Assessment of Pressor 
Effects of Drugs 
Guidance for Industry 
 
 
 
DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 electronic comments to https://www.regulations.gov. Submit written 
comments to the Dockets Management Staff (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 (CDER) Devi Kozeli at 301-796-2240.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
February 2022 
Clinical/Medical 
Revision 1 
24216338dft.docx 
2/1/2022 
   
Assessment of Pressor 
Effects of Drugs 
Guidance for Industry 
 
Additional copies are available from: 
 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor 
Silver Spring, MD 20993-0002 
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 
Email: druginfo@fda.hhs.gov 
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
February 2022 
Clinical/Medical 
Revision 1 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 1 
III.  BLOOD PRESSURE ASSESSMENT: DRUGS INTENDED FOR SHORT-TERM 
VERSUS CHRONIC USE ............................................................................................................ 3 
A.  Drugs Intended for Short-Term Use ............................................................................................ 3 
B.  Drugs Intended for Chronic Use .................................................................................................. 4 
IV.  TYPES OF BLOOD PRESSURE ASSESSMENT ........................................................ 4 
A.  Clinic Blood Pressure Measurements .......................................................................................... 4 
B.  Recommended Use of ABPM ........................................................................................................ 4 
V.  BLOOD PRESSURE ASSESSMENT: STUDY DESIGN CONSIDERATIONS FOR 
DRUGS INTENDED FOR CHRONIC USE .............................................................................. 5 
A.  Control Group ................................................................................................................................ 5 
B.  Population ....................................................................................................................................... 5 
C.  Study Design ................................................................................................................................... 6 
VI.  REGULATORY RISK ASSESSMENT .......................................................................... 6 
VII.  LABELING CONSIDERATIONS .................................................................................. 7 
REFERENCES .............................................................................................................................. 9 
APPENDIX .................................................................................................................................. 11 
 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Assessment of Pressor Effects of Drugs  
2  Guidance for Industry1 
3   
4   
5   
6  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
7  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
8  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
9  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA office 
10  responsible for this guidance as listed on the title page. 
11   
12   
13   
14  I.  INTRODUCTION  
15   
16  This guidance is intended to advise sponsors on the premarketing assessment of a drugs effect 
17  on blood pressure. Elevated blood pressure is known to increase the risk of stroke, heart attack, 
18  and death. The effect of a drug on blood pressure is, therefore, an important consideration in risk 
19  assessment and product labeling.  
20   
21  The recommendations in the guidance are generally applicable to new drugs with systemic 
22  bioavailability and to approved drugs for a new indication/population with a higher 
23  cardiovascular risk or when a new dosing regimen results in significantly higher or more 
24  prolonged exposure. 
25   
26  This guidance revises the draft guidance for industry Assessment of Pressor Effects of Drugs 
27  issued in May 2018. This revision provides greater detail about study design, including specific 
28  statistical powering recommendations that were not included in the original document. 
29  Furthermore, this revision provides recommendations on how to incorporate information about 
30  increased blood pressure in the prescribing information of drug product labeling. 
31   
32  The contents of this document do not have the force and effect of law and are not meant to bind 
33  the public in any way, unless specifically incorporated into a contract. This document is intended 
34  only to provide clarity to the public regarding existing requirements under the law. FDA 
35  guidance documents, including this guidance, should be viewed only as recommendations, unless 
36  specific regulatory or statutory requirements are cited. The use of the word should in Agency 
37  guidances means that something is suggested or recommended, but not required. 
38   
39   
40  II.  BACKGROUND 
41   
42  Data from multiple sources indicate that elevated systolic and diastolic blood pressures increase 
43  cardiovascular risk. Epidemiologic evidence demonstrates a monotonically increasing risk of 
 
1 This guidance has been prepared by the Division of Cardiology and Nephrology in the Center for Drug Evaluation 
and Research at the Food and Drug Administration.  
