Reduction of diastolic blood pressure: Should hypertension guidelines include a lower threshold target?

Table 1 Summary of studies evaluating blood pressure thresholds

Study	Type	n	Age1	CAD2	DM2	CKD2	CVA2	Baseline DBP3	DBP J-curve by outcome	DBP J-curve Nadir3
Studies to target DBP
1967 JAMA	RCT	143	51	22	6			121	CV events and all-cause mortality	Not observed at 92
1970 JAMA	RCT	380	51					104	CV events and all-cause mortality	Not observed at 86
1979 Lancet	Case-Control	169	51					124	MI	90
1998 Lancet (HOT)	RCT	18790	62	6	8		1	105	CV events; CV and all-cause mortality	82-86
Studies in the elderly
1991 JAMA (SHEP)	RCT	4736	72	5	10		1	77	CVA and other CV events; CV mortality	Not observed at 70
1997 Lancet (Syst- Eur)	RCT	4695	70	30			4	86	CVA and other CV events; all-cause and CV mortality	Not observed at 81
2008 N Engl J Med (HYVET)	RCT	3845	84	12	6.8		7	90	CVA; all-cause mortality; CV mortality; CVA mortality	Not observed at 84
2016 JAMA (SPRINT)	RCT	2636	80	25	0	44	0	71	All CV events; CV mortality; all-cause mortality	Not observed at 65
Studies in CAD
2005 J Hypertens (ACTION)	Post-Hoc	7661	64	100	15			80	CV mortality; event or procedure; all-cause mortality; CVA	73
2006 Ann Intern Med (INVEST)	Post-Hoc	22576	66	100	29	2	5	87	All-cause mortality; non-fatal MI or CVA	84
2009 J Hypertension (ONTARGET)	Post-Hoc	25588	66	75	37		21	82	CV mortality and all CV events	75-79
2010 Am J Med (INVEST)	Post-Hoc	22576	66	100	29	2	5	87	All-cause mortality; non-fatal MI or CVA	70-75
2010 Eur Heart J (TNT)	Post-Hoc	10001	60	100	15		5	79	All CV events; CV and all-cause mortality	81
2010 Circulation (PROVE IT-TIMI)	Post-Hoc	4162	58	100	18	11	6	75	All-cause mortality and all CV events	84-85
2011 Circulation (ONTARGET)	Post-Hoc	12554	66	75	37		21	82	CV mortality and all CV events	80
2012 Hypertension (SMART)	Post-Hoc	5788	57 vs 65	60	17		28	82	CV events and all-cause morality	82
2016 Eur Rev MedPharmacol Sci	RCT	369	67	100	7			105	All CV events	75-80
2016 Eur Heart J (VALUE)	Post-Hoc	15244	67	46	32		20	87	All CV events; all-cause mortality	80
Studies in DM
1998 BMJ (UKPDS)	RCT	1148	56		100			94	All cause mortality	Not observed at 83
2002 Kidney Int (ABCD)	RCT	480	59		100			84	GFR changes; CV event; retinopathy; neuropathy	Not observed at 75
2005 J Am SocNephrol (IDNT)	RCT	1715	59	29	100	100		87	CV events and mortality	85
2010 JAMA (INVEST)	Post-Hoc	6400	66	100	100	4	9	85	All-cause mortality; non-fatal MI or CVA	SBP nadir 115, but no corresponding DBP nadir reported
2010 N Engl J Med (ACCORD)	RCT	4733	62	34	100			76	Non-fatal MI or CVA; CV mortality	Not observed at 68
2012 BMJ	Cohort	126092	67	10	100			83	All-cause mortality	75
Epidemiology studies
1991 BMJ (Framingham)	Cohort	5209	30-62						CV mortality; non-CV mortality	75-79
2003 Ann Intern Med (NHANES II)	Cohort	7830	54		5			82	All-cause mortality; CV mortality	79
2011 J Gen InternMed (NHANES I)	Cohort	13792	25-75						All-cause mortality	70-79
2014 J Am CollCardiol	Cohort	398419	64	19	30	24	8	73	All-cause mortality; ESRD	60-79

¹Mean and

²Units are %;

³Units are mmHg. ABCD: Appropriate Blood Pressure Control in Diabetes; ACCORD: Action to Control Cardiovascular Risk in Diabetes; CV: Cardiovascular; HOT: Hypertension Optimal Treatment; HYVET: Hypertension in the Very Elderly Trial; IDNT: Irbesartan Diabetic Nephropathy Trial; INVEST: International Verapamil SR Trandolapril Study; MI: Myocardial Infarction; NHANES: National Health and Nutrition Examination Survey; ONTARGET: Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial; PROVE IT-TIMI: Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction; RCT: Randomized Controlled Trial; SHEP: Systolic Hypertension in the Elderly Program; SMART: Secondary Manifestations of Arterial Disease; SPRINT: Systolic Blood Pressure Intervention Trial; Syst-Eur: Systolic Hypertension in Europe; TNT: Treating to New Targets; UKPDS: United Kingdom Prospective Diabetes Study; VALUE: Valsartan Antihypertensive Long-term use Evaluation.

