Cochrane for Clinicians

Putting Evidence into Practice

Antihypertensive Agents for Prevention of Diabetic Nephropathy

Richard L. Dressler, M.D., M.P.H., University of Maryland School of Medicine, Baltimore, Maryland

The Cochrane Abstract below is a summary of a review from the Cochrane Library. It is accompanied by an interpretation that will help clinicians put evidence into practice. Richard L. Dressler, M.D., M.P.H., presents a clinical scenario and question based on the Cochrane Abstract, followed by an evidence-based answer and a full critique of the review.

Clinical Scenario

A 54-year-old woman with type 2 diabetes comes into your office. She has no evidence of diabetic nephropathy and needs medication for hypertension.

Clinical Question

Is one class of antihypertensive agents superior to others for the prevention of diabetic nephropathy?

Evidence-Based Answer

Angiotensin-converting enzyme (ACE) inhibitors are the only antihypertensive agents with proven effectiveness for the primary prevention of diabetic nephropathy (defined as an albumin excretion of less than 30 mg per day on three serial measurements) caused by type 1 or type 2 diabetes. However, ACE inhibitors have not been shown to decrease all-cause mortality in patients with diabetes. Based on limited data, ACE inhibitors have not been shown to reduce end-stage renal disease significantly when compared with placebo.1

Practice Pointers

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, the American Diabetes Association, and the American Association of Clinical Endocrinologists each recommend aggressive treatment of hypertension in patients with diabetes.2-4 The recommendations include ACE inhibitors among various other classes of antihypertensive agents. Secondary prevention of kidney disease in patients with diabetes who have microalbuminuria is well established. However, none of these recommendation statements addresses the primary prevention of nephropathy using antihypertensive agents in patients who have normal kidney function with or without hypertension.

This Cochrane review1 included studies involving patients with type 1 and type 2 diabetes regardless of blood pressure. However, most trials involved patients with type 2 diabetes and hypertension. Study duration ranged from six to 72 months.

The review clearly identified ACE inhibitors as having the most substantial evidence for their usefulness in preventing diabetic nephropathy compared with placebo. It also demonstrated that, compared with calcium channel blockers, ACE inhibitors reduced progression to microalbuminuria but did not reduce all-cause mortality. The few data available do not show a significant reduction in end-stage renal disease with ACE inhibitor therapy. The number of patients with diabetes who need to be treated with an ACE inhibitor to prevent microalbuminuria in one patient is 25.

An additional question is whether patients with diabetes who are normotensive receive a marginal benefit from treatment with ACE inhibitors in preventing nephropathy. However, randomized controlled trials have not included a sufficient number of patients who are normotensive to provide an answer. Although some physicians prescribe ACE inhibitors to prevent nephropathy in patients with diabetes who are normotensive, there is no compelling evidence to support this.

Of primary importance is that, although a body of evidence addresses the intermediate outcome of microalbuminuria as a key point in the progression to end-stage renal disease, there is no evidence to prove that ACE inhibitors affect all-cause mortality. This may be because of the burden of cardiovascular disease, the most common cause of death among patients with diabetes. It is possible that all antihypertensive medications that are protective against cardiovascular mortality are equally effective in preventing morbidity and mortality in patients with diabetes, and that therapy with ACE inhibitors is no more effective than therapy with beta blockers (which have no known effect in preventing diabetic nephropathy) for the prevention of cardiovascular mortality in these patients. Another possibility is that preventing end-stage renal disease has no benefit for mortality because patients with diabetes may die at a similarly premature age from other causes. Considering that cardiovascular disease is the primary cause of mortality in patients with diabetes, other classes of antihypertensive agents that are effective in preventing coronary artery disease, such as beta blockers, diuretics, calcium channel blockers, and angiotensin-receptor blockers, also should be considered in this population.

The Author

RICHARD L. DRESSLER, M.D., M.P.H., is assistant professor and assistant residency director in the Department of Family Medicine at the University of Maryland School of Medicine, Baltimore.

