Practical Pointers - April 2005

Blacks have the highest morbidity and mortality from hypertension of any population group in the USA. The choice of the most effective and efficacious first-choice antihypertension drug is therefore important. This has been controversial in blacks.

This study asks if the benefits of thiazide diuretic therapy (chlorthalidone) compared with an ACE –inhibitor (lisinopril) and Calcium blocker (amlodipine) extended to black patients.

In blacks, neither the ACE nor the CB was more effective than the thiazide diuretic in preventing the primary outcome of fatal CVD + non-fatal-MI, or any other major cardiovascular or renal outcome.

Chlorthalidone was superior to ACE and CB in reducing incidence of heart failure.

Chlorthalidone was associated with a lower incidence of stroke than lisinopril.

Much of the comparative benefit may have been due to the greater reduction in systolic BP associated with chlorthalidone.

“Thiazide-type diuretics remain the drugs of choice for initial therapy of hypertension in both black and non-black hypertensive patients.”

Using a diuretic as first-line therapy in both blacks and whites is associated with considerably lower costs over the years.

Costs; Chlorthalidone and hydrochlorothiazide cost 9 to 12 cents a day

Prinivil 53 cents a day; Norvasc $1.40 a day.

“ Hypertensive End-Organ Damage Begins With A BP Below 140/90.”

4-2 ELEVATED BLOOD PRESSURE AND RISK OF END-STAGE RENAL DISEASE IN SUBJECTS WITHOUT BASELINE KIDNEY DISEASE

Establishing a detrimental effect of lesser degrees of BP elevation on the kidneys is difficult because kidney disease itself can elevate BP. This study asks: What is the importance of hypertension as a risk factor for ESRD?

A graded association between baseline BP and risk of ESRD existed among subjects without clinical evidence of kidney disease at baseline. Even relatively modest elevations of BP were associated with an increased risk of ESRD. “Hypertensive end-organ damage begins with a BP below 140/90.”

At any given level of BP there was a much higher risk of ESRD among blacks and patients with diabetes. Again demonstrating that risk of disease follows a linear pattern. There is no “normal” BP cut point.

Extra vigilance is required for black patients and for those with diabetes.

Neither Amlodipine Nor Lisinorpil Was Superior To Chlorthalidone

4-3 RENAL OUTCOMES IN HIGH-RISK HYPERTENSIVE PATIENTS WITH AN ANGIOTENSIN-CONVERTING ENZYME INHIBITOR OR A CALCIUM CHANNEL BLOCKER VS DIURETIC

In both diabetic and non-diabetic participants, the 6-year rate of ESRD for those assigned to chlorthalidone was no different from those assigned to lisinorpil. The benefits of ACE inhibitors (and angiotensin blockers) have been attributed to their effects on the renin-angiotensin system and their unique anti-proteinuric effects. Epidemiological studies have demonstrated a strong association between BP and ESRD outcomes. There was, however little difference in BP between the chlorthalidone and lisinorpil groups.

What is the message for primary care clinicians? Fortunately, we are not limited to an either-or choice of therapy as in the trial. Most high-risk hypertensive patients (with and without diabetes) will require two or three drugs to reduce BP as much as possible. A combination of a diuretic, an ACE, and a calcium blocker would be appropriate.. The diuretic should not be omitted. Addition of a beta-blocker should be considered in some patients.

Associated with longer survival.

4-4 MODIFIED MEDITERRANEAN DIET AND SURVIVAL

The Mediterranean diet (MD) is characterized by a high intake of vegetables, legumes, fruits, and cereals (largely unrefined); a moderate to high intake of fish; a low intake of saturated fats; a high intake of unsaturated fats (particularly olive oil); low to moderate dairy products; a low intake of meat; and a modest intake of ethanol, mostly as wine.

This study examined whether adherence to a modified MD (poly-unsaturated fats substituted for mono-unsaturates) was associated with longer life expectancy among elderly Europeans.

Means scores on the 10-point MD scale varied considerably between countries. Greece was highest (6.25); Spain next (5.61); Netherlands was lowest (2.92).

An increase in this modified MD score was associated with lower overall mortality. A two-unit increment corresponded to a reduction on 8% in mortality.

I believe the modification (substituting poly-unsaturated fats for mono-unsaturated fat) is a clinically important point. Poly-fats are more accessible in our culture than mono-fats.

Too Often, Large Numbers Of Patients Are Being Treated Without Benefit.