  1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
44  stroke, heart attack, and death with increasing blood pressure; even a few millimeters of mercury 
45  (mmHg) can be clinically relevant. MacMahon et al. (1990) evaluated the relationship between 
46  diastolic blood pressure and the rates of stroke and coronary heart disease (CHD) events, defined 
47  as nonfatal myocardial infarctions and CHD deaths, in nine major, prospective, observational 
48  studies. Diastolic blood pressures that were lower by 5.0, 7.5, and 10 mmHg were associated 
49  with 34, 46, and 56 percent fewer strokes, respectively, and 21, 29, and 37 percent fewer CHD. 
50  Of note, the relative reduction in risk associated with a particular decrease in diastolic blood 
51  pressure was similar within the entire range of diastolic blood pressures evaluated (70 to 110 
52  mmHg), including levels that would be considered normal. When the highest risk category of 
53  diastolic blood pressure (greater than or equal to 110 mmHg) was compared with the lowest risk 
54  category (less than or equal to 79 mmHg), the risk of stroke was about 10 to 12 times higher; the 
55  risk of CHD was about 5 to 6 times higher. 
56   
57  The incremental cardiovascular risk imparted by higher systolic blood pressure is a function of 
58  the underlying cardiovascular risk. Equations from pooled cohorts of 10-year atherosclerotic 
59  cardiovascular disease (ASCVD) event risk models can be used to describe the effect of a higher 
60  systolic blood pressure on the risk of developing an ASCVD event, defined as the occurrence of 
61  coronary death or fatal stroke, or the first occurrence of nonfatal myocardial infarction or stroke 
62  (Goff et al. 2014). FDA generated Figure 1 (see the Appendix) to show the expected increases in 
63  ASCVD events for a chronic elevation in systolic blood pressure (1 to 7 mmHg) in patients 
64  whose risks fall within three risk levels (low/borderline, intermediate, and high). 
65   
66  Results from controlled trials of antihypertensive drugs show that decreases in blood pressure led 
67  to decreased rates of stroke and cardiovascular deaths in populations with all levels of risk from 
68  other factors, such as elevated low-density lipoprotein cholesterol or smoking status. 
69  Maintenance of a reduction in blood pressure with antihypertensive drug regimens consistently 
70  reduced rates of stroke and cardiovascular death, with a less consistent effect on nonfatal 
71  myocardial infarction (see Table 1 in the Appendix). Furthermore, the beneficial effect on 
72  cardiovascular outcome occurs within a relatively short period of time (0.5 to 1 year), suggesting 
73  that an increased risk from elevated blood pressure would also occur relatively rapidly (Staessen 
74  et al. 1997; Veterans Administration Cooperative Study 1970). In the Systolic Hypertension in 
75  the Elderly Program (SHEP Cooperative Research Group 1991), for example, the reduced rate of 
76  stroke is clearly seen within 1.5 years (and perhaps earlier), and findings were similar in the 
77  European Working Party on High Blood Pressure in the Elderly trial (Amery et al. 1985). 
78   
79  This relationship of lower blood pressure to lower rates of stroke and cardiovascular death shown 
80  in Table 1 has been observed in outcome studies involving a wide array of antihypertensive 
81  drugs, including diuretics, reserpine, hydralazine, beta blockers, calcium channel blockers, and 
82  renin-angiotensin system inhibitors. FDA, with the concurrence of the Cardiovascular and Renal 
83  Drugs Advisory Committee,2 considers this relationship to be sufficiently well-established to 
84  conclude that all antihypertensive drugs should be labeled with a cardiovascular risk reduction 
85  claim, even if a drug has not been evaluated in a cardiovascular outcome study (see the guidance 
 
2 Summary minutes of the Cardiovascular and Renal Drugs Advisory Committee meeting for June 15, 2005, 
available at https://wayback.archive-
it.org/7993/20170404055351/https://www.fda.gov/ohrms/dockets/ac/05/minutes/2005-4145M1.pdf. 
