Guidance for Industry 

Hypertension Indication: Drug 

Labeling for Cardiovascular 

Outcome Claims 

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only. 

Comments and suggestions regarding this draft document should be submitted within 60 days of 

publication in the Federal Register of the notice announcing the availability of the draft 

guidance. Submit comments to the Division of Dockets Management (HFA-305), Food and 

Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments 

should be identified with the docket number listed in the notice of availability that publishes in 

the Federal Register. 

For questions regarding this draft document contact Mr. Devi Kozeli at 301-796-1128. 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

March 2008 

Labeling 

I:\6954dft.doc 

03/03/08 
Guidance for Industry 

Hypertension Indication: Drug 

Labeling for Cardiovascular 

Outcome Claims 

Additional copies are available from: 

Office of Training and Communications 

Division of Drug Information 

Center for Drug Evaluation and Research 

Food and Drug Administration 

10903 New Hampshire Ave., Bldg. 51, rm. 2201 

Silver Spring, MD 20993 

(Tel) 301-827-4573 

http://www.fda.gov/cder/guidance/index.htm 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

March 2008 

Labeling 
TABLE OF CONTENTS 

I. INTRODUCTION............................................................................................................. 1

II. BACKGROUND ............................................................................................................... 2

III. JUSTIFICATION FOR ADDING OUTCOME CLAIMS TO LABELING............... 2

IV. LABELING RECOMMENDATIONS............................................................................ 3

A. Highlights........................................................................................................................................3

B. Full Prescribing Information — Indications and Usage ............................................................4

C. Full Prescribing Information — Clinical Studies .......................................................................5

V. DRUG CLASSIFICATIONS FOR ANTIHYPERTENSIVE DRUGS ........................ 5

REFERENCES.............................................................................................................................. 7
Contains Nonbinding Recommendations 

Draft — Not for Implementation 

Guidance for Industry1 1 

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Hypertension Indication: Drug Labeling for 

Cardiovascular Outcome Claims 

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8 This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s) current 

9 thinking on this topic. It does not create or confer any rights for or on any person and does not operate to 

10 bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of 

11 the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA 

12 staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call 

13 the appropriate number listed on the title page of this guidance. 

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I. INTRODUCTION 

This guidance is intended to assist applicants in developing labeling for cardiovascular outcome 

claims for drugs2

 that are indicated to treat hypertension. With few exceptions, current labeling 

for antihypertensive drug products includes only the information that these drugs are indicated to 

reduce blood pressure; the labeling does not include information on the clinical benefits related 

to cardiovascular outcomes expected from such blood pressure reduction. However, blood 

pressure control is well established as beneficial in preventing serious cardiovascular events, and 

inadequate treatment of hypertension is acknowledged as a significant public health problem. 

The Food and Drug Administration (FDA) believes that the appropriate use of these drugs can be 

encouraged by making the connection between lower blood pressure and improved 

cardiovascular outcomes more explicit in labeling. This guidance is intended to recommend 

standard labeling for antihypertensive drugs except where differences are clearly supported by 

clinical data. After this guidance has been finalized, applicants will be encouraged to submit 

labeling supplements containing the new language. 

FDA’s guidance documents, including this guidance, do not establish legally enforceable 

responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should 

be viewed only as recommendations, unless specific regulatory or statutory requirements are 

cited. The use of the word should in Agency guidances means that something is suggested or 

recommended, but not required. 

1

 This guidance has been prepared by the Division of Cardiovascular and Renal Products in the Center for Drug 

Evaluation and Research (CDER) at the Food and Drug Administration. 

2

 For the purposes of this guidance, drug includes drugs regulated under section 505 of the Federal Food, Drug, and 

Cosmetic Act and biological products regulated under section 351 of the Public Health Service Act. 

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II. BACKGROUND 

On June 15, 2005, the Cardiovascular and Renal Drugs Advisory Committee met in open public 

session to discuss class labeling for cardiovascular outcome claims for drugs that are indicated to 

treat hypertension.3 The committee voiced a broad consensus in favor of labeling changes to 

describe briefly the clinical benefits related to cardiovascular outcome expected from lowering 

blood pressure with any antihypertensive drug. The labeling proposed in this guidance is 

consistent with the advisory committee’s recommendations. 

III. JUSTIFICATION FOR ADDING OUTCOME CLAIMS TO LABELING 

Actuarial data and epidemiological studies such as the Framingham Heart Study have shown that 

elevations in blood pressure (systolic or diastolic) are associated with an increased risk of 

cardiovascular events. These data show that this relationship is monotonic — the higher the 

blood pressure, the higher the absolute risk — and nonlinear, approximately exponential — the 

higher the blood pressure, the greater the absolute risk increase per mmHg. Systolic pressure 

may be more important than diastolic pressure, especially in the elderly. 

The effect of blood pressure on relative risk appears to be similar in people at high or low 

absolute risk. Therefore, absolute risk increase per mmHg of blood pressure elevation is much 

greater in patients whose risk for cardiovascular events is high for reasons other than blood 

pressure, such as patients with diabetes mellitus, chronic kidney disease, a history of stroke, or 

cardiovascular disease. 