Table 2 Comments on studies evaluating blood pressure thresholds

Study	Comment
Studies to target DBP
1967 JAMA	Small sample size
1970 JAMA	Small sample size
1979 Lancet	Small sample size, lacking data on baseline comorbidities
1998 Lancet (HOT)	Event rate lower than expected; difficult to recognize between-group outcomes due to small differences in achieved BP targets among three groups
Studies in the elderly
1991 JAMA (SHEP)	Stepwise titration of Chlorthalidone and addition of Atenolol vs placebo elderly isolated systolic hypertension; reduced all CV events with Rx
1997 Lancet (Syst-Eur)	Stepwise titration of Nifedipine and addition of enalapril and HCTZ vs placebo in elderly isolated systolic hypertension; reduced CV events and mortality but not all-cause mortality with Rx
2008 N Engl J Med (HYVET)	Indapamide ± Perindopril vs placebo; reduction of CVA, all-cause mortality and CHF
2016 JAMA (SPRINT)	Significant reduction in primary and secondary outcomes
Studies in CAD
2005 J Hypertens (ACTION)	Non-significant trends towards higher CV events in normotensives on Nifedipine
2006 Ann Intern Med (INVEST)	J-curve more prominent in DBP; DBP categories of < 60 through > 110 with 10 increments
2009 J Hypertension (ONTARGET)	High risk patients with known CAD or DM with target organ damage; Rx increased CV mortality if baseline SBP < 130; But CVA risk increased with high baseline SBP, but reduced with further BP lowering
2010 Am J Med (INVEST)	Prespecified secondary analysis; Verapamil SR or Atenolol based Rx, add-on ACE-I, HCTZ allowed; J-curve DBP nadir similar in all age groups, while SBP nadir increasing with age
2010 Eur Heart J (TNT)	Exponential increase in primary outcome for SBP < 110-120 or DBP < 60-70 except CVA which was further reduced with lower SBP
2010 Circulation (PROVE IT- TIMI)	All ACS patients; DBP categories of < 60 through >100 with 10 increments exponential increase in outcomes for SBP < 110 or DBP < 70
2011 Circulation (ONTARGET)	High risk patients with known CAD or DM with target organ damage, stratified by % of on-treatment visits in which BP was < 140/90 or < 130/80; no MI benefit for lowering < 130/80; but better CVA outcome with lower BP
2012 Hypertension (SMART)	DBP nadir 82 for all CV events, including CVA; DBP nadir 84 for mortality
2016 Eur Rev Med Pharmacol Sci	Small sample size when randomized to 5 groups; J-Curve for all outcomes except CVA
2016 Eur Heart J (VALUE)	High CV risk patients stratified by % of on-treatment visits in which BP was < 140/90 or < 130/80; data adjusted for baseline covariates by propensity score; worse outcomes with BP lowering < 130/80 except CVA
Studies in DM
1998 BMJ (UKPDS)	All newly diagnosed DM patients; tight vs less tight BP control (target < 150/85 vs 180/105) with Captopril or Atenolol as main agent and follow-up > 8 yr; tight BP control improved mortality and DM complications.
2002 Kidney Int (ABCD)	All diabetic normotensive patients; Rx with ACE-I or CCB vs placebo; achieved DBP of 75 vs 81 after 5 yr
2005 J Am Soc Nephrol (IDNT)	Achieving DBP < 85 associated with a trend towards increased all-cause mortality, a significant increase in risk of MI, but a decrease in risk of CVA
2010 JAMA (INVEST)	J Curve nadir eat SBP < 115 for all cause mortality
2010 N Engl J Med (ACCORD)	SBP < 120 vs < 140 did not further reduce the rate of composite CV outcomes, except CVA
2012 BMJ	All newly diagnosed DM; DBP < 75 and SBP < 110 in CAD patients associated with worse outcome
Epidemiology studies
1991 BMJ (Framingham)	J curve between DBP and CV death only in those with MI, independent of age, sex, BP Rx; J curve not significant for SBP after adjusting for confounders
2003 Ann Intern Med (NHANES II)	J curve between DBP and all mortality in age ≥ 65
2011 J Gen Intern Med (NHANES I)	J-curve for DBP even after adjusting for SBP
2014 J Am Coll Cardiol	DBP categories of < 50 through > 100 with 10 increments; data adjusted for confounders by CCI; DBP nadir lower for DM and age > 70 yr