 
  2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
86  for industry Hypertension Indication: Drug Labeling for Cardiovascular Outcome Claims 
87  (March 2011)).3 This guidance now suggests that a drug-induced increase in blood pressure is 
88  likely to have similar deleterious effects, no matter the mechanism of the increase. 
89   
90  This hypothesis is supported by the observation that some drugs that produce sustained increases 
91  in blood pressure (e.g., rofecoxib, sibutramine, torcetrapib, celecoxib) have been associated with 
92  adverse cardiovascular effects. In light of these findings, it is reasonable to expect that chronic 
93  use of drugs that increase blood pressure measured by either ambulatory blood pressure 
94  monitoring (ABPM) or clinically will increase cardiovascular risk, with an absolute increase in 
95  risk related to the baseline risk, the baseline blood pressure, the duration of treatment, and the 
96  magnitude of the blood pressure increase. 
97   
98  Although nearly every drug development program has some assessment of the drugs blood 
99  pressure effects, the methods used for assessing blood pressure are not consistent and not always 
100  adequate. As a result, small increases in blood pressure that could be relevant to the risks of a 
101  drug may not be reliably detected in some drug development programs.  
102   
103  Several factors can influence the importance of blood pressure effects to the benefit-risk 
104  assessment, including the magnitude of the blood pressure increase, the seriousness of the 
105  condition being treated, the effect of the drug on the condition, the underlying cardiovascular risk 
106  in the patient population most likely to use the drug, the availability of other effective therapies 
107  that do not raise blood pressure, strategies that can be used to mitigate the blood pressure effects, 
108  and the anticipated duration of drug treatment. 
109   
110  For a drug that increases blood pressure, differences in blood pressure effects across subgroups 
111  of the patient population may exist, just as differences across subgroups may exist in response to 
112  a blood pressurelowering treatment. Characterizing such differences is important. 
113   
114   
115  III.  BLOOD PRESSURE ASSESSMENT: DRUGS INTENDED FOR SHORT-TERM 
116  VERSUS CHRONIC USE  
117   
118  Whether a drug is intended for short-term or chronic use is a significant factor for determining 
119  how to assess blood pressure during a clinical trial. 
120   
121  A.  Drugs Intended for Short-Term Use 
122   
123  There is little concern about a drug indicated for short-term use that has small effects on blood 
124  pressure because the cardiovascular risk of small, short-term elevations in blood pressure does 
125  not appear to be meaningful. FDAs analysis of placebo-controlled hypertension trials less than 
126  12 weeks in duration (most were shorter) did not find an increased risk of cardiovascular events 
127  in the placebo groups (DeFelice et al. 2008). Large blood pressure increases are of concern, 
128  however, even with drugs intended for short-term use. Therefore, in general, careful assessment 
 
3 We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA 
guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
129  of blood pressure using clinic blood pressure measurement during routine study visits (section 
130  IV. B.) is recommended. 
131   
132  B.  Drugs Intended for Chronic Use 
133   
134  There is greater concern with the effects of a drug on blood pressure when the drug will be used 
135  chronically. As noted above, the risk related to blood pressure is a continuous function, and 
136  sustained increases in blood pressure correlate with long-term increases in the risk of 
137  cardiovascular events. It follows that drug-induced sustained elevations in blood pressure, even if 
138  small, would have such effects. Sponsors, therefore, should include a thorough blood pressure 
139  assessment for any drug intended for chronic use. FDA recommends use of ABPM for this 
140  assessment, as ABPM is capable of detecting small, but potentially relevant, blood pressure 
141  effects (see section IV). ABPM also assesses effects over a 24-hour period, which is more 
142  informative than assessment at a single time point (Pickering 2000). 
143   
144   
145  IV.  TYPES OF BLOOD PRESSURE ASSESSMENT 
146   
147  A.  Clinic Blood Pressure Measurements 
148   
149  Clinic blood pressure measurements can be used for three purposes: to assess the effects of drugs 
150  intended for short-term use, to characterize the dose or exposure-response relationship for drugs 
151  that increase blood pressure, and to serve as part of the overall safety assessment to identify 
152  patients with large increases in blood pressure. 