Address correspondence to Richard L. Dressler, m.d., m.p.h., University of Maryland School of Medicine, Department of Family Medicine, 29 S. Paca St., Lower Level, Baltimore, MD 21201-1771 (e-mail: rdressler@som.umaryland.edu). Reprints are not available from the author.

REFERENCES

1. Strippoli GF, Craig M, Craig JC. Antihypertensive agents for preventing diabetic kidney disease. Cochrane Database Syst Rev 2005;(4):CD004136.

2. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al., for the National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; and the National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report [Published correction appears in JAMA 2003;290:197]. JAMA 2003;289:2560-72.

3. American Diabetes Association. Standards of medical care in diabetes [Published correction appears in Diabetes Care 2005;28:990]. Diabetes Care 2005;28(suppl 1):S4-S36.

4. American Association of Clinical Endocrinologists. Medical guidelines for the management of diabetes mellitus: the AACE system of intensive diabetes self-management-2002 update. Diabetes Medical Guidelines Task Force. Endocr Pract 2002;8(suppl 1):40-82.

Cochrane Briefs

Systemic Lidocaine or Mexiletine for Neuropathic Pain

Clinical Question

When used systemically, are lidocaine (Xylocaine) and its oral analogue mexiletine (Mexitil) safe and effective for the treatment of neuropathic pain?

Evidence-Based Answer

Intravenous lidocaine and oral mexiletine provide a modest reduction in neuropathic pain with no indication of serious adverse effects. However, safety data are limited because most studies were of relatively short duration and fewer than 400 patients have been studied in total for each drug. Intravenous lidocaine and oral mexiletine should be considered second- or third-line options for the treatment of neuropathic pain and should be given only after a careful discussion with the patient regarding risks and benefits.

Practice Pointers

Case reports from the 1950s suggest that intravenous lidocaine, typically used as a local anesthetic, could provide pain relief in patients with cancer or postoperative pain. Subsequent reports in the 1980s suggested a similar benefit for the oral analogues mexiletine, flecainide (Tambocor), and tocainide (Tonocard). In the past decade, several better-designed clinical trials have been published; this Cochrane review provides an update on the safety and efficacy of lidocaine and its oral analogue mexiletine for the systemic treatment of neuropathic pain.

The authors reviewed randomized, double-blind, controlled studies that involved patients with neuropathic pain, including peripheral neuropathy, regional pain syndromes, spinal cord injury, trigeminal neuralgia, phantom limb pain, and fibromyalgia. Of the 30 studies identified, 12 were of good methodologic quality and all were small (median number of participants 28, range 8 to 87). The amount of intravenous lidocaine typically infused was between 1 and 5 mg per kg.

In 11 studies of lidocaine with a total of 373 patients, the researchers found a mean reduction of 11 mm in a 100-mm visual pain scale (95% confidence interval [CI], −17 to −5). The same benefit (mean difference −11 mm, 95% CI, −16 to −6) was found in nine studies of oral mexiletine (median dosage 600 mg per day for a median of nine weeks) with a total of 377 patients. Results generally were consistent and of similar magnitude among studies. Although statistically significant, an 11-mm improvement on a 100-mm scale generally is felt to be of borderline clinical significance. Adverse events (none serious) were more common in patients receiving lidocaine or mexiletine than in those receiving placebo (35 versus 12 percent, respectively).

A consensus guideline from the Reflex Sympathetic Dystrophy Syndrome Association1 mentions mexiletine as a "somewhat experimental" option for treatment of this condition. A second consensus guideline2 similarly notes that although mexiletine is an option, it is not considered a first- or second-line medication.

mark h. ebell, m.d., m.s.

Source: Challapalli V, et al. Systemic administration of local anesthetic agents to relieve neuropathic pain. Cochrane Database Syst Rev 2005;(4):CD003345.

REFERENCES

1. Reflex Sympathetic Dystrophy Syndrome Association. Clinical practice guidelines (second edition) for the diagnosis, treatment, and management of reflex sympathetic dystrophy/complex regional pain syndrome (RSD/CRPS). Milford, Conn.: Reflex Sympathetic Dystrophy Syndrome Association, 2002.

2. Dworkin RH, Backonja M, Rowbotham MC, Allen RR, Argoff CR, Bennett GJ, et al. Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol 2003;60:1524-34.