4-5 NUMBERS NEEDED TO TREAT (NEEDLESSLY?)

The authors suggest a new index NNT(needlessly) to complement NNT(benefit). The higher the number, the greater the treatment burden.

For example, if the absolute difference between drug compared to placebo is 2% over 5 years, the NNT(benefit one patient) = 50. Of these, only one of 50 is benefited; 49 are treated (needlessly).

NNT(benefit) puts the emphasis on the positive side. But it tends to obscure the reality, that, too often, large numbers of patients are being treated without benefit.

The authors believe the new parameter will remind us that we should not be complacent about our inability to better identify patients who will benefit from our well-meaning interventions.

NNT(needlessly) may also help patients decide on their course of therapy.

This is a good illustration of the uncertainty principle of therapeutics, which is related to all treatments. We cannot judge beforehand which patients will benefit and which ones will be treated unnecessarily. The numbers in the latter will almost always be higher than the former.

The number needed to harm [NNT(harm)] is another helpful index. It can be easily calculated from data presented in trials. Usually, the older a patient becomes the greater the NNT(harm).

We might also consider the “Money Needed to Treat” (MNT). (Ie, the cost of a drug to benefit one patient + the cost of treating many patients needlessly. See the following. RTJ

The Cost Of Treating Patients Who Benefit + Those Who Do Not Benefit.

4-6 “MONEY” NEEDED TO TREAT (MNT)

The costs of treatment (money needed to treat to benefit one patient) can be easily calculated from analysis of trials which report the NNT (to benefit one patient over a given duration of therapy) in absolute terms. And by determining the cost of the drug.

A trial reported in NEJM April 7, 2005 “Intensive Lipid Lowering with Atorvastatin in Patients with Stable Coronary Disease” compared use of 80 mg the statin drug atorvastatin (Lipitor) with 10 mg. The LDL-cholesterol was lowered to a greater extent in the 80 mg group.

Over 5 years, major cardiac events occurred in 8.7% in the 80 mg group, and 10.9% in the 10 mg group Absolute difference = 2.2%; NNT(over 5 years to benefit one patient) = 45. Thus, 44 would be treated needlessly.

Based on the NNT (benefit) + the NNT (needlessly), the total cost of the 80 mg dose (44 + 1) = $65 700

Conversely, patients may be told that they will spend $1460 over 5 years to achieve a one in 45 chance of benefit.

“The Moral Basis of the Right to Die is the Right to Good Quality Life” “Mere Existence Is Not An Automatic Good.”

4-7 “RIGHT TO DIE”

A general question is whether there such a thing as a right to die. The editorialist believes there is for the following reasons:

1) Every human rights convention recognizes a fundamental right to life.

2) Paradoxically, as it might at first seem, this also entails a right to die.

A. Life in the phrase “the right to life” does not mean bare existence. It means existence that has a certain minimum quality.

B. Mere existence is not an automatic good

“It is perhaps characteristic of humankind that it regards reasoned choices about when and how to die as morally problematic, whereas ignoring the question and hoping for the best is seen as acceptable or even right.”

Lawyers and doctors distinguish between withholding treatment with death as the result, and giving treatment that causes death. The first is considered permissible in law and ethics. The second is not. “But in fact, there is no difference between them.” Withholding treatment is an act, based on a decision, just as giving treatment is an act based on a decision. “Like the doctrine of double effect, which allows death-hastening levels of analgesia with the putative aim of controlling pain, the distinctions are fictitious. Death, after all, is the ultimate analgesic.”

This one page commentary sums it up nicely

Primary Hyperparathyroidism Does Not Progress In Most Patients. “Most Have No Symptoms”

4-8 A 64-YEAR OLD WOMAN WITH PRIMARY HYPERPARATHYROIDISM

This “Clinical Crossroads” conference presents the history of Mrs. Q, a 64-year old woman with mild hypercalcemia over 7 years. Her serum calcium has varied from time to time (10.1 to 11.3 mg/dL; normal = 9.0 – 10.5 mg/dL). Her parathyroid hormone level was 102 pg/mL (normal = 10 – 60 pg/mL); phosphate level = 3.4 mg/dL;

albumin level = 4.1 g/dL

She was asymptomatic; never had any fracture or renal stone. No depression or mood swings. She did not take vitamin D or calcium. Her bone mineral density had decreased by 7% at the spine and by 5% at the femoral neck. 24 hour calcium excretion = 226 mg. Creatinine clearance normal.