153   
154  The accuracy of clinic blood pressure measurement can be improved by collecting triplicate 
155  measurements of sitting blood pressure in all subjects at baseline (predose), at several visits (at 
156  least two visits before the end of the trial), at the end of the interdosing interval (trough 
157  measurement; predose), and at peak concentration of test drug or active metabolites. 
158  Measurements should be made approximately 1 to 3 minutes apart, using the same arm at each 
159  visit. For studies with entrance criteria that include specific blood pressure ranges or cutoffs, 
160  separate predose measurements should be obtained; screening measurements should not be used 
161  as the baseline. 
162   
163  If a large blood pressure effect is not detected by clinical blood pressure measurements in early, 
164  small studies, FDA recommends an ABPM study for drugs intended to be used chronically. 
165   
166  B.  Recommended Use of ABPM 
167   
168  FDA recommends the use of ABPM rather than routine clinic blood pressure measurement for 
169  drugs intended to be used chronically, as ABPM provides more accurate measurements of blood 
170  pressure throughout the day. 
171   
172  Several factors influence the ability to detect small changes in blood pressure. First, blood 
173  pressure naturally varies throughout the day (diurnal variation), as well as with meals, activity, 
174  and changes in response to stress, including the stress of having ones blood pressure measured 
  4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
175  (white coat hypertension). In addition to these true variations in blood pressure, clinic blood 
176  pressure measurement is associated with measurement error (e.g., calibration error, improper 
177  auscultation, rounding). Given these variations, blood pressure assessment using a small number 
178  of measurements may not reliably detect small, but potentially relevant, increases in blood 
179  pressure. Moreover, increased nocturnal blood pressure has been recognized recently as an 
180  important predictor of cardiovascular risk (Parati et al. 2014; Whelton et al. 2017).  
181   
182  The advantages of ABPM over clinic blood pressure measurements include the following: 
183   
184    Assesses blood pressure effects over a 24-hour period 
185   
186    Provides insight into the nocturnal blood pressure response 
187   
188    Allows a more precise measure of an individuals blood pressure throughout the day 
189   
190    Can be programmed to collect measurements at specified times or to capture a 
191  standardized schedule of measurements over 24 hours 
192   
193    Is free of potential investigator bias, including tendencies to round up or down 
194   
195   
196  V.  BLOOD PRESSURE ASSESSMENT: STUDY DESIGN CONSIDERATIONS FOR 
197  DRUGS INTENDED FOR CHRONIC USE 
198   
199  A.  Control Group 
200   
201  ABPM studies of less than 12 weeks suggest there is little or no change on placebo; whether to 
202  include a placebo group may depend on a number of factors (Harrison et al. 2020).  For example, 
203  changes in blood pressure with time may obscure drug effects, making inclusion of a placebo 
204  group desirable in studies with longer duration. A placebo control group can also be desirable 
205  when design elements other than drug treatment (e.g., lifestyle modifications) could affect blood 
206  pressure. 
207   
208  An active control is generally not needed but can provide useful information if, for example, the 
209  investigational drug is a member of a chemical or therapeutic class of compounds that are known 
210  to increase blood pressure. Including a member of the same class as an active control could be 
211  used to compare the blood pressure effects between drugs with appropriate sample size and 
212  statistical power. 
213   
214  B.  Population 
215   
216  The ABPM study should be performed in the patient population for which the drug is being 
217  developed, either in a targeted study or as part of a larger study already being conducted for other 
218  purposes. The study may also be performed in a related patient population with characteristics 
219  similar to those of the intended target patient population (i.e., similar demographic and disease-
220  specific characteristics). 