Planned Early Birth vs. Expectant Management for PROM

Clinical Question

Is induction or expectant management more appropriate for premature rupture of membranes at term (PROM)?

Evidence-Based Answer

Induction of labor in patients with PROM does not increase the rates of cesarean delivery or operative vaginal delivery. Among patients who are induced there is a slightly lower incidence of chorioamnionitis (relative risk [RR] 0.74; 95% confidence interval [CI], 0.56 to 0.97) and a lower rate of infant admissions to the neonatal intensive care unit (NICU; RR 0.73; 95% CI, 0.58 to 0.91). The evidence in this study shows induction to be a reasonable option with no increased risk of operative delivery or of harm to mother or neonate.

Practice Pointers

PROM is defined as rupture of membranes that occurs at term but before the onset of labor. It occurs in approximately 8 percent of pregnancies; 50 percent of patients deliver within five hours of membrane rupture, and 95 percent of patients deliver within 28 hours.1 The most significant risk of PROM is intrauterine infection, which increases with duration of rupture. Fetal risks include cord compression and ascending infection.1 Historically, two approaches have been used: induction or expectant management. Induction involves intervening to induce labor at diagnosis or within six to eight hours of rupture of membranes. Expectant management allows the onset of labor to occur spontaneously without intervention.

Dare and colleagues performed a systematic review of randomized controlled trials to compare outcomes of induction with oxytocin (Pitocin) or prostaglandin E2 gel (Prostin E2) versus expectant management of PROM in low-risk patients. They identified 12 trials with a total of 6,814 women. Maternal mortality was examined in one study and there were no maternal deaths in either arm. There was no difference between the two management approaches in the rates of cesarean delivery or of operative vaginal deliveries. Fewer women who underwent induction developed chorioamnionitis. Compared with expectant management, one case of chorioamnionitis will be avoided for every 50 women undergoing induction for PROM. Also, there were fewer cases of endometritis in the induction groups (RR 0.30; 95% CI, 0.12 to 0.74; four trials, 445 women).

Time from rupture of membranes to birth was reduced by 13 hours in patients receiving oxytocin and by eight hours in those receiving prostaglandin compared with expectant management. Patients who underwent expectant management also had higher rates of dissatisfaction. Only one study reported uterine rupture, with one rupture in the prostaglandin arm of that study and none in the expectant management arm. This difference was not statistically significant (95% CI, 0.12 to 68.50).

There were fewer NICU admissions in the induction group. One NICU admission was avoided for every 20 women induced for PROM. In one large study, neonates born in the expectant management group were more likely to spend more than 24 hours in the NICU. However, there were no statistically significant differences between the two groups regarding infant success of breastfeeding or incidences of cord prolapse and neonatal infection.

A meta-analysis2 published in 2005 found that misoprostol (Cytotec) was as safe and effective as oxytocin for induction of patients with PROM.

REBECCA ROSEN, M.D.

Source: Dare MR, et al. Planned early birth versus expectant management (waiting) for prelabour rupture of membranes at term (37 weeks or more). Cochrane Database Syst Rev 2006;(1):CD005302.

REFERENCES

1. ACOG Practice Bulletin. Premature rupture of membranes. Clinical management guidelines for obstetrician-gynecologists. Number 1, June 1998. American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet 1998;63:75-84.

2. Lin MG, Nuthalapaty FS, Carver AR, Case AS, Ramsey PS. Misoprostol for labor induction in women with term premature rupture of membranes: a meta-analysis. Obstet Gynecol 2005;106:593-601.

This clinical content conforms to AAFP criteria for evidence-based continuing medical education (EB CME). EB CME is clinical content presented with practice recommendations supported by evidence that has been reviewed systematically by an AAFP-approved source. The practice recommendations in this activity are available at http://www.cochrane.org/reviews/en/ab004136.html.

The series coordinator for AFP is Clarissa Kripke, M.D., Department of Family and Community Medicine, University of California, San Francisco.

A collection of Cochrane for Clinicians published in AFP is available at http://www.aafp.org/afp/cochrane.

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