A sestamibi scan revealed a localized increased uptake in the lower pole of the thyroid.

The consultant parathyroid surgeon concurred that the patient had mild chronic primary hyperparathyroidism.

How to proceed?

The article discusses epidemiology, pathophysiology, evaluation, end-organ effects, progression of the disease, effects on general well-being, surgical treatment, and recommendations of the National Institutes of Health for surgery.

Our understanding of the natural history of primary hyperparathyroidism has been clarified and expanded over the years.

The article describes several points which were new to me:

Hyperparathyroidism in all its forms is characterized by a re-setting of the activity of the parathyroid glands to maintain a calcium level above normal range. A new balance is reached wherein the parathyroid hormone (PTH) excretion is increased to maintain the serum calcium at a higher than normal level. The higher calcium level restrains the gland and maintains its secretion at a higher set level. In all other forms of hypercalcemia PTH is suppressed.

Prospective studies over 10 years have reported that primary hyperparathyroidism does not progress in most patients. “The stability of most cases of primary hyperparathyroidism is surprising, considering the neoplastic nature of the disorder.” It may be related to the previously mentioned set-point for secretion of PTH. (Secretion of the adenoma is suppressed by the elevated serum calcium levels.) The adenoma may grow until the serum calcium set-point is reached. Then secretion of PTH secretion remains steady and the tumor stops growing.

A new approach, minimally invasive parathyroidectomy, requires preoperative localization of the adenoma by scanning with Technicium Tc99m-labeled sestamibi. If an adenoma is located, a limited incision may be made. Morbidity is lowered, operating time shortened, and hospital stay reduced.

If you practice primary care long enough you will unexpectedly encounter a patient with primary hyperparathyroidism. Most are identified by a chemical screen, which reveals high serum calcium.

I believe many primary care clinicians would inform this patient:

1) The disease will not go away. It may progress and lead to increased bone loss over time.

2) You have already undergone 7 years of testing, worry, inconvenience, and expense.

3) Surgery will cure you and end all these concerns. The minimally invasive technique is safe. Recovery is rapid.

Primary care clinicians choose your surgical consultant carefully.

Reduced Complications and Risk Of Death.

4-9 THE EFFECT OF CARDIAC RESYNCHRONIZATION ON MORBIDITY AND MORTALITY IN HEART FAILURE

Despite improvements in pharmacologic treatment, many patients with heart failure (HF) have severe and persistent symptoms. Their prognosis is poor. Such patients commonly have regions of delayed myocardial activation (left bundle branch block), leading to cardiac dyssynchrony.

Resynchronization was accomplished by a pacemaker containing 3 leads (right atrium, right ventricle, and left ventricle. This resulted in a reduction in intraventricular mechanical delay and end-systolic volume, and an increase in the left ventricular ejection volume. It improved symptoms and quality-of-life.

CR substantially reduced the risk of complications and deaths among patients with HF due to left

ventricular systolic dysfunction and cardiac dyssynchrony. The benefits were in addition to those afforded by pharmacologic therapy. Over the study period, for every nine devices implanted, one death and 3 hospitalizations for major cardiovascular events were prevented. The reduction in risk of death is similar to that associated with beta-blocker therapy.

Obviously not a panacea. Experienced consultants must be chosen with care. Patients should be aware of the high rate of complications, and the likelihood of improvement. The greatest benefit may be improving quality-of-life.

See illustration of lead placement on page 1595

Enables The Ventricles To Contract Simultaneously.

4-10 RESYNCHRONIZING VENTRICULAR CONTRACTION IN HEART FAILURE

The biventricular-pacemaker implantation is technically demanding. It provides atrial-based, biventricular stimulation. Three leads are placed to pace 1) the right atrium, the 2) right ventricle, and the 3) left ventricle The left ventricular lead is inserted into the coronary sinus (in the right atrium) and advanced into a cardiac vein on the lateral wall of the lateral wall of the left ventricle. This enables the ventricles to contract simultaneously.

Complications of insertion are more frequent than for conventional pacemaker insertion

See illustration of the placement of the pacemaker leads on page 1595.

Primary care clinicians should be able to advise this subset of patients if the procedure is available.

The Clinical Hallmark Is Fatigable Muscle Weakness Which Improves With Rest and Application Of Cold

4-11 DOES THIS PATIENT HAVE MYASTHENIA GRAVIS?

