Guidance for Industry 
Hypertension Indication:  Drug 
Labeling for Cardiovascular 
Outcome Claims  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
March 2011 
Labeling 
 
OMB Control No. 0910-0572 
Current expiration date available at https://www.reginfo.gov 
(Search ICR and enter OMB control number) 
See additional PRA statement in section VII of this guidance. 
 
   
Guidance for Industry 
Hypertension Indication:  Drug 
Labeling for Cardiovascular 
Outcome Claims  
 
 
 
Additional copies are available from: 
 
Office of 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  20993-0002 
Tel: 301-796-3400; Fax: 301-847-8714; E-mail: druginfo@fda.hhs.gov 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
March 2011 
Labeling 
 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  JUSTIFICATION FOR ADDING OUTCOME CLAIMS TO LABELING............... 2 
IV.  LABELING RECOMMENDATIONS............................................................................ 4 
A.  Highlights ........................................................................................................................................ 4 
B.  Full Prescribing Information  Indications and Usage ............................................................ 4 
C.  Full Prescribing Information  Clinical Studies ....................................................................... 5 
V.  DRUG CLASSIFICATIONS FOR ANTIHYPERTENSIVE DRUGS ........................ 5 
VI.  CARDIOVASCULAR OUTCOME CLAIM CONSIDERATIONS ............................ 6 
A.  Applicability of User Fees to Cardiovascular Outcome Claim Supplements ........................... 6 
B.  Format of Cardiovascular Outcome Claim Supplements .......................................................... 7 
C.  Applicability of Cardiovascular Outcome Claims in Promotional Materials .......................... 7 
VII.  PAPERWORK REDUCTION ACT OF 1995 ................................................................ 8 
REFERENCES .............................................................................................................................. 9 
  Contains Nonbinding Recommendations 
Guidance for Industry1 
Hypertension Indication:  Drug Labeling for  
Cardiovascular Outcome Claims 
 
 
 
 
This guidance represents the Food and Drug Administrations (FDAs) current thinking on this topic.  It 
does not create or confer any rights for or on any person and does not operate to bind FDA or the public.  
You can use an alternative approach if the approach satisfies the requirements of the applicable statutes 
and regulations.  If you want to discuss an alternative approach, contact the FDA staff responsible for 
implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate 
number listed on the title page of this guidance. 
 
 
 
 
I.  INTRODUCTION  
 
This guidance is intended to assist applicants in developing labeling for cardiovascular outcome 
claims for drugs that are indicated to treat hypertension.2  With few exceptions, current labeling 
for antihypertensive drugs 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 recommends standard labeling 
for antihypertensive drugs except where differences in labeling are supported by clinical data.  
We encourage applicants to submit labeling supplements containing the new language.   
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the Agencys 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. 
  1  Contains Nonbinding Recommendations 
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 advisory 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 committees 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  absolute risk 
increases progressively with increasing blood pressure  and approximately exponential  the 
absolute risk increase per mmHg increases with increasing blood pressure.  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, the 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 trials have been conducted with combination 
regimens of drugs in numerous pharmacologic classes (e.g., diuretics, reserpine, beta-adrenergic 
receptor blockers, direct vasodilators, and calcium channel blockers), and large trials 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.   
 
It is no longer ethical to conduct outcome trials that leave one group with untreated hypertension.  
Positive- (or active-)4 controlled trials with antihypertensive drugs from more recently developed 
classes (e.g., angiotensin converting enzyme inhibitors and angiotensin receptor antagonists) 
indicate that these drugs share these cardiovascular clinical benefits (although whether these 
benefits are identical across drugs or drug classes is bound to be less clear).  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 
 
3 Links to meeting materials, including a transcript, can be found at 
http://www.fda.gov/ohrms/dockets/ac/cder05.html#cardiovascularRenal. 
 
4 21 CFR 314.126(b)(2)(iv) 
  2  Contains Nonbinding Recommendations 
pressure goals are for a lower target blood pressure in patients at high cardiovascular risk (e.g., 
diabetes mellitus, lipid abnormalities). 
 
The outcome trials have all involved treatment regimens using 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 trials (e.g., ALLHAT)5 
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 with different mechanisms of action.  
This observation 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 to antihypertensive drugs 
generally, 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 STUDIES section of labeling 
for those drugs.  Placebo-controlled trials and positive-controlled trials demonstrating a superior 
outcome are interpretable.  Positive-controlled trials showing no differences on major outcomes, 
such as from ALLHAT or other trials of substantial size, also can be included in labeling if the 
drugs effect can be interpreted as reasonably similar to that of the established 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 interactions 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. 
 