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221   
222  C.  Study Design 
223   
224  In general, the study should be powered to exclude a 3-mmHg increase in 24-hour average 
225  systolic blood pressure using an upper bound of the two-sided 95% confidence interval assuming 
226  the true effect is 0 mmHg. Such an increase would lead to an increase of approximately 0.5 to 1 
227  cardiovascular event per 1,000 patient years in patients with intermediate to high cardiovascular 
228  risk at baseline (see Figure 1) using the ASCVD risk model. Sponsors and the review division 
229  should consider the underlying cardiovascular risk in the patient population and the perceived 
230  benefit of the drug when selecting an appropriate effect to be ruled out. 
231   
232  Blood pressure should be measured at least twice an hour over 24 hours using ABPM at baseline 
233  and on-treatment to assess the overall effect; on-treatment measurements should be performed 
234  only after the drug has reached its steady state effect on blood pressure. Based on a meta-analysis 
235  of antihypertensive agents, which showed that maximal effect was not observed until 4 weeks of 
236  treatment, we recommend that ABPM trials be of at least 4 weeks duration (Lasserson et al. 
237  2011).  
238   
239  In general, sponsors should present the results as 24-hour average as well as the daytime (awake) 
240  and nighttime (asleep) averages. Other presentations may be appropriate depending on the 
241  mechanism of action and the expected pharmacokinetic and pharmacodynamic properties of the 
242  drug. Results may suggest that blood pressure elevations are related to drug concentration 
243  exposure, which could, in turn, relate to dose and dosing interval. Sponsors should collect 
244  pharmacokinetic samples at appropriate time points in an effort to demonstrate treatment 
245  compliance and to explore the relationship between blood pressure increases and drug exposure. 
246   
247  If the drug increases blood pressure in the overall patient population, sponsors should obtain 
248  additional information about the effects of the drug in relevant subsets of the population with 
249  potentially larger blood pressure effects, if applicable (e.g., patients with preexisting 
250  hypertension, patients with impaired renal status, patients at increased cardiovascular risk, older 
251  patients). 
252   
253   
254  VI.  REGULATORY RISK ASSESSMENT  
255   
256  Large drug-induced elevations in blood pressure are relevant for all drugs, even for those 
257  intended for short-term use. Smaller sustained elevations of blood pressure of even a few 
258  millimeters of mercury are a concern when the drug is intended for chronic use, particularly 
259  when the target population is at increased cardiovascular risk. As noted above, the increment in 
260  proportional risk for a given blood pressure increase appears to be similar across the range of 
261  blood pressures, including normal blood pressure. Conversely, the increase in absolute risk 
262  would be very small for a person at low baseline risk (e.g., age 25, normal low-density 
263  lipoprotein and high-density lipoprotein, not diabetic, and normotensive) and becomes 
264  progressively greater as the number and severity of risk factors increase, as shown in Figure 1. 
265  Sponsors should consider Figure 1 when formulating their approach to assessing the importance 
266  of the pressor effect of a particular drug.  
  6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
267   
268  The finding that a drug increases blood pressure and the magnitude and pattern of that increase 
269  should be factored into the overall risk assessment for the drug. This assessment should include 
270  consideration of any steps that could be taken to mitigate the risk of increased blood pressure, 
271  such as patient selection, pretreatment assessments, blood pressure monitoring in some or all 
272  patients, and expectant use of blood pressurelowering treatments. 
273   
274   
275  VII.  LABELING CONSIDERATIONS 
276   
277  The ABPM study results should be generally summarized in the Pharmacodynamics subsection 
278  in the CLINICAL PHARMACOLOGY section of labeling. A brief description of the ABPM 
279  study design and study population should be included regardless of whether the drug was shown 
280  to increase blood pressure. If the drug is associated with an increase in blood pressure from clinic 
281  blood pressure measurements or ABPM, this subsection should include the following, as 
282  appropriate: 
283   
284    Effects on systolic and/or diastolic blood pressure with the doses studied  
285    The distribution of blood pressure effect sizes 
286    The dose or exposure response 
287    The time course of the blood pressure effect 
288    Important subgroup differences in blood pressure response (e.g., demographics, 
289  concomitant illness, concomitant treatments) 
290   
291  If a drug has been shown to increase blood pressure from clinic blood pressure measurements or 
292  ABPM, the adverse reaction must be included in the ADVERSE REACTIONS section.4  
293   
294  If the drug is associated with a clinically significant increase in blood pressure (see section V.C.), 
295  then the following should be included in the WARNINGS AND PRECAUTIONS section:5 
296   
297    A description of the blood pressure increases (e.g., mean observed blood pressure effect, 
298  distribution of blood pressure increases, adverse events of hypertension and related 
299  terms). 