This article reviews: anatomical and physiological origins of symptoms and signs; how to elicit symptoms and signs; anticholinesterase tests; and analysis of articles reviewed.

The approaches to diagnosis and treatment have evolved over the years. Testing now includes the ice pack test, the rest test, the sleep test, and the peek sign.

“Fluctuating weakness that worsens with exertion and improves with rest or with application of ice or cold is never normal.” The fluctuation is dramatic and occurs rapidly.

Bear in mind that the initial fluctuating weakness of MG may become fixed over time if severe enough.

Certain historical features (speech becoming unintelligible after prolonged periods) of signs (peek test) maybe useful in diagnosis. Their absence does not rule it out.

The ice test, sleep test, and response to anticholinesterase agents are useful in confirming the diagnosis

A positive test result should prompt proceeding with acetylcholine receptor antibody testing and specialist referral.

The authors did not mention a common associated abnormality—enlargement of the thymus. This is frequent enough, I believe, to warrant imaging in suspected cases of MG.

The patient with MG, on first presentation, should present suggestive symptoms and signs. Speaking from personal experience, it is embarrassing to miss the diagnosis.

“Ask Your Doctor if X is Right for You”

4-12 DIRECT-TO-CONSUMER ADVERTISING

A Haphazard Approach to Health Promotion

DTCA drives sales of newer, more expensive products for symptomatic relief of chronic conditions. The market potential is huge. Erectile dysfunction, arthritis, and allergies are the most common conditions advertised.

“Relying on emotional appeals, most advertisements provide a minimal amount of health information, describe benefits in vague, qualitative terms, and rarely offer evidence of support claims.”

The great majority of physicians believe that DTCA does not provide balanced information. The FDA rarely writes regulatory letters. “Millions of patients are exposed to misleading advertisements.” Nearly 80% of physicians think that DTCA encourages patients to seek treatments they do not need. Less than 10% of physicians consider DTCA a positive trend in health care.

Is ED a manufactured “disease”? Is drug treatment mainly recreational?

I confess that advertisements on TV touting a drug in market terms and then asking the listener to “Ask your doctor if the drug is right for you” irritates me. It would require considerable time and patience to educate individual patients about the benefit/harm-cost ratio of a given drug. It may be easier to submit as gracefully as possible.

I believe claims by drug companies that DTCA is for instruction and benefit of the consumer are specious. The purpose is to market the drug and increase profits.. After all, we live in a capitalistic society.

Associated With A Slight Reduction In Days Of Heavy Drinking.

4-13 EFFICACY AND TOLERABILITY OF LONG-ACTING INJECTABLE NALTREXONE FOR ALCOHOL DEPENDENCE

The opioid antagonist naltrexone has been shown to be effective for treatment of alcohol dependence (AD). The FDA approved naltrexone in 1994 to treat AD after it was shown to reduce drinking frequency and likelihood of relapse to heavy drinking.

However, adherence to daily oral therapy is problematic, as it is with other medications.

Recently a new formulation of naltrexone has been made available. When given by injection, it releases the drug over a period of one month without daily peaks in concentration.

A randomized, double-blind, placebo-controlled multicenter trial followed over 400 patients (mean age = 45). All were considered to be AD and almost all were still actively drinking (median heavy drinking days per month = 20). All were seeking treatment for their AD.

Randomized to: 1) monthly injections of 380 mg long-acting naltrexone, or 2) placebo injections.

All also received low-intensity psychosocial intervention.

Follow-up = 6 months.

Conclusion: Long-acting naltrexone, given by injection once a month, was associated with a slight reduction in days of heavy drinking.

Authors (with concurrence from journal editors) persist in reporting efficacy as percentages. (“Naltrexone resulted in a 25% reduction in the event rate of heavy drinking days”).

Results of the trial were not impressive. Dropout rate was high. Women did not benefit. Adverse effects were frequent. “Spin” was evident.

The most evident benefit shown by the study was in the “placebo” group (motivated patients who received counseling). At 6 months there was a median reduction in days of heavy drinking per month from about 19 to about 6. Naltrexone was associated with a further reduction from 6 to 3 days. (My assessment of the figure 2 page 1622). Over the 6 months, in the placebo group there was a median of 56 cumulative days of heavy drinking vs 47 cumulative days in the naltrexone group, a difference of only about 9 days.

