Clinical review: Impact of statin substitution policies on patient outcomes

Figures & data

Figure 1.  Cardiovascular mortality in men across European regions. Age-standardized mortality from cardiovascular disease (ischaemic heart disease and cerebrovascular disease combined), in European regions (men; age group 45–74 years), based on data from Eurostat and the National Statistical Offices of the respective countries (2000). Reprinted with permission from [6].

Table

ACS	acute coronary syndrome
ALLIANCE	Aggressive Lipid Lowering Abates New Cardiac Events
ALT	alanine aminotransferase
AST	aspartate aminotransferase
A to Z	Aggrastat to Zocor
BP	blood pressure
CHD	coronary heart disease
CK	creatine kinase
CTT	Cholesterol Treatment Trialists
CVD	cardiovascular disease
ESC	European Societies of Cardiology
GRACE	Global Registry of Acute Coronary Events
GUSTO IIB	Global Use of Strategies to Open Occluded Coronary Arteries IIB
HbA1c	haemoglobin A1c
HPS	Heart Protection Study
ICER	incremental cost-effective ratios
IDEAL	Incremental Decrease in End Points Through Aggressive Lipid-Lowering
IPCI	Integrated Primary Care Information
LDL	low-density lipoprotein
MI	myocardial infarction
MIRACL	Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering
NHANES	National Health and Nutrition Examination Survey
NSTEMI	non-ST-segment elevation
OPUS-TIMI 16	Orbofiban in Patients with Unstable coronary Syndromes
OR	odds ratio
PACT	Pravastatin in Acute Coronary Treatment
PCT	primary care trust
PROVE-IT-TIMI-22	Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction-22
PURSUIT	Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy
QALY	quality adjusted life-years
RCT	randomized controlled trial
STEMI	ST-segment elevation acute MI
THIN	The Health Improvement Network
TNT	Treating to New Targets
ULN	upper limit of normal

Figure 2.  Lipid-lowering was the most important contributor to reduction in cardiovascular risk in the STENO-2 study. CV risk was estimated using the UKPDS risk engine. (BP = blood pressure; CVD = cardiovascular disease; HbA_1c=haemoglobin A_1c.) Reprinted with permission from [10].

Table I.  Examples of range of statin reimbursement policies in countries across Europe.

Country	Policy
Denmark	• Generic simvastatin, lovastatin, and pravastatin are reimbursed without restrictions
	• Branded statins can be prescribed if treatment goals are not achieved or generic statins not tolerated (‘reimbursement’ has to be if specifically stated on the prescription)
	• General Practitioner (GP) prescribing habits monitored electronically
United Kingdom	• National Health Service distributes funds to primary care trusts (PCT)
	• Generic simvastatin reimbursed
	• Prescribing target of 69%–75% set by Department of Health for GPs
	• Restricted use of high-dose statins for patients with acute coronary syndrome (ACS)
	• GPs reimbursed to achieve targets of: total cholesterol (TC) < 5, and low-density lipoprotein (LDL) <3
Germany	• Fixed maximum reimbursement amount for statins, obligatory for compulsory health insurance
	• All generic statins fully reimbursed
	• Branded statins reimbursed up to fixed maximum amount; patient co-payment required
	• Ezetimibe fully reimbursed (different drug class, no fixed maximum reimbursement amount)
	• Pressure to prescribe inexpensive medication through definition of ‘budgets’/patient/drug class/3 months
	• Branded statins more frequently prescribed for patients with private health insurance
Norway	• National reimbursement policy
	• Generic simvastatin reimbursed as ‘preferred drug’
	• Branded statin reimbursed, but clinical justification required in patient chart, i.e. very high risk/secondary prevention/not reaching goal, etc.
	• Authorities monitor prescribing patterns: occasional external review of issued prescriptions/patients’ records to ensure physician compliance with rules
Netherlands	• Generic statins are reimbursed without restrictions for high-risk patients
	• National guidelines advise to achieve an LDL target <2.5 mmol/L for patients with coronary heart disease (CHD) or type 2 diabetes mellitus. If goals cannot be achieved using generic statins other treatment strategies are allowed
	• Patients at risk (10-year > 5%) but no CHD or diabetes: the LDL goal is <2.5 mmol/L or a 1 mmol/L LDL reduction. Branded statins are restricted
	• Compulsory health insurance (5–6 large companies)
	• Generally reimburse generic statin. Branded statins are reimbursed if doctors specify ‘medical indication’
	• Pressure to prescribe generic statins: financial incentive for GPs if 80% of patients are prescribed simvastatin
Spain	• Pressure increasing to prescribe generic over branded statins
	• All statins reimbursed; patient pays 40%
	• Statins fully reimbursed in patients >65 years and patients with familial hypercholesterolaemia

Source: From individual authors and physicians’ survey, February 2008.