ABCD: Appropriate Blood Pressure Control in Diabetes; ACCORD: Action to Control Cardiovascular Risk in Diabetes; CV: Cardiovascular; HOT: Hypertension Optimal Treatment; HYVET: Hypertension in the Very Elderly Trial; IDNT: Irbesartan Diabetic Nephropathy Trial; INVEST: International Verapamil SR Trandolapril Study; MI: Myocardial Infarction; NHANES: National Health and Nutrition Examination Survey; ONTARGET: Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial; PROVE IT-TIMI: Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction; RCT: Randomized Controlled Trial; SHEP: Systolic Hypertension in the Elderly Program; SMART: Secondary Manifestations of Arterial Disease; SPRINT: Systolic Blood Pressure Intervention Trial; Syst-Eur: Systolic Hypertension in Europe; TNT: Treating to New Targets; UKPDS: United Kingdom Prospective Diabetes Study; VALUE: Valsartan Antihypertensive Long-term use Evaluation.

Table 3 Meta-analyses and systematic reviews of blood pressure lowering trials

Study	No.	Trials	DBP J-curve Nadir1	Findings	Limitations
2009 Cochrane Database Syst Rev	22089	7	Not observed at 85	In hypertensive patients, lower vs standard BP targets (DBP 85 vs < 90) did not improve mortality or CV events	Difference in mean DBP was 3.4 mmHg between groups. In 2 trials, most did not achieve lower DBP targets. Failure to demonstrate harms with “lower targets” may be due to reporting bias
2011 Ann Intern Med	2272	3	Not observed at 75-80	In patient with CKD, lower BP targets (DBP < 75-80) did not improve renal outcomes	Data on deaths and CV disease outcomes were not informative given the lack of ascertainment or low event rate. Included very few patients with CKD; trial duration may have been too short to detect events
2013 Cochrane Database Syst Rev	2580	4	Not observed at 76	In diabetics, comparing lower vs standard DBP targets, no difference observed in CV mortality or CV events. Lower groups showed trend towards reduced non-cardiac mortality	High risk of selection bias for every outcome analyzed in favor of the “lower” DBP target
2013 CMAJ	9287	11	Not observed at 75-92	In patients with CKD, intensive BP lowering, compared to standard therapy, reduced risk of kidney failure, but not the risk of CV events (CV outcome data available only in 5 of 11 trials)	Did not include patient with diabetes. Heterogeneity of individual study limits the strength of conclusions
2015 Lancet	44989	19	Not observed at 76	In high risk patients, intensive vs standard BP therapy reduced major CV events, including CVA; but more intensive BP lowering no further benefits on mortality	Many trials did not achieve target BP levels in most patients. Mean BP in intensive groups was 133/76
2015 JAMA	100354	40	Not observed at 64-83	In diabetics, BP lowering improved mortality and CV events if baseline SBP > 140, but no outcome benefit if baseline SBP < 140 except CVA and albuminuria	Scarcity of large trials with achieved BP levels of < 70-80 (baseline DBP 70-106)
2016 BMJ	73738	49	78	In diabetics, if SBP < 140, risk of CV mortality increased by 28 percentage points for each 10 mmHg decrease in baseline DBP (P = 0.013)	Most included trials were not designed to evaluate different BP targets, but randomized patients to drugs or placebo

¹mmHg. BP: Blood pressure; CKD: Chronic kidney disease; CV: Cardiovascular; DBP: Diastolic blood pressure.

Table 4 Hypertension guidelines

Society	Year updated	DBP upper threshold1	DBP lower threshold1	Individualized to comorbidities				Discuss
				Age	CAD	DM	CKD	J-curve
ACCF/AHA (elderly)	2011	< 90	-	Yes	-	-	-	Yes
ADA	2016	< 90	-	Yes	-	-	-	-
CHEP	2016	< 90 (< 80 in diabetes)	60 in CAD	Yes	Yes	Yes	Yes	Yes
ESH/ESC	2013	< 90 (< 85 in diabetes)	-	Yes	Yes	Yes	Yes	Yes
ESC	2016	< 85	80	Yes	-	Yes	-	Yes
French	2013	< 90	-	Yes	-	-	-	-
JNC8	2014	< 90 (including DM and CKD)	-	-	-	-	-	Yes
KDIGO	2012	≤ 90 ( ≤ 80 if microalbuminuria)	-	Yes	-	Yes	Yes	Yes
NICE	2011	< 85	-	-	-	-	-	-
Renal Association (United Kingdom)	2011	< 90 (< 80 if proteinuria)	-	-	-	-	Yes	-

¹mmHg. ACCF/AHA: American College of Cardiology Foundation and the American Heart Association; ADA: American Diabetes Association; ASH: American Society of Hypertension; CAD: Coronary artery disease; CHEP: Canadian Hypertension Education Program; CKD: Chronic kidney disease; DM: Diabetes mellitus; ESC: European Society of Cardiology; ESH: European Society of Hypertension; JNC8: Eighth Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; KDIGO: Kidney Disease: Improving Global; NICE: National Institute for Health and Clinical Excellence.