Should primary care clinicians administer long-acting naltrexone by injection? I believe only in exceptional circumstances. If a patient with AD approaches the primary care clinician for help, the desire to quit must be understood to be strongly motivated. The clinician must be able to provide adequate counseling. Follow-up must be rigid. The clinician and patient must enter a contract to guide compliance. The small added benefit from naltrexone must be made clear.

We await better treatments, perhaps with the addition of two or more pharmacological agents (eg, acamprosate).

The study was sponsored by Alkermes and Pharmacological Product Development Inc. who collected and monitored the data. Data were managed and analyzed by Alkermes clinical and statistical staff.

“May Lead To Treatment Which Slows Disease Progress”

4-14 GENE DISCOVERY PROVIDES CLUES TO CAUSE OF AGE-RELATED MACULAR DEGENERATION

A gene variant may be responsible for about half of the 15 million cases of AMD in the US. Using techniques from the Human Genome Project, investigators have identified a common variant of the complement factor H (CFH) gene that explains about 50% of cases:

Individual who possess a certain variant of the CFH gene are at increased risk of AMD. The protein [tyrosine replaced by histidine] encoded by the variant fails to bind to receptors on cells on the retina and surrounding blood vessels. The protective effect of normal CFH is lost. This leads to increased inflammation in the retina and choroid.

Discovery of this variant may lead to treatment which slows disease progress. A modest slow-down would be sufficient to preserve a patient’s vision for the rest of his life.

While not a practical point at this time, I felt the “News” was provocative enough to abstract.

ABSTRACTS APRIL 2005

Thiazide The Drug Of First-Choice For Blacks as Well as Whites.

4-1 OUTCOMES IN HYPERTENSIVE BLACK AND NON-BLACK PATIENTS TREATED WITH CHLORTHALIDONE, AMLODIPINE, AND LISINOPRIL

Blacks have the highest morbidity and mortality from hypertension of any population group in the USA. Mortality from end-stage renal disease, coronary heart disease (CHD), heart failure (HF), and stroke is higher than in the white population.

The choice of the most effective and efficacious first-choice antihypertension drug is therefore important. This has been controversial in blacks.

The ALLHAT trial ¹ (over 42 000 high risk black and white hypertensive subjects) determined that a regimen based on a thiazide-type diuretic was just as effective in preventing CHD as regimens based on an alpha-blocker, an ACE inhibitor (ACE), or a calcium blocker (CB). Overall, in the entire cohort of subjects, the thiazide was more effective than the other agents in preventing heart failure, and more effective than the alpha-blocker and the ACE inhibitor in preventing stroke and a composite of cardiovascular disease outcomes.

This study asks if the benefits of diuretic therapy (compared with ACE and CB) extended to black patients.

Conclusion: As initial therapy, diuretic was just as beneficial as ACE and CB, and in some respects superior. Thiazides remain the drug of first choice for initial therapy for blacks as well as whites.

STUDY

1. Followed a prespecified subset of over 11 000 black patients in the ALLHAT study.

2. All had a history of hypertension; mean BP = 146/85. (Most were already receiving treatment)

3. All were over age 55 and had at least one other risk factor for CVD. (A high-risk group)

4. Randomized to regimens based on: 1) a calcium blocker (amlodipine; Norvasc; Lortrel);

2) an ACE inhibitor (lisinopril; Prinivil; Zestril; generic ), or 3) a thiazide (chlorthalidone; generic)

5. Other drugs (eg, a beta-blocker or an alpha blocker) could be added to achieve a goal BP less than 140/90.

The protocol prohibited any of the 3 study drugs from being used at the same time as either of the other 2.

6. Primary outcome = combined fatal CHD or non-fatal myocardial infarction (MI).

7. Secondary outcomes included all-cause mortality, stroke, combined cardiovascular disease, and end-stage

renal disease.

8. Follow-up = up to 6 years.

RESULTS

1. At baseline, blacks were more likely than whites to be women, have diabetes, smoke cigarettes, and have ECG evidence of left ventricular hypertrophy.

2. Outcomes over 6 years:

A. Combined fatal CHD + nonfatal MI; no significant difference between the 3 drugs.

B. Blood pressure: Chlorthalidone was associated with a slightly lower systolic BP than the other 2 drugs. At 4 years more blacks taking chlorthalidone reached the cut point of BP under 140/90.