Figure 3.  Linear relationship between low-density lipoprotein (LDL)-lowering and reduction in major coronary events in the Cholesterol Treatment Trialists’ (CTT) Collaborators meta-analysis of data from 90,056 participants in 14 randomized trials of statins. Relation between proportional reduction in incidence of major coronary events and mean absolute low-density lipoprotein (LDL) reduction at 1 year. Reprinted with permission from [5].

Figure 4.  Rate of major cardiovascular events across quintiles in the Treating to New Targets (TNT) study. Patients with coronary heart disease and LDL <130 mg/dL (3.4 mmol/L) were randomized to therapy with atorvastatin 10 mg/day (n=5,006) or 80 mg/day (n=4,995). P<0.0001 for trend across LDL. Reprinted with permission from [24].

Figure 5.  Intensive statin therapy was more effective than moderate statin therapy in reducing coronary death or any CV event in a meta-analysis of four trials including 27,548 patients with either stable coronary heart disease or acute coronary syndromes. Individual trials and pooled analysis showing reduction in the risk of coronary death or any CV event (myocardial infarction, stroke, hospitalization for unstable angina, or revascularization) (P<0.0001). (CV = cardiovascular; CI = confidence interval; OR = odds ratio.) Reprinted with permission from [28].

Table II.  Low rates of laboratory abnormalities and rhabdomyolysis in trials comparing intensive versus moderate statin therapy in patients at high cardiovascular risk.

	AST and/or ALT >3×ULN^a		CK >10×ULN^b		Rhabdomyolysis^c
Trial (ref)/patient population: n – follow-up	Moderate	Intensive	Moderate	Intensive	Moderate	Intensive
PROVE-IT [26]/ACS: 4162 – 2 years	1.1%	3.3%	0.10%	0.15%	0%	0%
A to Z [27]/ACS: 4497 – 2 years	0.36%	0.84%	0.04%	0.4%	0%	0.13%
TNT [23]/CHD: 10001 – 4.9 years	0.18%	1.2%	0%	0%	0.06%	0.04%
IDEAL [25]/CHD: 8888 – 4.8 years	0.16%	1.37%	0%	0%	0.07%	0.05%

^aPROVE-IT reported elevations in ALT; IDEAL reported number of abnormalities.

^bA to Z reported 1 additional patient with an alcohol-related rise in CK without muscle symptoms.

^cCase definition: TNT and IDEAL were based on the treating physician's diagnosis; A to Z defined as CK levels >10,000 U/L.

ACS = acute coronary syndromes; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CHD = coronary heart disease; CK = creatine kinase; ULN = upper limit of normal.

Table III.  Observational studies on the consequences of policy-driven statin substitution.

Data sources (n-value)	Outcomes
US pharmacy claims database (n=38,866) [62]	Patients who switched statins for any reasons were: –19% less compliant –21%–48% less persistent over the long term
National US database (n=453,409) [63]	Switching from atorvastatin to simvastatin was associated with lower therapeutic doses in: –38% of patients overall –73%–100% of patients previously on atorvastatin 40 or 80 mg
US medical records database (n=277) [64]	Switching to simvastatin from other statins: –38% of patients experienced an increase in LDL levels
UK PCTs (n=303) [70]	PCTs with high versus lower proportions of generic statin use: –No difference in rate of successfully achieving total cholesterol targets for high-risk patients (<5 mmol/L)
UK PCT (n=70) [71], [72]	Switch from atorvastatin to an equipotent dose of simvastatin: –No change in serum cholesterol levels, short or long term –Substantial cost savings –Switching not appropriate for 35% of patients on atorvastatin 10 or 20 mg
Colorado Indigent Care Program (n = 117) [73]	Switch from atorvastatin to other statins using a LDL target-driven algorithm versus usual care switching associated with more patients achieving LDL goals: –Target-driven algorithm (80% before and 97% after) –Usual care group (90% before and 75% after)
The Health Improvement Network (THIN)
(n=2,511 switch patients versus n=9,009 controls) [65]	Switch from atorvastatin to simvastatin: –Significant 30% increase in risk of death or major CV events –Double rate of discontinuation
New Zealand Hospital records database (n=127) [66]	Switch from simvastatin to fluvastatin: –34% increase in LDL over 6 months –More CV events with fluvastatin (n=27) versus simvastatin (n=9)
UK ACS treatment policy change audit, hospital records database (n=221 patients with ACS) [67]	Hospital switch from atorvastatin 80 mg to simvastatin 20–40 mg: –Higher mortality rates: simvastatin (17%) versus atorvastatin (5%) –More cardiac and non-cardiac readmissions with simvastatin

ACS = acute coronary syndrome; CV = cardiovascular; LDL = low-density lipoprotein; PCT = primary care trust.

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