Among adults, placebo-controlled outcome studies have been conducted with combination 

regimens of drugs in numerous pharmacologic classes (diuretics, reserpine, beta-adrenergic 

receptor blockers, direct vasodilators, and calcium channel blockers), and large studies have 

consistently found reductions in the risk of cardiovascular events. The largest effect has been 

reduction in the risk of stroke, but reductions in the risk of myocardial infarction and 

cardiovascular mortality also have been seen. Positive- (or active-)4

 controlled studies with 

drugs from more recently developed classes (angiotensin converting enzyme inhibitors and 

angiotensin receptor antagonists) indicate that these drugs share these clinical benefits. The 

similar effects with multiple drug classes with disparate mechanisms of action indicate that it is 

the decrease in blood pressure, rather than any other property of the drugs, that is largely 

responsible for these benefits. Because the relative risk from a given blood pressure reduction is 

the same in people otherwise at high or low absolute cardiovascular risk, the commonly 

recommended blood pressure goals are lower in patients at high cardiovascular risk (e.g., 

diabetes mellitus, lipid abnormalities). 

3 Links to meeting materials, including a transcript, can be found at 

http://www.fda.gov/ohrms/dockets/ac/cder05.html#cardiovascularRenal. 

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 See 21 CFR 314.126(b)(2)(iv). 

2
Contains Nonbinding Recommendations 

Draft — Not for Implementation 

The outcome studies have all involved treatment regimens with more than one drug to achieve 

the goal blood pressure, so the data cannot easily be used to distinguish the contributions of 

individual drugs or classes. Numerous meta-analyses and a few large studies (e.g., ALLHAT)

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have found no consistent differences by class in effects on survival, myocardial infarction, or 

stroke for regimens achieving the same blood pressure goals, but some differences may exist. In 

addition, individual drugs, and perhaps drug classes, may have differences in effects on other 

important endpoints, presumably because of pharmacological effects other than blood pressure 

reduction. These other properties of antihypertensive drugs (e.g., effects on heart failure or 

diabetic nephropathy) often will be a reasonable basis for deciding which drugs to use or which 

drugs to use first. 

There is no regulatory precedent for extending an outcome claim across a set of 

pharmacologically distinct drug classes. In this case, however, there have been consistently 

favorable effects on outcomes across many drug classes. This situation has led us to conclude 

that the general, qualitative claim of cardiovascular outcome benefits pertains to all classes of 

antihypertensive drugs. 

Although the effects of lowering blood pressure appear to apply generally to antihypertensive 

drugs, the fact that some drugs (or drug classes) have been studied for specific outcomes also is 

of interest, and such data should be reflected in the Clinical Trials section of labeling for those 

drugs. Placebo-controlled trials and positive-controlled trials demonstrating a superior outcome 

are clearly interpretable. Positive-controlled trials showing no differences on major outcomes, 

such as from ALLHAT or other studies of substantial size, also can be included in labeling, if the 

drug’s effect can be interpreted as reasonably similar to that of the control drug. 

Blood pressure is one of numerous risk factors for cardiovascular disease, and disease 

management should address all risk factors. Most placebo-controlled outcome trials in 

hypertension preceded current lipid-lowering therapy or wide use of aspirin, so formal measures 

of their interaction are unavailable. It is clear, however, that these other therapies are effective in 

reducing cardiovascular events whether or not a patient is receiving antihypertensive therapy. 

The clinical benefit of treating hypertension is not well established in pediatric populations. 

IV. LABELING RECOMMENDATIONS 

A. Highlights 

The Indications and Usage section of Highlights should conform in style to other labeled 

indications, if any, but both hemodynamic and cardiovascular outcomes should be cited. For 

example: 

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 See JAMA 2002; 288(23): 2998-3007. 

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DRUGNAME is a [name of class] indicated for the treatment of hypertension. 

DRUGNAME reduces blood pressure and thereby reduces the risks of stroke and 

myocardial infarction. 

In addition, any important limitations of use should be listed in this section. 

B. Full Prescribing Information — Indications and Usage 

The Indications and Usage section of the Full Prescribing Information should be modeled after 

the following paragraph and should be substituted for a drug’s indication in hypertension. 

Optional language and language specific to a drug are shown in braces. 

DRUGNAME is indicated for the treatment of hypertension. Blood pressure reduction 

reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and 

myocardial infarctions. These benefits have been seen in controlled trials of 

antihypertensive drugs from a wide variety of pharmacologic classes { including this 

drug | including the class to which this drug principally belongs }. { There are no 

controlled trials demonstrating risk reduction with DRUGNAME. } 

Control of high blood pressure should be part of comprehensive cardiovascular risk 

management, including lipid control, diabetes management, appropriate use of aspirin, 

smoking cessation, and exercise. For specific advice on goals and management, see 

published guidelines, such as those of the National High Blood Pressure Education 

Program’s Joint National Committee on Prevention, Detection, Evaluation, and 

Treatment of High Blood Pressure (JNC). 