300   
301    Clinical implications (e.g., increased risk of major adverse cardiovascular reactions, 
302  including nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death) 
303   
304    Steps to take to prevent, mitigate, monitor for, or manage the blood pressure increases 
305  (e.g., recommendations for checking blood pressure before and during drug treatment, for 
306  use of the drug in patients at higher risk of major adverse cardiovascular reactions or 
 
4 See 21 CFR 201.57(c)(7) and the guidance for industry Adverse Reactions Section of Labeling for Human 
Prescription Drug and Biological Products  Content and Format (January 2006). 
 
5 See the guidance for industry Warnings and Precautions, Contraindications, and Boxed Warning Sections of 
Labeling for Human Prescription Drug and Biological Products  Content and Format (October 2011) and 21 CFR 
201.57(c)(6). 
  7  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
307  those taking other drugs that increase blood pressure, and for continued use of the drug in 
308  patients who develop hypertension or who have exacerbation of preexisting hypertension)   
309   
310  Clinically significant increases in blood pressure should also be described in other sections of 
311  labeling as appropriate (e.g., BOXED WARNING, CONTRAINDICATIONS). 
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312  REFERENCES 
313   
314  Literature 
315   
316  Amery A, Brixko P, Clement D, De Schaepdryver A, Fagard R, Forte J, Henry JF, Leonetti G, 
317  OMalley K, Strasser T, Birkenhager W, Bulpitt C, Deruyttere M, Dollery C, Forette F, Hamdy 
318  R, Joossens JV, Lund-Johansen P, Petrie J, Tuomilehto J, and Williams B, 1985, Mortality and 
319  Morbidity Results from the European Working Party on High Blood Pressure in the Elderly 
320  Trial, Lancet, 325(8442):13491354. 
321   
322  Arnett DK, Blumenthal RS, Albert MA, Buroker AB, Goldberger ZD, Hahn EJ, Dennison 
323  Himmelfarb C, Khera A, Lloyd-Jones D, McEvoy JW, Michos ED, Miedema MD, Munoz D, 
324  Smith SC, Virani SS, Williams KA, Yeboah J, and Ziaeian B, 2019, 2019 ACC/AHA Guideline 
325  on the Primary Prevention of Cardiovascular Disease: A Report of the American College of 
326  Cardiology/American Heart Association Task Force on Clinical Practice Guidelines, J Am Coll 
327  Cardiol, 74(10):e177e232. 
328   
329  DeFelice A, Willard J, Lawrence J, Hung J, Gordon MA, Karkowsky A, Targum S, 
330  Throckmorton DC, Girton J, Stertz B, Glasser SP, and Lipicky RJ, 2008, The Risks Associated 
331  with Short-Term Placebo-Controlled Antihypertensive Clinical Trials: A Descriptive Meta-