 
 
5 JAMA 2002; 288(23): 2998-3007 
  3  Contains Nonbinding Recommendations 
IV.  LABELING RECOMMENDATIONS 
 
A.  Highlights  
 
The INDICATIONS AND USAGE section of Highlights, as it pertains to treatment of 
hypertension, should read as follows: 
 
DRUGNAME is a [name of pharmacologic class] indicated for the treatment of 
hypertension, to lower blood pressure.  Lowering blood pressure reduces the risk of fatal 
and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.   
 
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.  Optional language and language specific to a drug are shown in 
braces. 
 
DRUGNAME is indicated for the treatment of hypertension, to lower blood pressure.  
Lowering blood pressure 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, as appropriate, lipid control, diabetes management, 
antithrombotic therapy, smoking cessation, exercise, and limited sodium intake.  Many 
patients will require more than one drug to achieve blood pressure goals.  For specific 
advice on goals and management, see published guidelines, such as those of the National 
High Blood Pressure Education Programs Joint National Committee on Prevention, 
Detection, Evaluation, and Treatment of High Blood Pressure (JNC).   
 
Numerous antihypertensive drugs, from a variety of pharmacologic classes and with 
different mechanisms of action, have been shown in randomized controlled trials to 
reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood 
pressure reduction, and not some other pharmacologic property of the drugs, 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.  
 
Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the 
absolute risk increase per mmHg is greater at higher blood pressures, 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 
  4  Contains Nonbinding Recommendations 
the absolute benefit is greater in patients who are at higher risk independent of their 
hypertension (for example, patients with diabetes or hyperlipidemia), and such patients 
would be expected to benefit from more aggressive treatment to a lower blood pressure 
goal.   
 
Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in 
black patients, and many antihypertensive drugs have additional approved indications and 
effects (e.g., on angina, heart failure, or diabetic kidney disease).  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 Full Prescribing Information should include a summary 
of placebo- or active-controlled trials showing evidence of the specific drugs effectiveness in 
lowering blood pressure.  If trials demonstrating cardiovascular outcome benefits exist, those 
trials also should be summarized in this section.  See Table 1 in section V for the specific drugs 
for which the FDA has concluded that such trials exist.  If there are no cardiovascular outcome 
data to cite, one of the following two paragraphs should appear:  
 
There are no trials of DRUGNAME or members of the [name of pharmacologic class] 
pharmacologic class demonstrating reductions in cardiovascular risk in patients with 
hypertension.  
 
or 
 
There are no trials 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 applicants submission generally should refer to Table 1 in section V.  If the 
applicant believes that Table 1 is incomplete, it should submit the clinical evidence for the 
additional information to Docket No. FDA-2008-D-0150.  The labeling submission should 
reference the submission to the docket.  The trial descriptions should not appear in labeling.   
 
 
V.  DRUG CLASSIFICATIONS FOR ANTIHYPERTENSIVE DRUGS 
 
Table 1 lists, by pharmacologic class, approved drugs for chronic treatment of hypertension.  The 
drugs shown in bold type have specific outcome data in either placebo-controlled or active-
controlled trials as either primary or secondary treatment.   
  5  Contains Nonbinding Recommendations 
 
Table 1.  Approved Drugs 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 
non-dihydropyridine calcium channel blockers  diltiazem, verapamil 
dihydropyridine calcium channel blockers  amlodipine, felodipine, isradipine, 
nicardipine, nifedipine, nisoldipine 
loop diuretics  bumetanide, ethacrynic acid, furosemide, 
torsemide 
renin inhibitors  aliskiren 
thiazide diuretics  chlorothiazide, hydrochlorothiazide, 
hydroflumethiazide, methyclothiazide, 
polythiazide 
thiazide-like diuretics  chlorthalidone, indapamide, metolazone 
 
 
VI.  CARDIOVASCULAR OUTCOME CLAIM CONSIDERATIONS 
 
A.  Applicability of User Fees to Cardiovascular Outcome Claim Supplements 
 
We anticipate that few cardiovascular outcome claim supplements will require the payment of 
user fees because they will not need clinical data for approval.6   
 
For example, if applicants follow the recommended language in section IV.B. without additional 
changes that are supported by clinical data, then we would not normally anticipate assessment of 
 
6 The definition of clinical data for user fee purposes is provided in the guidance for industry  
Submitting Separate Marketing Applications and Clinical Data for Purposes of Assessing  
User Fees.  The guidance is available on the FDA Drugs guidance Web page at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  Contact  
CDERs User Fee Staff for questions concerning the definition of clinical data for user fee purposes.  
  6  Contains Nonbinding Recommendations 
a user fee.  In addition, if applicants follow the recommended language in section IV.C. that 
states that no cardiovascular outcome data are available, again, without additional changes that 
are supported by clinical data, we would not normally anticipate assessment of a user fee.  
However, if applicants provide for changes to the labeling that need clinical data for approval 
(e.g., summary of controlled trials showing evidence of the specific drugs effectiveness in 
lowering blood pressure), then we would normally anticipate a fee. 
 