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the 

absolute risk increase per mmHg is greater at higher blood pressures. Numerous 

antihypertensive drugs, from a variety of pharmacologic classes and having different 

mechanisms of action, have been shown to reduce cardiovascular morbidity and 

mortality, and it can be concluded that it is blood pressure reduction, and not some other 

pharmacologic mechanism, that is largely responsible for those benefits. The largest and 

most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, 

but reductions in myocardial infarction and cardiovascular mortality also have been seen 

regularly. 

Absolute cardiovascular risks increase steeply with increased blood pressure, so that even 

modest reductions of severe hypertension can provide substantial benefit. Relative risk 

reduction from blood pressure reduction is similar across populations with varying 

absolute risk, so the absolute benefit is greater in patients, such as diabetics, who are at 

higher risk independent of their hypertension, and such patients would be expected to 

benefit from more aggressive treatment to a lower blood pressure goal. Many patients 

will require more than one drug to achieve blood pressure goals. 

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in 

black patients and many antihypertensive drugs have additional effects (e.g., on angina, 

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heart failure, or diabetic kidney disease), and these considerations may guide selection of 

therapy. 

Extra language, such as “DRUGNAME may be used alone or in combination...,” can be 

retained. 

C. Full Prescribing Information — Clinical Studies 

The Clinical Studies section of the label should include a summary of placebo- or activecontrolled trials showing evidence of the specific drug’s effectiveness in lowering blood 

pressure. If studies demonstrating cardiovascular outcome benefits exist, those studies also 

should be summarized in this section. If there are no cardiovascular outcome data to cite, one of 

the following two paragraphs should appear: 

There are no studies of DRUGNAME or members of the DRUGCLASS demonstrating 

reductions in cardiovascular risk in patients with hypertension. 

or 

There are no studies of DRUGNAME demonstrating reductions in cardiovascular risk in 

patients with hypertension, but at least one pharmacologically similar drug has 

demonstrated such benefits. 

In the latter case, the applicant’s application should describe the studies of the other drugs that 

support the statement, but the trial descriptions should not appear in labeling. 

V. DRUG CLASSIFICATIONS FOR ANTIHYPERTENSIVE DRUGS 

Table 1 lists, by pharmacologic class, examples of drugs approved for chronic treatment of 

hypertension. The drugs shown in bold type have specific outcome data in either placebocontrolled or active-controlled as either primary or secondary treatment. For a complete list of 

approved drugs for chronic treatment of hypertension, contact the Division of Cardiovascular 

and Renal Products. 

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Contains Nonbinding Recommendations 

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203 Table 1: Examples of Drugs Approved for Chronic Treatment of Hypertension 

Pharmacologic Class Approved Drugs 

aldosterone antagonists eplerenone, spironolactone

alpha adrenergic blockers doxazosin, phenoxybenzamine, phentolamine, 

prazosin, terazosin 

angiotensin converting enzyme inhibitors benazepril, captopril, enalapril, fosinopril, 

lisinopril, moexipril, perindopril, quinapril, 

ramipril, trandolapril 

angiotensin II receptor blockers candesartan, eprosartan, irbesartan, 

losartan, olmesartan, telmisartan, valsartan 

arteriolar vasodilators hydralazine, minoxidil

autonomic ganglionic vasodilators mecamylamine 

beta adrenergic blockers acebutolol, atenolol, betaxolol, bisoprolol, 

carvedilol, carteolol, esmolol, labetolol, 

metoprolol, nadolol, penbuterol, pindolol, 

propranolol, timolol 

catecholamine-depleting sympatholytics deserpidine, reserpine

central alpha-2 adrenergic agonists clonidine, guanabenz, guanfacine, 

methyldopa

calcium channel blockers diltiazem, verapamil

dihydropyridine calcium channel blockers amlodipine, felodipine, isradipine, 

nicardipine, nifedipine, nisoldipine

loop diuretics bumetanide, ethacrynic acid, furosemide, 

torsemide 

potassium-sparing diuretics amiloride, triamterene 

renin inhibitors aliskiren 

thiazide diuretics chlorothiazide, hydrochlorothiazide, 

hydroflumethiazide, methyclothiazide, 

polythiazide 

thiazide-like diuretics chlorthalidone, indapamide, metolazone 

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Blood Pressure Lowering Treatment Trialists’ Collaboration, 2003, Effects of Differing Blood 

Pressure-Lowering Regimens on Major Cardiovascular Events: Results of ProspectivelyDesigned Overviews of Randomized Trials, Lancet, 362:1527-1535. 

Collins, R and S MacMahon, 1994, Blood Pressure, Antihypertensive Drug Treatment, and the 

Risks of Stroke and of Coronary Heart Disease, Brit. Med. Bull., 50(2):272-298. 

Psaty, BM et al., 1997, Health Outcomes Associated with Antihypertensive Therapies Used as 

First-Line Agents, JAMA, 277(9):739-745. 

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