332  Analysis, J Hum Hypertens, 22(10):659668. 
333   
334  Goff Jr DC, Lloyd-Jones DM, Bennett G, Coady S, DAgostino RB, Gibbons R, Greenland P, 
335  Lackland DT, Levy D, ODonnell CJ, Robinson JG, Schwartz JS, Shero ST, Smith Jr SC, Sorlie 
336  P, Stone NJ, and Wilson PWF, 2014, 2013 ACC/AHA Guideline on the Assessment of 
337  Cardiovascular Risk: A Report of the American College of Cardiology/American Heart 
338  Association Task Force on Practice Guidelines, Circulation, 129(25 Suppl 2):S49S73. 
339   
340  Harrison NR, Sager PT, Krucoff MW, Weber MA, and White WB, Methodological and 
341  Regulatory Considerations for Updated Guidance on the Pressor Effects of Drugs, 2020, Ther 
342  Innov Regul Sci, 54(6):14731476. 
343   
344  Lasserson DS, Buclin T, Glasziou P, 2011, How Quickly Should We Titrate Antihypertensive 
345  Medication? Systematic Review Modelling Blood Pressure Response from Trial Data, Heart, 
346  97(21):17711775. 
347   
348  MacMahon S, Peto R, Collins R, Godwin J, Cutler J, Sorlie P, Abbott R, Neaton J, Dyer A, and 
349  Stamler J, 1990, Blood Pressure, Stroke, and Coronary Heart Disease. Part 1, Prolonged 
350  Differences in Blood Pressure: Prospective Observational Studies Corrected for the Regression 
351  Dilution Bias, Lancet, 335(8692):765774. 
352   
353  Parati G, Stergiou G, O'Brien E, Asmar R, Beilin L, Bilo G, Clement D, de la Sierra A, de 
354  Leeuw P, Dolan E, Fagard R, Graves J, Head GA, Imai Y, Kario K, Lurbe E, Mallion J-M, 
355  Mancia G, Mengden T, Myers M, Ogedegbe G, Ohkubo T, Omboni S, Palantini P, Redon J, 
356  Ruilope LM, Shennan A, Staessen JA, van Montfrans G, Verdecchia P, Waeber B, Wang J, 
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357  Zanchetti A, and Zhang Y, 2014, European Society of Hypertension Practice Guidelines for 
358  Ambulatory Blood Pressure Monitoring, J Hypertens, 32(7):13591366. 
359   
360  Pickering TG, 2000, Ambulatory Blood Pressure Monitoring, Curr Hypertens Rep, 2(6):558
361  564. 
362   
363  SHEP Cooperative Research Group, 1991, Prevention of Stroke by Antihypertensive Drug 
364  Treatment in Older Persons with Isolated Systolic Hypertension. Final Results of the Systolic 
365  Hypertension in the Elderly Program (SHEP), JAMA, 265(24):32553264.  
366   
367  Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhager WH, Bulpitt CJ, de Leeuw 
368  PW, Dollery CT, Fletcher AE, Forette F, Leonetti G, Nachev C, OBrien ET, Rosenfeld J, 
369  Rodicio JL, Tuomilehto J, and Zanchetti A, 1997, Randomised Double-Blind Comparison of 
370  Placebo and Active Treatment for Older Patients with Isolated Systolic Hypertension. The 
371  Systolic Hypertension in Europe (Syst-Eur) Trial Investigators, Lancet, 350(9080):757764. 
372   
373  Veterans Administration Cooperative Study Group on Antihypertensive Agents, 1970, Effects 
374  Morbidity of Treatment on in Hypertension: II. Results in Patients With Diastolic Blood Pressure 
375  Averaging 90 Through 114 mmHg, JAMA, 213(7):11431152.  
376   
377  Whelton PK, Carey RM, Aronow WS, Casey Jr DE, Collins KJ, Dennison Himmelfarb C, 
378  DePalma SM, Gidding S, Jamerson KA, Jones DW, MacLaughlin EJ, Munter P, Ovbiagele B, 
379  Smith Jr SC, Spencer CC, Stafford RS, Taler SJ, Thomas RJ, Williams Sr KA, Williamson JD, 
380  and Wright Jr JT, 2018, 2017 
381  ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the 
382  Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report 
383  of the American College of Cardiology/American Heart Association Task Force on Clinical 
384  Practice Guidelines, Hypertension, 71(6):e13e115. 
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385  APPENDIX 
386   
387  FDA generated Figure 1 to show the expected increases in ASCVD events for a chronic 
388  elevation in systolic blood pressure (1 to 7 mmHg) in patients whose risks fall within three risk 
389  levels (low/borderline, intermediate, and high). 
