Physical therapy was used in 73% of the patients, epidural injections in 50%, and medical therapies (e.g., nonsteroidal antiinflammatory drugs) in more than 50%. In the case of Mr. Winston, pregabalin has been tried, but physical therapy and epidural glucocorticoid injections have not been attempted. Despite widespread use of physical therapy for the treatment of lumbar disk herniation, the evidence supporting its effectiveness is inconclusive, according to published guidelines of the North American Spine Society.3 On the other hand, there is evidence that transforaminal epidural glucocorticoid injection provides short-term relief (30 days) in patients with nerve-root symptoms directly related to a herniated disk.4 Overall, there is evidence, from SPORT and from a randomized trial from the Netherlands published in the Journal,5 that early surgery between 6 and 12 weeks after the onset of symptoms provides greater alleviation of leg pain and better overall pain relief than prolonged conservative therapy.
The ability to return to work has not been formally studied in comparisons of operative with nonoperative treatments for lumbar disk herniation. Registry data from the NeuroPoint-SD study showed that more than 80% of the patients who were working before disk herniation returned to work after surgery.6 The ability to return to work may be dependent on the type of vocation, since patients who are manual laborers may need more time to recover to reduce the risk of reherniation.
It is well recognized that many patients who have a symptomatic lumbar disk herniation will have improvement spontaneously over several months. Surgery can alleviate symptoms more quickly by immediately removing the offending disk herniation from the affected nerve root. The risk–benefit equation will vary among individual patients. In the case of Mr. Winston, obesity and mild pulmonary disease might increase the risk of complications from surgery, although in SPORT, 95% of surgical patients did not have any operative or postoperative complication. For Mr. Winston, a patient with pain that has persisted for more than 6 weeks, microdiskectomy is a rational option that is supported by high-quality evidence.
What are some of the clinical and laboratory findings associated with primary adrenal insufficiency?
Hyponatremia can occur in all forms of adrenal insufficiency, although it tends to occur most prominently in primary adrenal insufficiency (Addison’s disease). Primary adrenal insufficiency is caused by impairment of the adrenal glands, whereas secondary adrenal insufficiency is the result of corticotropin deficiency caused by either pituitary or hypothalamic disease. A Case Record of the Massachusetts General Hospital explains.
- What is the most common cause of primary adrenal insufficiency in high-income countries?
Primary adrenal insufficiency is a rare entity, and in high-income countries, autoimmune adrenalitis is the most common cause.
- Do patients with adrenal insufficiency have a normal life expectancy?
Patients with adrenal insufficiency have a mortality rate that is 2 or 3 times the normal rate, and they have an increased incidence of certain cancers. Morbidity is considerable. Patients often have absences from school or work, frequent hospitalizations, and alterations in work life, social life, family life, and physical activity.
Morning Report Questions
Q: What are some of the clinical and laboratory findings associated with primary adrenal insufficiency?
A: The signs and symptoms are nonspecific and include fatigue, dizziness, gastrointestinal illness, salt craving, and hyperpigmentation. Hyperpigmentation is almost always present in chronic primary adrenal insufficiency. There are also some case reports of chronic primary adrenal insufficiency in which hyperpigmentation is absent, most likely because there are adequate resting levels of plasma cortisol, which would prevent increased corticotropin secretion and subsequent melanocyte stimulation. Among patients with adrenal insufficiency, hyperkalemia occurs only in those with the primary form, owing to the aldosterone deficiency. Hyperkalemia occurs in only 50 to 60% of patients with primary adrenal insufficiency, perhaps because of aldosterone-independent regulatory mechanisms in the distal nephron that maintain eukalemia. A fraction of patients with adrenal insufficiency have a peripheral eosinophilia.
Figure 1. Laboratory Abnormalities in Primary Adrenal Insufficiency.
Q: How sensitive is the 21-hydroxylase antibody test for autoimmune adrenal insufficiency?
A: A 21-hydroxylase antibody test is approximately 60 to 75% sensitive, so a positive test would indicate an autoimmune cause, but a negative test does not rule it out. Other antibodies have been identified in patients with autoimmune primary adrenal insufficiency, such as antibodies against the steroid 17α-hydroxylase and side-chain cleavage enzymes. These tests are not widely available and are not specific.