C. Stroke: Chlorthalidone treatment was associated with a significantly lower incidence of stroke when compared with lisinopril. (RR = 1.4)

D. Heart failure: Chlorthalidone was associated with a significantly lower incidence of HF than either lisinopril or amlodipine.

F. End stage renal disease: No difference between groups.

G. All-cause mortality: No difference between groups.

2. Adverse effects: Chlorthalidone was associated with a greater incidence of lowering of serum potassium

(< 3.5 MEq/L) and slightly higher fasting glucose levels. ACE was associated with a higher incidence of angioedema.

3. Serious adverse effects were rare in all 3 groups.

DISCUSSION

1. The findings by race mostly parallel those in the entire cohort of the ALLHAT trial (where 2/3 of the subjects were white). Neither ACE nor the CB was more effective than the thiazide diuretic in preventing the primary outcome of fatal CVD + non-fatal-MI, or any other major cardiovascular or renal outcome.

2. Chlorthalidone was superior to ACE (lisinopril) and CB (amlodipine) in reducing incidence of heart failure.

3. Chlorthalidone was associated with a lower incidence of stroke than lisinopril.

4. Much of the comparative benefit may have been due to the greater reduction in systolic BP associated with chlorthalidone.

5. A high % of subjects required 2 or more antihypertension drugs. Since ACE, CB, and thiazide were being compared in the trial as first-line agents, and by protocol, could not be used in combination, the most commonly added 2^nd drug was the beta-blocker atenolol. Clonidine (alpha blocker) was next.

6. Thiazide-type diuretics are indicated as the drug of choice for initial treatment of high BP in both blacks and whites.

7. What is the second or third (add-on) choice? (Clinically, we are not limited to using the 3 drugs simultaneously. Choice would depend on response of BP and concomitant abnormalities. I believe a beta-blocker should be considered based on cost and safety. In the trial it was the most used add-on. RTJ)

CONCLUSION

For blacks, thiazide diuretic therapy based on chlorthalidone as first-line therapy was equally as effective as an ACE and a CB for any prespecified outcome. Thiazide diuretic therapy resulted in the lowest risk of heart failure and a lower risk of stroke (compared with ACE).

“Thiazide-type diuretics remain the drugs of choice for initial therapy of hypertension in both black and non-black hypertensive patients.”

JAMA April 6, 2005; 293: 1595-1608 Original investigation by the “Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial” (ALLHAT) Collaborative Research Group, first author Jackson Wright Jr. Case Western Reserve University, Cleveland, Ohio.

1 JAMA 2002; 288: 2981-97 See Practical Pointers December 2002 [1-12]

“ Hypertensive End-Organ Damage Begins With A BP Below 140/90.”

4-2 ELEVATED BLOOD PRESSURE AND RISK OF END-STAGE RENAL DISEASE IN SUBJECTS WITHOUT BASELINE KIDNEY DISEASE

Many cases of end-stage renal disease (ESRD) are ascribed to hypertension. But, because renal disease itself can cause hypertension, is the hypertension seen in patients with ESRD due to the underlying renal disease? Or does hypertension contribute to the renal disease?

This study asks: What is the importance of hypertension as a risk factor for ESRD?

Conclusion: Even modest elevations of BP are an independent risk factor for ESRD.

STUDY

1. Considered a large cohort (over 316 000) adult members of the Kiser Permanente health care delivery system. All received Multiphasic Health Checkups between 1964 and 1985. Mean age at baseline = 37

2. All had estimated glomerular filtration rates of 60 mL/min per 1.73 m² or higher. All had negative urine dipsticks for proteinuria and hematuria. None were considered to have renal disease.

3. The cohort was divided into 7 BP levels.

4. Determined incidence of ESRD over 8 210 000 person-years of follow-up.

RESULTS

1. During follow-up, 1149 cases of ESRD occurred.

2. There was a strong, graded relationship between BP and risk of ESRD.

3. Overall, the relationship between BP and ESRD persisted after adjustment for multiple other factors.

Adjusted relative risk of ESRD

1) Optimal; <120.80 1.00

2) Normal, not optimal; 120-129/80-84 1.60

3) High normal; 130-139/85-89 2.00

4) Stage 1 hypertension; 140-159/90-99 2.60

5) Stage 2 hypertension; 160-179/100-109 3.80

6) Stage 3 hypertension; 180-209/110-119 3.90

7) Stage 4 hypertension; 210/120 and higher 4.20

4. The age-adjusted associations between BP and ESRD were much higher in blacks vs white and among diabetics.

DISCUSSION

1. There are few studies to support the widely held belief that non-malignant hypertension is an important cause of ESRD. Establishing a detrimental effect of lesser degrees of BP elevation on the kidneys is difficult because kidney disease itself can elevate BP.