As noted in section IV.C., an applicant can submit clinical evidence on cardiovascular outcome 
data to Docket No. FDA-2008-D-150 and include a reference to the docket submission in the 
labeling submission.  This guidance will be revised to include any new labeling changes 
supported by clinical data submitted to the docket.  We anticipate that labeling changes 
supported by evidence submitted to the docket would not normally be assessed a user fee. 
 
Applicants should contact the appropriate FDA project manager if there is a question about a 
specific submission.  The review division will determine whether approval for a specific 
cardiovascular outcome claim supplement needs clinical data for approval. 
 
B.  Format of Cardiovascular Outcome Claim Supplements  
 
The following information should be included in a prior approval supplement in the order 
shown:7 
 
1.  A statement that the submission is a cardiovascular outcome claim supplement, with 
reference to this guidance and related Docket No. FDA-2008-D-0150  
2.  Applicable FDA forms (e.g., 356h, 3397) 
3.  Detailed Table of Contents 
4.  Revised labeling: 
a.  Include draft revised labeling conforming to the requirements in 21 CFR 201.56 
and 201.57 
b.  Include marked-up copy of the latest approved labeling, showing all additions and 
deletions, with annotations of where supporting data (if applicable) are located in 
the submission 
 
To avoid the imposition of fees, other labeling changes (e.g., the addition of adverse event data) 
should be minimized and provided in separate supplements.  However, the revision of labeling to 
conform to 21 CFR 201.56 and 201.57 may require substantial revision to the ADVERSE 
REACTIONS or other labeling sections.  This is not anticipated to result in a user fee.  
 
C.  Applicability of Cardiovascular Outcome Claims in Promotional Materials 
 
Applicants are encouraged to cite the outcome claims in promotional materials.  Although 
reproduction of the entire INDICATIONS AND USAGE section is encouraged, the minimum 
description that is recommended is as follows: 
 
 
7 See 21 CFR 314.50. 
  7  Contains Nonbinding Recommendations 
DRUGNAME reduces blood pressure.  Lowering blood pressure reduces the risk of fatal 
and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.  Control 
of high blood pressure should be part of comprehensive cardiovascular risk management, 
including, as appropriate, lipid control, diabetes management, antithrombotic therapy, 
smoking cessation, exercise, and limited sodium intake.  Many patients will require more 
than one drug to achieve blood pressure goals.  
 
 
VII.  PAPERWORK REDUCTION ACT OF 1995 
 
This guidance contains information collection provisions that are subject to review by the Office 
of Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 
3501-3520).  
 
The time required to complete the information collection for a submission to Docket No. FDA-
2008-D-0150 is estimated to average 10 hours per response, including the time to review 
instructions, search existing data sources, gather the data needed, and complete and review the 
information collection.  The time required to complete the information collection for a 
cardiovascular outcome claim supplement submission is estimated to average 20 hours per 
response, including the time to review instructions, search existing data sources, gather the data 
needed, and complete and review the information collection.  Send comments regarding this 
burden estimate or suggestions for reducing this burden to: 
 
Food and Drug Administration, Center for Drug Evaluation and Research, Division of 
Cardiovascular and Renal Products, Attention:  Document Control Room, 5901-B Ammendale 
Road, Beltsville, MD  20705. 
 
An agency may not conduct or sponsor, and a person is not required to respond to, a 
collection of information unless it displays a currently valid OMB control number.  The 
OMB control number for this information collection is 0910-0572.  The current expiration 
date is available at https://www.reginfo.gov (search ICR and enter OMB control number). 
   
 
 
  8  Contains Nonbinding Recommendations 
REFERENCES 
 
Blood Pressure Lowering Treatment Trialists Collaboration, 2003, Effects of Differing Blood 
Pressure-Lowering Regimens on Major Cardiovascular Events:  Results of Prospectively-
Designed 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. 
 
  9