390   
391  Figure 1: Relationship of ASCVD Events to Chronic Elevations in Systolic Blood Pressure 
392  by Risk Level 
Risk categories:  
  Low/borderline: <7.4% 10-year risk 
for ASCVD event (n=10,686) 
  Intermediate: 7.5% to 19.9% 10-year 
risk for ASCVD event (n=4,880)  
  High: 20% 10-year risk for ASCVD 
event (n=5,391) 
 
FDA created Figure 1 by applying the 
ASCVD risk model to the demographic, 
vital sign, and laboratory data for each 
subject (age 30 years) collected in the 
National Health and Nutrition 
Examination Survey 200320181 and 
calculating the ASCVD risk after 
increasing the systolic blood pressure by 
1-mmHg increments for each subject. 
Solid lines are the median increases in 
ASCVD risk, and the shaded area 
represents the increases in ASCVD risk 
for the 5th and 95th percentiles within 
each risk category (see Arnett et al. 
2019 for risk categories). 
 
393   
394   
 
1 The National Health and Nutrition Examination Survey datasets can be found at 
https://wwwn.cdc.gov/nchs/nhanes/Default.aspx. 
  11  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
395  The relationship of lower blood pressure to lower rates of stroke and cardiovascular death are 
396  shown in Table 1 below. 
397   
398  Table 1: Reduction in Blood Pressure and Cardiovascular Events with Antihypertensive 
399  Drugs in Placebo-Controlled Trials 
Mean 
Change  Number of Events (%) 
from  [Event Rate, 1,000 patient-years] 
Mean  Baseline 
Number  Follow- in SBP /  Nonfatal 
of  Up  DBP  Nonfatal  Myocardial  Cardiovascular 
Source  Intervention  Subjects  (years)  (mmHg)*  Stroke  Infarction  Death 
Veterans  Active  186  3  -27 / -17  5**  5 (2.7%)  8 (4.3%) 
Administration  (2.7%)   [NR]  [NR] 
Cooperative  [NR] 
Study Group on  Placebo  194  +4 / +1  20**  2 (1.0%)  19 (9.8%) 
Antihypertensive  (10.3%)  [NR]  [NR] 
Agents (1970)  [NR] 
European  Active  416  3***  -33 / -16  13  19 (4.6%)   42 (10.1%)  
Working Party  (3.1%)   [14]  [30] 
on High Blood  [9] 
Pressure in the  Placebo  424  -11 / -6  24  12 (2.8%)   61 (14.4%)  
Elderly Trial  (5.7%)   [9]  [48] 
(Amery et al.  [20] 
1985) 
Systolic  Active  2,365  4.5  -27 / -9  96  50 (2.1%)   90 (3.8%)  
Hypertension in  (4.1%)   [NR]  [NR] 
the Elderly  [NR] 
Program (SHEP  Placebo  2,371  -15 / -5  149  74 (3.1%)   112 (4.7%)  
Cooperative  (6.3%)   [NR]  [NR] 
Research Group  [NR] 
1991) 
Systolic  Active  2,398  2  -23 / -7  34  26 (1.1%)   59 (2.5%)  
Hypertension in  (1.4%)   [4.4]  [9.8] 
Europe (Syst- [5.7] 
Eur) Trial  Placebo  2,297  -13 / -2  57  31 (1.3%)   77 (3.4%) 
Investigators  (2.5%)   [5.5]  [13.5] 
(Staessen et al.  [10.1] 
1997) 
400  Abbreviations: DBP = diastolic blood pressure; SBP = systolic blood pressure; NR = not reported. 
401  *Obtained using routine clinic blood pressure measurements. 
402  **Cerebral vascular accident defined as either a thrombosis (clinical diagnosis) or a transient ischemic attack with 
403  objective neurological signs. 
404  ***Results presented for the double-blind part of trial. 
  12