3. This study demonstrated a graded association between baseline BP and risk of ESRD existed among subjects without clinical evidence of kidney disease at baseline. Even relatively modest elevations of BP were associated with an increased risk of ESRD. “ Hypertensive end-organ damage begins with a BP below 140/90.”

4. At any given level of BP there was a much higher risk of ESRD among blacks and patients with diabetes. .

CONCLUSION

Non-malignant hypertension is an independent risk factor for ESRD in patients without baseline kidney disease. Risk is increased even with relatively modest elevations of BP.

Archives Int Med April 25, 2005; 165: 923-28 Original investigation, first author Chi-yuan Hsu, University of California, San Francisco.

Neither Amlodipine Nor Lisinorpil Was Superior To Chlorthalidone

4-3 RENAL OUTCOMES IN HIGH-RISK HYPERTENSIVE PATIENTS WITH AN ANGIOTENSIN-CONVERTING ENZYME INHIBITOR OR A CALCIUM CHANNEL BLOCKER VS DIURETIC

This post hoc analysis is a companion to the preceding article. It is a report from the ALLHAT group and many of the same investigators.

This subset of the study assessed outcomes in the entire group ( n = 33 000) for renal outcomes. The methods used were identical to those in the study of blacks. Chlorthalidone, lisinorpil, and amlodipine were used separately as first line therapy. A beta-blocker and an alpha-blocker could be used as add-on therapy to reduce BP. (The protocol specified that none of the 3 primary drugs could be used together.)

At baseline the study divided the entire group of patients into 3 groups according to: 1) a normal GFR; 2) mild decrease in GFR; and 3) moderate or severe decrease in GFR. Then compared renal outcomes (development of end-stage renal disease of and/or a decrement of 50% or more in glomerular filtration rate; GFR) over 5 years in patients taking the three different drugs.

RESULTS

1. Over 5 years 448 patients developed ESRD.

2. Chlorthalidone vs amlodipine: No significant differences in incidence of ESRD in any of the three GFR groups. No significant difference in combined ESRD + 50% decline in GFR.

3. Chlorthalidone vs lisinorpil: No significant difference in incidence of ESRD in any of the three GFR

groups. No significant difference in combined ESRD + 50% decline in GFR.

4. The 5-year rate of ESRD in diabetic patients was about twice that of non-diabetics.

DISCUSSION

1. This study pre-specified renal outcomes as a secondary outcome. The large number of participants with reduced GFRs and diabetes allowed a head-to-head comparison of the effects of 3 drugs on renal disease outcomes.

2. In participants with reduced renal function, neither amlodipine nor lisinorpil was superior to chlorthalidone in lowering the incidence of ESRD or a composite of ESRD + a 50% or greater decline in GFR.

3. Regardless of whether hypertension is the cause or the consequence of kidney disease, when the two present together, high BP is associated with rapid progression, and adequate treatment of hypertension slows progression of the kidney disease and reduces the risk of ESRD. Thus there has been great interest in whether the choice of antihypertension drugs has an impact on renal disease progression.

4. Comparing diuretic with ACE inhibitor:

In both diabetic and non-diabetic participants, the 6-year rate of ESRD for those assigned to chlorthalidone was no different from those assigned to lisinorpil, The benefits of ACE inhibitors (and angiotensin blockers) have been attributed to their effects on the renin-angiotensin system and their unique anti-proteinuric effects. Epidemiological studies have demonstrated a strong association between BP and ESRD outcomes. There was, however little difference in BP between the chlorthalidone and lisinorpil groups in this study.

5. “Our findings have particular relevance for the treatment of patients with established diabetic nephropathy.” Inhibitors of the renin-angiotensin system have been shown to be superior to conventional treatment in patients with diabetes. Guidelines recommend use of ACE inhibitors (and angiotensin blockers) as first-line treatment of diabetic nephropathy. But, the ALLHAT study showed no difference in outcomes between diuretic and ACE at any level of GFR. However, ALLHAT study did not specifically study patients with diabetic nephropathy and proteinuria. Thus, the study does not refute current recommendations for treatment. ¹

CONCLUSION